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1
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Kassab AE, Gedawy EM. Repurposing of Indomethacin and Naproxen as anticancer agents: progress from 2017 to present. RSC Adv 2024; 14:40031-40057. [PMID: 39717807 PMCID: PMC11664213 DOI: 10.1039/d4ra07581a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 12/12/2024] [Indexed: 12/25/2024] Open
Abstract
Inflammation is strongly linked to cancer and is essential for the growth and development of tumors. Targeting inflammation and the mediators involved in the inflammatory process could therefore provide a suitable method for cancer prevention and therapy. Numerous studies have shown that inflammation can predispose tumors. Non-steroidal anti-inflammatory drugs (NSAIDs) can affect the tumor microenvironment through increasing apoptosis and chemo-sensitivity while decreasing cell migration. Since the development of novel drugs requires a significant amount of money and time and poses a significant challenge for drug discovery, there has been a recent increase in interest in drug repositioning or repurposing. The growing body of research suggests that drug repurposing is essential for the quicker and less expensive development of anticancer therapies. In order to set the course for potential future repositioning of NSAIDs for clinical deployment in the treatment of cancer, the antiproliferative activity of derivatives of Indomethacin and Naproxen as well as their mechanism of action and structural activity relationships (SARs) published in the time frame from 2017 to 2024 are summarized in this review.
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Affiliation(s)
- Asmaa E Kassab
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University Kasr El-Aini Street, P. O. Box 11562 Cairo Egypt +2023635140 +2023639307
| | - Ehab M Gedawy
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University Kasr El-Aini Street, P. O. Box 11562 Cairo Egypt +2023635140 +2023639307
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Badr University in Cairo (BUC) Badr City, P. O. Box 11829 Cairo Egypt
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2
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Tchaparian E, Lin HY, Chen Y, Hunter JN, Yin S, Ng H, Wu A. Mass balance, metabolic disposition, and pharmacokinetics of a single IV dose of [14C]CA102N in HT-29 xenograft athymic nude mice. Front Pharmacol 2024; 15:1440679. [PMID: 39703390 PMCID: PMC11655901 DOI: 10.3389/fphar.2024.1440679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 11/05/2024] [Indexed: 12/21/2024] Open
Abstract
Introduction CA102N is a novel anticancer drug developed by covalently linking H-Nim (N-(4-Amino-2-phenoxyphenyl methanesulfonamide) to Hyaluronic Acid to target CD44 receptor-rich tumors. The proposed approach seeks to enhance the efficacy and overcome limitations associated with H-Nim, including poor solubility and short half-life. Methods The study aimed to evaluate the pharmacokinetics, biodistribution, metabolism, and tumor permeability of [14C] CA102N in xenograft mice following a single intravenous dose of 200 mg/kg. Liquid scintillation counting analysis was used for the pharmacokinetics and mass balance analysis. Metabolite profiling was assessed by HPLC-MS coupled with a radio flow-through detector. Quantitative Whole-Body Autoradiography was used to determine tissue distribution. Concentrations of CA102N and its metabolites were measured using total radioactivity data from urine, feces, and tissue samples. Results About 94.9% of the administered dose was recovered at 240 h post-dose. The primary route of radioactivity elimination was through urine, accounting for an average of 77% of the dose with around 13.2% excreted in the feces. Tissue distribution showed rapid accumulation within 0.5 h post-administration, followed by a fast decline in most tissues except for the tumor, where slow elimination was observed. CA102N/metabolites exhibited a two-phase pharmacokinetic profile, characterized by an initial rapid distribution phase and a slower terminal elimination, with a half-life (t1/2) of 22 h. The mean maximum concentration (Cmax) of 1798.586 µg equivalents per ml was reached at 0.5 h (Tmax). Most of the radioactivity in plasma was attributed to CA102N, while small-molecule hydrolysis products dominated the excreta and tissue samples. Metabolite profiling revealed two major hydrolysis products: H-Nim-disaccharide and H-Nim-tetrasaccharide. No unchanged [14C] CA102N was detected in urine or feces, suggesting that CA102N undergoes extensive metabolism before excretion. Conclusion The current data provided valuable insights into the pharmacokinetics, metabolism, and tissue/tumor distribution of CA102N in mice. These findings demonstrated that metabolic clearance is the primary elimination pathway for CA102N and that the drug exhibits tumor retention, supporting its development as an anticancer therapy. Our results provided a strong pharmacological basis for the advancement of CA102N into the clinic.
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Affiliation(s)
- Eskouhie Tchaparian
- Holy Stone Healthcare, Preclinical and Development Div Hsinchu, Taipei, Taiwan
| | - Hua-Yang Lin
- Holy Stone Healthcare, Preclinical and Development Div Hsinchu, Taipei, Taiwan
| | - Yuchih Chen
- Holy Stone Healthcare, Preclinical and Development Div Hsinchu, Taipei, Taiwan
| | - J. Neil Hunter
- Holy Stone Healthcare, Preclinical and Development Div Hsinchu, Taipei, Taiwan
| | - Sindy Yin
- Holy Stone Healthcare, Preclinical and Development Div Hsinchu, Taipei, Taiwan
| | - Huey Ng
- MDT Int’l SA, Geneva, Switzerland
| | - Albert Wu
- Holy Stone Healthcare, Preclinical and Development Div Hsinchu, Taipei, Taiwan
- MDT Int’l SA, Geneva, Switzerland
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3
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Zuo WF, Pang Q, Zhu X, Yang QQ, Zhao Q, He G, Han B, Huang W. Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies. J Hematol Oncol 2024; 17:81. [PMID: 39232809 PMCID: PMC11375894 DOI: 10.1186/s13045-024-01601-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024] Open
Abstract
Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.
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Affiliation(s)
- Wei-Fang Zuo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qiwen Pang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xinyu Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qian-Qian Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qian Zhao
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Gu He
- Department of Dermatology and Venereology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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4
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Kassab AE, Gedawy EM. Recent Advancements in Refashioning of NSAIDs and their Derivatives as Anticancer Candidates. Curr Pharm Des 2024; 30:1217-1239. [PMID: 38584541 DOI: 10.2174/0113816128304230240327044201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 03/02/2024] [Accepted: 03/09/2024] [Indexed: 04/09/2024]
Abstract
Inflammation is critical to the formation and development of tumors and is closely associated with cancer. Therefore, addressing inflammation and the mediators that contribute to the inflammatory process may be a useful strategy for both cancer prevention and treatment. Tumor predisposition can be attributed to inflammation. It has been demonstrated that NSAIDs can modify the tumor microenvironment by enhancing apoptosis and chemosensitivity and reducing cell migration. There has been a recent rise in interest in drug repositioning or repurposing because the development of innovative medications is expensive, timeconsuming, and presents a considerable obstacle to drug discovery. Repurposing drugs is crucial for the quicker and less expensive development of anticancer medicines, according to an increasing amount of research. This review summarizes the antiproliferative activity of derivatives of NSAIDs such as Diclofenac, Etodolac, Celecoxib, Ibuprofen, Tolmetin, and Sulindac, published between 2017 and 2023. Their mechanism of action and structural activity relationships (SARs) were also discussed to set the path for potential future repositioning of NSAIDs for clinical deployment in the treatment of cancer.
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Affiliation(s)
- Asmaa E Kassab
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt
| | - Ehab M Gedawy
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Badr University in Cairo (BUC), Badr City, Cairo, P.O. Box 11829, Egypt
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5
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Modh DH, Kulkarni VM. Anticancer Drug Discovery By Structure-Based Repositioning Approach. Mini Rev Med Chem 2024; 24:60-91. [PMID: 37165589 DOI: 10.2174/1389557523666230509123036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/07/2023] [Accepted: 03/28/2023] [Indexed: 05/12/2023]
Abstract
Despite the tremendous progress that has occurred in recent years in cell biology and oncology, in chemical, physical and computer sciences, the disease cancer has continued as the major cause of death globally. Research organizations, academic institutions and pharmaceutical companies invest huge amounts of money in the discovery and development of new anticancer drugs. Though much effort is continuing and whatever available approaches are being attempted, the success of bringing one effective drug into the market has been uncertain. To overcome problems associated with drug discovery, several approaches are being attempted. One such approach has been the use of known, approved and marketed drugs to screen these for new indications, which have gained considerable interest. This approach is known in different terms as "drug repositioning or drug repurposing." Drug repositioning refers to the structure modification of the active molecule by synthesis, in vitro/ in vivo screening and in silico computational applications where macromolecular structure-based drug design (SBDD) is employed. In this perspective, we aimed to focus on the application of repositioning or repurposing of essential drug moieties present in drugs that are already used for the treatment of some diseases such as diabetes, human immunodeficiency virus (HIV) infection and inflammation as anticancer agents. This review thus covers the available literature where molecular modeling of drugs/enzyme inhibitors through SBDD is reported for antidiabetics, anti-HIV and inflammatory diseases, which are structurally modified and screened for anticancer activity using respective cell lines.
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Affiliation(s)
- Dharti H Modh
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Erandwane, Pune, 411038, Maharashtra, India
| | - Vithal M Kulkarni
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Erandwane, Pune, 411038, Maharashtra, India
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6
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Vunnam N, Young MC, Liao EE, Lo CH, Huber E, Been M, Thomas DD, Sachs JN. Nimesulide, a COX-2 inhibitor, sensitizes pancreatic cancer cells to TRAIL-induced apoptosis by promoting DR5 clustering †. Cancer Biol Ther 2023; 24:2176692. [PMID: 36775838 PMCID: PMC9928464 DOI: 10.1080/15384047.2023.2176692] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2023] Open
Abstract
Nimesulide is a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor with antitumor and antiproliferative activities that induces apoptosis in oral, esophagus, breast, and pancreatic cancer cells. Despite being removed from the market due to hepatotoxicity, nimesulide is still an important research tool being used to develop new anticancer drugs. Multiple studies have been done to modify the nimesulide skeleton to develop more potent anticancer agents and related compounds are promising scaffolds for future development. As such, establishing a mechanism of action for nimesulide remains an important part of realizing its potential. Here, we show that nimesulide enhances TRAIL-induced apoptosis in resistant pancreatic cancer cells by promoting clustering of DR5 in the plasma membrane. In this way, nimesulide acts like a related compound, DuP-697, which sensitizes TRAIL-resistant colon cancer cells in a similar manner. Our approach applies a time-resolved FRET-based biosensor that monitors DR5 clustering and conformational states in the plasma membrane. We show that this tool can be used for future high-throughput screens to identify novel, nontoxic small molecule scaffolds to overcome TRAIL resistance in cancer cells.
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Affiliation(s)
- Nagamani Vunnam
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Malaney C Young
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Elly E Liao
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Chih Hung Lo
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Evan Huber
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - MaryJane Been
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - David D Thomas
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Jonathan N Sachs
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
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7
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Hassan AY, Abou-Amra ES, El-Sebaey SA. Design and Synthesis of New Series of Chiral Pyrimidine and Purine analogs as COX-2 Inhibitors: Anticancer Screening, Molecular Modelling, and In Silico Studies. J Mol Struct 2023. [DOI: 10.1016/j.molstruc.2023.134930] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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8
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Mohsin NUA, Aslam S, Ahmad M, Irfan M, Al-Hussain SA, Zaki MEA. Cyclooxygenase-2 (COX-2) as a Target of Anticancer Agents: A Review of Novel Synthesized Scaffolds Having Anticancer and COX-2 Inhibitory Potentialities. Pharmaceuticals (Basel) 2022; 15:ph15121471. [PMID: 36558921 PMCID: PMC9783503 DOI: 10.3390/ph15121471] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/19/2022] [Accepted: 11/21/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is a serious threat to human beings and is the second-largest cause of death all over the globe. Chemotherapy is one of the most common treatments for cancer; however, drug resistance and severe adverse effects are major problems associated with anticancer therapy. New compounds with multi-target inhibitory properties are targeted to surmount these challenges. Cyclooxygenase-2 (COX-2) is overexpressed in cancers of the pancreas, breast, colorectal, stomach, and lung carcinoma. Therefore, COX-2 is considered a significant target for the synthesis of new anticancer agents. This review discusses the biological activity of recently prepared dual anticancer and COX-2 inhibitory agents. The most important intermolecular interactions with the COX-2 enzyme have also been presented. Analysis of these agents in the active area of the COX-2 enzyme could guide the introduction of new lead compounds with extreme selectivity and minor side effects.
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Affiliation(s)
- Noor ul Amin Mohsin
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan
| | - Sana Aslam
- Department of Chemistry, Government College Women University, Faisalabad 38000, Pakistan
| | - Matloob Ahmad
- Department of Chemistry, Government College University, Faisalabad 38000, Pakistan
- Correspondence: (M.A.); (M.E.A.Z.)
| | - Muhammad Irfan
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan
| | - Sami A. Al-Hussain
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
| | - Magdi E. A. Zaki
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
- Correspondence: (M.A.); (M.E.A.Z.)
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9
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Lucia Ruiz Benitez M, Severo Sabedra Sousa F, Peter Furtado I, Carlos Rodrigues Junior J, Victoria Mascarenhas Borba M, Vieira Segatto N, Tabarelli G, Klein Couto G, Júlia Damé Fonseca Paschoal M, Silveira Pacheco B, E. D. Rodrigues O, Collares T, Kömmling Seixas F. Chiral β‐arylchalcogenium azide induce apoptosis and regulate Oxidative Damage on Human Bladder Cancer Cells. ChemistrySelect 2022. [DOI: 10.1002/slct.202203207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Martha Lucia Ruiz Benitez
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
- School of Basic and Biomedical Sciences Universidad Simón Bolívar Barranquilla Colombia
| | - Fernanda Severo Sabedra Sousa
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Izadora Peter Furtado
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - João Carlos Rodrigues Junior
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Msc. Victoria Mascarenhas Borba
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Natália Vieira Segatto
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Greice Tabarelli
- LabSelen-NanoBio - Chemistry Department Federal University of Santa Maria, Santa Maria Rio Grande do Sul Brazil
| | - Gabriela Klein Couto
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Msc. Júlia Damé Fonseca Paschoal
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Bruna Silveira Pacheco
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Oscar E. D. Rodrigues
- LabSelen-NanoBio - Chemistry Department Federal University of Santa Maria, Santa Maria Rio Grande do Sul Brazil
| | - Tiago Collares
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
| | - Fabiana Kömmling Seixas
- Laboratory of Cancer Biotechnology, Technology Development Center Federal University of Pelotas Pelotas Rio Grande do Sul Brazil
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10
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Pecyna P, Wargula J, Murias M, Kucinska M. More Than Resveratrol: New Insights into Stilbene-Based Compounds. Biomolecules 2020; 10:E1111. [PMID: 32726968 PMCID: PMC7465418 DOI: 10.3390/biom10081111] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023] Open
Abstract
The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant "drug-likeness" scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the "fresh outlook" about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.
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Affiliation(s)
- Paulina Pecyna
- Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, Swiecickiego 4 Street, 60-781 Poznan, Poland;
| | - Joanna Wargula
- Department of Organic Chemistry, University of Medical Sciences, Grunwaldzka 6 Street, 60-780 Poznan, Poland;
| | - Marek Murias
- Department of Toxicology, University of Medical Sciences, Dojazd 30 Street, 60-631 Poznan, Poland;
| | - Malgorzata Kucinska
- Department of Toxicology, University of Medical Sciences, Dojazd 30 Street, 60-631 Poznan, Poland;
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11
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Abstract
The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant "drug-likeness" scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the "fresh outlook" about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.
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12
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New pyrimidines and triazolopyrimidines as antiproliferative and antioxidants with cyclooxygenase-1/2 inhibitory potential. Future Med Chem 2020; 11:1583-1603. [PMID: 31469327 DOI: 10.4155/fmc-2018-0285] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aim: Cyclooxygenase-2 (COX-2) inhibition and scavenging-free radicals are important targets in cancer treatment. Materials & methods: Sulfanylpyrimidines and triazolopyrimidines were synthesized and evaluated as anticancer and antioxidant COX-1/2 inhibitors. Results: Compound 7 showed the same growth inhibitory activity as 5-fluorouracil against MCF-7. Compound 6f displayed broad-spectrum anticancer activity against the four tested cancer cell lines. Compounds 5b, 6a, 6c, 6d and 8 were found to be more active antioxidants than trolox. Compounds 6a, 6c, 6f and 8 revealed high COX-2 inhibitory activity and selectivity, which was confirmed by docking studies. Conclusion: Compound 6f could be considered as promising anticancer and antioxidant structural lead with COX-2 inhibition that deserve further derivatization and investigation.
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13
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Liu Y, Zhang T, Li G, Li S, Li J, Zhao Q, Wu Q, Xu D, Hu X, Zhang L, Li Q, Zhang H, Liu B. Radiosensitivity enhancement by Co-NMS-mediated mitochondrial impairment in glioblastoma. J Cell Physiol 2020; 235:9623-9634. [PMID: 32394470 DOI: 10.1002/jcp.29774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/27/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
Abstract
We investigated the radiosensitizing effects of Co-NMS, a derivative of nimesulide based on a cobalt carbonyl complex, on malignant glioma cells. In the zebrafish exposed to Co-NMS ranging from 5 to 20 μM, cell death and heat shock protein 70 expression in the brain and neurobehavioral performance were evaluated. Our data showed that Co-NMS at 5 μM did not cause the appreciable neurotoxicity, and thereby was given as a novel radiation sensitizer in further study. In the U251 cells, Co-NMS combined with irradiation treatment resulted in significant inhibition of cell growth and clonogenic capability as well as remarkable increases of G2/M arrest and apoptotic cell population compared to the irradiation alone treatment. This demonstrated that the Co-NMS administration exerted a strong potential of sensitizing effect on the irradiated cells. With regard to the tumor radiosensitization of Co-NMS, it could be primarily attributed to the Co-NMS-derived mitochondrial impairment, reflected by the loss of mitochondrial membrane potential, the disruption of mitochondrial fusion and fission balance as well as redox homeostasis. Furthermore, the energy metabolism of the U251 cells was obviously suppressed by cotreatment with Co-NMS and irradiation through repressing mitochondrial function. Taken together, our findings suggested that Co-NMS could be a desirable drug to enhance the radiotherapeutic effects in glioblastoma patients.
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Affiliation(s)
- Yang Liu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Taofeng Zhang
- Institute of Radiochemistry, School of Nuclear Science and Technology, Lanzhou University, Lanzhou, China
| | - Guo Li
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Sirui Li
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
| | - Jili Li
- Institute of Medicinal Chemistry, School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Quanyi Zhao
- Institute of Medicinal Chemistry, School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Qingfen Wu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Dan Xu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoli Hu
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Luwei Zhang
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Qiang Li
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Hong Zhang
- Medical Physics Division, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.,Key Laboratory of Heavy Ion Radiation Medicine, Chinese Academy of Sciences, Lanzhou, China.,School of Life Science, University of Chinese Academy of Sciences, Beijing, China
| | - Bin Liu
- School/Hospital of Stomatology, Lanzhou University, Lanzhou, China
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14
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Singh H, Kinarivala N, Sharma S. Multi-Targeting Anticancer Agents: Rational Approaches, Synthetic Routes and Structure Activity Relationship. Anticancer Agents Med Chem 2020; 19:842-874. [PMID: 30657048 DOI: 10.2174/1871520619666190118120708] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 01/04/2019] [Accepted: 01/04/2019] [Indexed: 12/21/2022]
Abstract
We live in a world with complex diseases such as cancer which cannot be cured with one-compound one-target based therapeutic paradigm. This could be due to the involvement of multiple pathogenic mechanisms. One-compound-various-targets stratagem has become a prevailing research topic in anti-cancer drug discovery. The simultaneous interruption of two or more targets has improved the therapeutic efficacy as compared to the specific targeted based therapy. In this review, six types of dual targeting agents along with some interesting strategies used for their design and synthesis are discussed. Their pharmacology with various types of the molecular interactions within their specific targets has also been described. This assemblage will reveal the recent trends and insights in front of the scientific community working in dual inhibitors and help them in designing the next generation of multi-targeted anti-cancer agents.
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Affiliation(s)
- Harbinder Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, India
| | - Nihar Kinarivala
- Program in Chemical Biology, Sloan Kettering Institute, New York, NY 10065, United States
| | - Sahil Sharma
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, India.,Program in Chemical Biology, Sloan Kettering Institute, New York, NY 10065, United States
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15
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Zaręba M, Sareło P, Kopaczyńska M, Białońska A, Uram Ł, Walczak M, Aebisher D, Wołowiec S. Mixed-Generation PAMAM G3-G0 Megamer as a Drug Delivery System for Nimesulide: Antitumor Activity of the Conjugate Against Human Squamous Carcinoma and Glioblastoma Cells. Int J Mol Sci 2019; 20:ijms20204998. [PMID: 31601050 PMCID: PMC6834146 DOI: 10.3390/ijms20204998] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 09/30/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022] Open
Abstract
Polyhydroxylated dendrimer was synthesized from poly(amidoamine) (PAMAM) dendrimer generation 3 by addition of glycidol (G3gl). G3gl megamer was further modified by binding PAMAM G0 dendrimers by activation of G3gl with p-nitrophenylchloroformate, followed by the addition of excess PAMAM G0 and purification using dialysis. The maximum G0 binding capacity of G3gl was 12 in the case when G0 was equipped with two covalently attached nimesulide equivalents. Nimesulide (N) was converted into N-(p-nitrophenyl) carbonate derivative and fully characterized using X-ray crystallography and spectral methods. Nimesulide was then attached to G0 via a urea bond to yield G02N. The mixed generation G3gl–G02N megamer was characterized using 1H NMR spectroscopy, and its molecular weight was estimated to be 22.4 kDa. The AFM image of G3gl–G02N deposited on mica demonstrated aggregation of nimesulide-covered megamer. The height of the deposited megamer was 8.5 nm. The megameric conjugate with nimesulide was tested in vitro on three human cell lines: squamous cell carcinoma (SCC-15) and glioblastoma (U-118 MG) overexpressing cyclooxygenase-2 (COX-2), and normal skin fibroblasts (BJ). The conjugate efficiently penetrated into all cells and was more cytotoxic against SCC-15 than against BJ. Moreover, the conjugate produced a strong and selective antiproliferative effect on both cancer cell lines (IC50 < 7.5 µM).
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Affiliation(s)
- Magdalena Zaręba
- Faculty of Chemistry, Rzeszów University of Technology, 35-939 Rzeszów, Poland.
| | - Przemysław Sareło
- Department of Biomedical Engineering, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
| | - Marta Kopaczyńska
- Department of Biomedical Engineering, Wrocław University of Science and Technology, 50-370 Wrocław, Poland.
| | - Agata Białońska
- Faculty of Chemistry, University of Wrocław, 50-383 Wrocław, Poland.
| | - Łukasz Uram
- Faculty of Chemistry, Rzeszów University of Technology, 35-939 Rzeszów, Poland.
| | - Małgorzata Walczak
- Faculty of Chemistry, Rzeszów University of Technology, 35-939 Rzeszów, Poland.
| | - David Aebisher
- Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszów, 35-310 Rzeszów, Poland.
| | - Stanisław Wołowiec
- Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszów, 35-310 Rzeszów, Poland.
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16
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Uram Ł, Filipowicz-Rachwał A, Misiorek M, Winiarz A, Wałajtys-Rode E, Wołowiec S. Synthesis and Different Effects of Biotinylated PAMAM G3 Dendrimer Substituted with Nimesulide in Human Normal Fibroblasts and Squamous Carcinoma Cells. Biomolecules 2019; 9:biom9090437. [PMID: 31480608 PMCID: PMC6770390 DOI: 10.3390/biom9090437] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/26/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022] Open
Abstract
Squamous cell carcinoma (SCC) remains a main cause of mortality in patients with neck and head cancers, with poor prognosis and increased prevalence despite of available therapies. Recent studies have identified a role of cyclooxygenases, particularly inducible isoform cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in cancer cell proliferation, and its inhibition become a target for control of cancer development, particularly in the view of recognized additive or synergic action of COX-2 inhibitors with other forms of therapy. Nimesulide (N), the selective COX-2 inhibitor, inhibits growth and proliferation of various types of cancer cells by COX-2 dependent and independent mechanisms. In the presented study, the conjugates of biotinylated third generation poly(amidoamine) dendrimer (PAMAM) with covalently linked 18 (G3B18N) and 31 (G3B31N) nimesulide residues were synthesized and characterized by NMR spectroscopy. Biological properties of conjugates were evaluated, including cytotoxicity, proliferation, and caspase 3/7 activities in relation to COX-2/PGE2 axis signaling in human normal fibroblast (BJ) and squamous cell carcinoma (SCC-15). Both conjugates exerted a selective cytotoxicity against SCC-15 as compared with BJ cells at low 1.25-10 µM concentration range and their action in cancer cells was over 250-fold stronger than nimesulide alone. Conjugates overcome apoptosis resistance and sensitized SCC-15 cells to the apoptotic death independently of COX-2/PGE2 axis. In normal human fibroblasts the same concentrations of G3B31N conjugate were less effective in inhibition of proliferation and induction of apoptosis, as measured by caspase 3/7 activity in a manner depending on increase of PGE2 production by either COX-1/COX-2.
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Affiliation(s)
- Łukasz Uram
- Faculty of Chemistry, Rzeszow University of Technology, 6 Powstancow Warszawy, 35-959 Rzeszow, Poland.
| | | | - Maria Misiorek
- Faculty of Chemistry, Rzeszow University of Technology, 6 Powstancow Warszawy, 35-959 Rzeszow, Poland
| | - Aleksandra Winiarz
- Faculty of Chemistry, Rzeszow University of Technology, 6 Powstancow Warszawy, 35-959 Rzeszow, Poland
| | - Elżbieta Wałajtys-Rode
- Department of Drug Technology and Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, Poland
| | - Stanisław Wołowiec
- Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszow, 35-310 Rzeszow, Poland
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17
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Catarro M, Serrano JL, Ramos SS, Silvestre S, Almeida P. Nimesulide analogues: From anti-inflammatory to antitumor agents. Bioorg Chem 2019; 88:102966. [PMID: 31075744 DOI: 10.1016/j.bioorg.2019.102966] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/26/2019] [Accepted: 04/29/2019] [Indexed: 12/12/2022]
Abstract
Nimesulide is a nonsteroidal anti-inflammatory drug possessing analgesic and antipyretic properties. This drug is considered a selective cyclooxygenase-2 (COX-2) inhibitor and, more recently, has been associated to antitumor activity. Thus, numerous works have been developed to modify the nimesulide skeleton aiming to develop new and more potent and selective COX-2 inhibitors as well as potential anticancer agents. This review intends to provide an overview on analogues of nimesulide, including the general synthetic approaches used for their preparation and structural diversification and their main anti-inflammatory and/or antitumor properties.
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Affiliation(s)
- Mafalda Catarro
- CICS-UBI - Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - João L Serrano
- CICS-UBI - Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Susana S Ramos
- FibEnTech - UBI, Materiais Fibrosos e Tecnologias Ambientais, University of Beira Interior, Rua Marquês d'Ávila e Bolama, 6200-001 Covilhã, Portugal
| | - Samuel Silvestre
- CICS-UBI - Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-517 Coimbra, Portugal
| | - Paulo Almeida
- CICS-UBI - Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
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18
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Elmi-Mehr M, Davoodnia A, Pordel M. Facile Catalyst-Free Synthesis of New Functionalized 1H-Pyrazolo[1,2-b]phthalazines. RUSS J GEN CHEM+ 2019. [DOI: 10.1134/s1070363218120216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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19
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Dorostkar-Ahmadi N, Davoodnia A, Tavakoli-Hoseini N, Behmadi H, Nakhaei-Moghaddam M. Facile synthesis of new pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-ones via the tandem intramolecular Pinner–Dimroth rearrangement and their antibacterial evaluation. ZEITSCHRIFT FUR NATURFORSCHUNG SECTION B-A JOURNAL OF CHEMICAL SCIENCES 2018. [DOI: 10.1515/znb-2018-0166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Abstract
Some new 7-alkyl-4,6-dihydropyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-ones were prepared through heterocyclization of 6-amino-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles with aliphatic carboxylic acids in the presence of phosphoryl chloride under reflux in high yields. The suggested mechanism involves a tandem intramolecular Pinner–Dimroth rearrangement. The products were characterized on the basis of FT-IR, 1H NMR, and 13C NMR spectral and microanalytical data and evaluated for their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) using the disk diffusion method.
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Affiliation(s)
- Nadieh Dorostkar-Ahmadi
- Department of Chemistry , Mashhad Branch, Islamic Azad University , 9175687119 Mashhad , I.R. Iran
| | - Abolghasem Davoodnia
- Department of Chemistry , Mashhad Branch, Islamic Azad University , 9175687119 Mashhad , I.R. Iran
| | - Niloofar Tavakoli-Hoseini
- Young Researchers and Elite Club, Mashhad Branch, Islamic Azad University , 9175687119 Mashhad , I.R. Iran
| | - Hossein Behmadi
- Department of Chemistry , Mashhad Branch, Islamic Azad University , 9175687119 Mashhad , I.R. Iran
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20
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Design, Synthesis and Biological Evaluation of Novel 4-Substituted Coumarin Derivatives as Antitumor Agents. Molecules 2018; 23:molecules23092281. [PMID: 30200625 PMCID: PMC6225359 DOI: 10.3390/molecules23092281] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 09/01/2018] [Accepted: 09/04/2018] [Indexed: 11/17/2022] Open
Abstract
Herein, fifteen new compounds containing coumarin, 1,2,3-triazole and benzoyl- substituted arylamine moieties were designed, synthesized and tested in vitro for their anticancer activity. The results showed that all tested compounds had moderate antiproliferative activity against MDA-MB-231, a human breast cancer cell line, under both normoxic and hypoxic conditions. Furthermore, the 4-substituted coumarin linked with benzoyl 3,4-dimethoxyaniline through 1,2,3-triazole (compound 5e) displayed the most prominent antiproliferative activities with an IC50 value of 0.03 μM, about 5000 times stronger than 4-hydroxycoumarin (IC50 > 100 μM) and 20 times stronger than doxorubicin (IC50 = 0.60 μM). Meanwhile, almost all compounds revealed general enhancement of proliferation-inhibiting activity under hypoxia, contrasted with normoxia. A docking analysis showed that compound 5e had potential to inhibit carbonic anhydrase IX (CA IX).
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21
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Vafaee A, Davoodnia A, Bozorgmehr MR, Pordel M. Characterization and Molecular Docking Study of New 4-Acetamidoalkyl Pyrazoles As B-Raf /Cox-2 Inhibitors. J STRUCT CHEM+ 2018. [DOI: 10.1134/s0022476618020117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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22
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Zhao A, Zheng Q, Orahoske CM, Idippily ND, Ashcraft MM, Quamine A, Su B. Synthesis and biological evaluation of anti-cancer agents that selectively inhibit Her2 over-expressed breast cancer cell growth via down-regulation of Her2 protein. Bioorg Med Chem Lett 2018; 28:727-731. [PMID: 29352646 DOI: 10.1016/j.bmcl.2018.01.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 01/08/2018] [Accepted: 01/11/2018] [Indexed: 11/17/2022]
Abstract
Compound JCC76 selectively inhibited the proliferation of human epidermal growth factor 2 (Her2) over-expressed breast cancer cells. In the current study, a ligand based structural optimization was performed to generate new analogs, and we identified derivatives 16 and 17 that showed improved activity and selectivity against Her2 positive breast cancer cells. A structure activity relationship (SAR) was summarized. Compounds 16 and 17 were also examined by western blot assay to check their effect on Her2 protein. The results reveal that the compounds could decrease the Her2 protein, which explains their selectivity to Her2 over-expressed breast cancer cells. Furthermore, the compounds inhibited the chaperone activity of small chaperone protein that could stabilize Her2 protein.
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Affiliation(s)
- Anran Zhao
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Qiaoyun Zheng
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Cody M Orahoske
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Nethrie D Idippily
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Morgan M Ashcraft
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Aicha Quamine
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Bin Su
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
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23
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Li Q, Peng J, Liu T, Zhang G. Effects of celecoxib on cell apoptosis and Fas, FasL and Bcl-2 expression in a BGC-823 human gastric cancer cell line. Exp Ther Med 2017; 14:1935-1940. [PMID: 28962106 PMCID: PMC5609129 DOI: 10.3892/etm.2017.4769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 03/13/2017] [Indexed: 01/10/2023] Open
Abstract
Fas, which is an apoptotic-related protein, has an important role in cell apoptosis. Fas ligand (FasL) binds to Fas and activates apoptosis signal transduction. We previously demonstrated that the efficiency of celecoxib inhibited the proliferation and apoptosis of HT-29 colon cancer cell line. The BGC823 cell line was used as an experimental model to evaluate the potential role of celecoxib on gastric cancer cell apoptosis. Inhibitory effects of celecoxib on cell viability were determined by MTT assay. Cell apoptosis was evaluated by flow cytometric analysis and laser confocal microscopy. The results of the present study demonstrated that celecoxib inhibited the viability of BGC823 cells in a concentration- and time-dependent manner. Furthermore, the effect of BGC823 cells apoptosis was increased in a concentration-dependent manner. Western blotting was used to determine the protein expression levels of Fas, FasL, and B-cell lymphoma-2 (Bcl-2). During the celecoxib-induced apoptosis of BGC823 cells, celecoxib upregulated Fas expression and downregulated FasL and Bcl-2 expression in a concentration-dependent manner. These results suggest that celecoxib inhibited the growth and induced apoptosis of BGC823 gastric cancer cells by regulating the protein expression of Fas, FasL and Bcl-2.
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Affiliation(s)
- Qian Li
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jie Peng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Ting Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Guiying Zhang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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24
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Catarro M, Serrano J, Cavalheiro E, Ramos S, Santos AO, Silvestre S, Almeida P. Novel 4-acetamide-2-alkylthio- N -acetanilides resembling nimesulide: Synthesis, cell viability evaluation and in silico studies. Bioorg Med Chem 2017; 25:4304-4313. [DOI: 10.1016/j.bmc.2017.06.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/31/2017] [Accepted: 06/08/2017] [Indexed: 12/11/2022]
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25
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Bobba V, Nanavaty V, Idippily ND, Zhao A, Li B, Su B. Synthesis and biological evaluation of selective tubulin inhibitors as anti-trypanosomal agents. Bioorg Med Chem 2017; 25:3215-3222. [PMID: 28428042 DOI: 10.1016/j.bmc.2017.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/30/2017] [Accepted: 04/05/2017] [Indexed: 11/28/2022]
Abstract
African trypanosomiasis is still a threat to human health due to the severe side-effects of current drugs. We identified selective tubulin inhibitors that showed the promise to the treatment of this disease, which was based on the tubulin protein structural difference between mammalian and trypanosome cells. Further lead optimization was performed in the current study to improve the efficiency of the drug candidates. We used Trypanosoma brucei brucei cells as the parasite model, and human normal kidney cells and mouse macrophage cells as the host model to evaluate the compounds. One new analog showed great potency with an IC50 of 70nM to inhibit the growth of trypanosome cells and did not affect the viability of mammalian cells. Western blot analyses reveal that the compound decreased tubulin polymerization in T. brucei cells. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.
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Affiliation(s)
- Viharika Bobba
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Vishal Nanavaty
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Nethrie D Idippily
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Anran Zhao
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Bibo Li
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
| | - Bin Su
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
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26
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Jian YS, Chen CW, Lin CA, Yu HP, Lin HY, Liao MY, Wu SH, Lin YF, Lai PS. Hyaluronic acid-nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo. Int J Nanomedicine 2017; 12:2315-2333. [PMID: 28392690 PMCID: PMC5376212 DOI: 10.2147/ijn.s120847] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Carrier-mediated drug delivery systems are promising therapeutics for targeted delivery and improved efficacy and safety of potent cytotoxic drugs. Nimesulide is a multifactorial cyclooxygenase 2 nonsteroidal anti-inflammatory drug with analgesic, antipyretic and potent anticancer properties; however, the low solubility of nimesulide limits its applications. Drugs conjugated with hyaluronic acid (HA) are innovative carrier-mediated drug delivery systems characterized by CD44-mediated endocytosis of HA and intracellular drug release. In this study, hydrophobic nimesulide was conjugated to HA of two different molecular weights (360 kDa as HA with high molecular weight [HAH] and 43kDa as HA with low molecular weight [HAL]) to improve its tumor-targeting ability and hydrophilicity. Our results showed that hydrogenated nimesulide (N-[4-amino-2-phenoxyphenyl]methanesulfonamide) was successfully conjugated with both HA types by carbodiimide coupling and the degree of substitution of nimesulide was 1%, which was characterized by 1H nuclear magnetic resonance 400 MHz and total correlation spectroscopy. Both Alexa Fluor® 647 labeled HAH and HAL could selectively accumulate in CD44-overexpressing HT-29 colorectal tumor area in vivo, as observed by in vivo imaging system. In the in vitro cytotoxic test, HA-nimesulide conjugate displayed >46% cell killing ability at a nimesulide concentration of 400 µM in HT-29 cells, whereas exiguous cytotoxic effects were observed on HCT-15 cells, indicating that HA-nimesulide causes cell death in CD44-overexpressing HT-29 cells. Regarding in vivo antitumor study, both HAL-nimesulide and HAH-nimesulide caused rapid tumor shrinkage within 3 days and successfully inhibited tumor growth, which reached 82.3% and 76.4% at day 24 through apoptotic mechanism in HT-29 xenografted mice, without noticeable morphologic differences in the liver or kidney, respectively. These results indicated that HA-nimesulide with improved selectivity through HA/CD44 receptor interactions has the potential to enhance the therapeutic efficacy and safety of nimesulide for cancer treatment.
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Affiliation(s)
| | | | - Chih-An Lin
- PhD Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung
| | | | - Hua-Yang Lin
- Preclinical Development Research Department, Holy Stone Healthcare Co., Ltd., Taipei
| | | | | | | | - Ping-Shan Lai
- Department of Chemistry; PhD Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung; Research Center for Sustainable Energy and Nanotechnology; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
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27
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Sueth-Santiago V, Decote-Ricardo D, Morrot A, Freire-de-Lima CG, Lima MEF. Challenges in the chemotherapy of Chagas disease: Looking for possibilities related to the differences and similarities between the parasite and host. World J Biol Chem 2017; 8:57-80. [PMID: 28289519 PMCID: PMC5329715 DOI: 10.4331/wjbc.v8.i1.57] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/30/2016] [Accepted: 01/14/2017] [Indexed: 02/05/2023] Open
Abstract
Almost 110 years after the first studies by Dr. Carlos Chagas describing an infectious disease that was named for him, Chagas disease remains a neglected illness and a death sentence for infected people in poor countries. This short review highlights the enormous need for new studies aimed at the development of novel and more specific drugs to treat chagasic patients. The primary tool for facing this challenge is deep knowledge about the similarities and differences between the parasite and its human host.
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28
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Abd El Razik HA, Mroueh M, Faour WH, Shebaby WN, Daher CF, Ashour HMA, Ragab HM. Synthesis of new pyrazolo[3,4-d]pyrimidine derivatives and evaluation of their anti-inflammatory and anticancer activities. Chem Biol Drug Des 2017; 90:83-96. [PMID: 28032452 DOI: 10.1111/cbdd.12929] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Revised: 11/27/2016] [Accepted: 11/30/2016] [Indexed: 01/01/2023]
Abstract
This study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly synthesized compounds were evaluated for anticancer activity against four cell lines (MDA-MB-231, MCF-7, SF-268, B16F-10) and cyclooxygenase (COX-2) protein expression inhibition in lipopolysaccharide (LPS)-activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate-to-high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines (IC50 values 5.5-11 μg/ml) comparable to cisplatin. In addition, six of these compounds (7b, 10a-d, and 12c) demonstrated inhibition of LPS-induced COX-2 protein expression at low concentration (25 μg/ml) as compared to the control non-stimulated cells and showed a COX-2 selectivity index range comparable to diclofenac sodium. The overall results indicate that many of these pyrazolopyrimidine derivatives possess in vitro anti-inflammatory and anticancer activities at varying doses, and the most active compounds will be subjected to in vivo pharmacological evaluation.
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Affiliation(s)
- Heba A Abd El Razik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Mohamad Mroueh
- Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese American University, Byblos, Lebanon
| | - Wissam H Faour
- School of Medicine, Lebanese American University, Byblos, Lebanon
| | - Wassim N Shebaby
- Department of Natural Sciences, School of arts and sciences, Lebanese American University, Byblos, Lebanon
| | - Costantine F Daher
- Department of Natural Sciences, School of arts and sciences, Lebanese American University, Byblos, Lebanon
| | - Hayam M A Ashour
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Hanan M Ragab
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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Farrag AM. Synthesis and Biological Evaluation of Novel Indomethacin Derivatives as Potential Anti-Colon Cancer Agents. Arch Pharm (Weinheim) 2016; 349:904-914. [PMID: 27862196 DOI: 10.1002/ardp.201600238] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 10/16/2016] [Accepted: 10/17/2016] [Indexed: 12/29/2022]
Abstract
The molecular structure of indomethacin was used as a starting scaffold for the synthesis of 20 novel analogs and to study their effects on the proliferation of three human colon cancer cell lines, HCT-116, HT-29, and Caco-2, by MTT assay. The synthesized indomethacin analogs were characterized on the basis of IR, 1 H NMR, 13 C NMR, mass spectral data, and elemental analysis results. Cytotoxicity assay results showed that the indomethacin amide analog 2 was the most potent anticancer agent (IC50 = 0.78, 0.09, and 0.0127 μg/mL) against the three colon cancer cell lines, respectively, being more potent than the standard 5-fluorouracil (IC50 = 1.8, 0.75, and 5.45 μg/mL). Interestingly, the indomethacin oxazin analog 3 and the indomethacin amide analog 8 displayed very potent anticancer activity against the HCT-116 cell line with IC50 = 0.421 and 0.27 μg/mL, respectively, much better than the reference (IC50 = 1.8 μg/mL). Additionally, analogs 3, 4b, 11, 12c, and 13a exhibited excellent antitumor activity against Caco-2 cells, with IC50 ranging from 1.5 to 4.5 μg/mL. Furthermore, analogs 2 and 8 were additionally examined for their effect on the cell cycle of HCT-116 and HT-29 cells, respectively, using flow cytometric analysis. Analog 2 arrested the cell cycle of HT-29 cells at the S phase, while 8 was found to arrest the cell cycle of HCT-116 cells at the G0/G1 phase.
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Affiliation(s)
- Amel Mostafa Farrag
- Pharmaceutical Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
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Wang HY, Yu HZ, Huang SM, Zheng YL. p53, Bcl-2 and cox-2 are involved in berberine hydrochloride-induced apoptosis of HeLa229 cells. Mol Med Rep 2016; 14:3855-61. [PMID: 27601129 DOI: 10.3892/mmr.2016.5696] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 07/21/2016] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the effects of berberine hydrochloride on the proliferation and apoptosis of HeLa229 human cervical cancer cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to examine the cytotoxicity of berberine hydrochloride against HeLa229 cells. The effects of berberine hydrochloride on the apoptosis of HeLa229 cells was detected by immunofluorescence and flow cytometry, and the mRNA expression levels of p53, B‑cell lymphoma 2 (Bcl‑2) and cyclooxygenase‑2 (cox‑2) were analyzed by reverse transcription-quantitative polymerase chain reaction. Berberine hydrochloride inhibited the proliferation of HeLa229 cells in a dose‑dependent manner; minimum cell viability (3.61%) was detected following treatment with 215.164 µmol/l berberine hydrochloride and the half maximal inhibitory concentration value was 42.93 µmol/l following treatment for 72 h. In addition, berberine hydrochloride induced apoptosis in HeLa229 cells in a dose‑ and time‑dependent manner. Berberine hydrochloride upregulated the mRNA expression levels of p53, and downregulated mRNA expression levels of Bcl‑2 and cox‑2, in a dose‑dependent manner. In conclusion, berberine hydrochloride inhibited the proliferation and induced apoptosis of HeLa229 cells, potentially via the upregulation of p53 and the downregulation of Bcl‑2 and cox‑2 mRNA expression levels.
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Affiliation(s)
- Hai-Yan Wang
- Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang, Hubei 441053, P.R. China
| | - Hai-Zhong Yu
- Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang, Hubei 441053, P.R. China
| | - Sheng-Mou Huang
- Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang, Hubei 441053, P.R. China
| | - Yu-Lan Zheng
- Department of Respiratory Disease, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei 441021, P.R. China
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Banti CN, Papatriantafyllopoulou C, Manoli M, Tasiopoulos AJ, Hadjikakou SK. Nimesulide Silver Metallodrugs, Containing the Mitochondriotropic, Triaryl Derivatives of Pnictogen; Anticancer Activity against Human Breast Cancer Cells. Inorg Chem 2016; 55:8681-96. [DOI: 10.1021/acs.inorgchem.6b01241] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Christina N. Banti
- Inorganic and Analytical Chemistry, Department
of Chemistry, University of Ioannina, 45110 Ioannina, Greece
| | | | - Maria Manoli
- Department of Chemistry, University of Cyprus, 1678 Nicosia, Cyprus
| | | | - Sotiris K. Hadjikakou
- Inorganic and Analytical Chemistry, Department
of Chemistry, University of Ioannina, 45110 Ioannina, Greece
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Zavan B, De Almeida EM, Salles ÉDSL, do Amarante-Paffaro AM, Paffaro VA. COX-2 plays a role in angiogenic DBA(+) uNK cell subsets activation and pregnancy protection in LPS-exposed mice. Placenta 2016; 44:34-45. [PMID: 27452436 DOI: 10.1016/j.placenta.2016.06.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 06/02/2016] [Accepted: 06/10/2016] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Although uterine Natural Killer (uNK) cells have cytoplasmic granules rich in perforin and granzymes, these cells do not degranulate in normal pregnancy. DBA lectin(+) uNK cells produce angiogenic factors which stimulate remodeling of uterine arterioles to increase blood flow within the growing feto-placental unit. We sought to investigate the importance of COX-2 on mouse pregnancy inoculated with Gram-negative bacteria Lipopolysaccharide (LPS) by treating with a selective COX-2 inhibitor (nimesulide). METHODS We have combined histochemical, immunohistochemical, stereological, morphometric, behavioral, and litter analyses to investigate mouse pregnancy inoculated with LPS with or without pre-treatment with nimesulide 30 min before LPS injections, focusing on DBA(+) uNK cell response and viability of the pregnancy. RESULTS LPS caused sickness behavior, an immature DBA(+) uNK influx, decreased mature DBA(+) uNK cell numbers, and triggered a new DBA(low) uNK appearance. These effects of LPS, except the sickness behavior, were prevented by nimesulide. COX-2 inhibition also prevented the down-regulation of uNK perforin and spiral arteriole α-actin expression stimulated by LPS. While the litter size from Nimesulide + LPS-treated mothers was significantly smaller compared to those from LPS-treated group, nimesulide alone showed no effect on the offspring. DISCUSSION Collectively, our data indicate that COX-2 changes angiogenic DBA(+) uNK cells in order to protect mouse pregnancy after LPS injection.
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Affiliation(s)
- Bruno Zavan
- Integrative Animal Biology Laboratory, Department for Cell and Developmental Biology, Biomedical Science Institute, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-000, Brazil.
| | - Eliana Martins De Almeida
- Integrative Animal Biology Laboratory, Department for Cell and Developmental Biology, Biomedical Science Institute, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-000, Brazil.
| | - Évila da Silva Lopes Salles
- Integrative Animal Biology Laboratory, Department for Cell and Developmental Biology, Biomedical Science Institute, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-000, Brazil.
| | - Andréa Mollica do Amarante-Paffaro
- Integrative Animal Biology Laboratory, Department for Cell and Developmental Biology, Biomedical Science Institute, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-000, Brazil.
| | - Valdemar Antonio Paffaro
- Integrative Animal Biology Laboratory, Department for Cell and Developmental Biology, Biomedical Science Institute, Federal University of Alfenas, Alfenas, Minas Gerais, 37130-000, Brazil.
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Voggu RR, Zhou X, Su B, Guo B. A Simple and Rapid LC-MS/MS Method for the Determination of BMCL26 a Novel Anti-Parasitic Agent in Rat Plasma. ACTA ACUST UNITED AC 2016; 6. [PMID: 26823991 PMCID: PMC4727756 DOI: 10.4172/2155-9872.1000266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BMCL26 is a potential drug derived from nimesulide, which has exhibited the substantial anti-parasitic activity in various cell lines. To conduct various pharmacological and toxicological properties of this drug, we developed and validated a rapid LC-MS/MS method for its quantification in accordance with the FDA guidelines. Protein precipitation with 0.1% formic acid in acetonitrile was used to extract the analytes along with the internal standard (JCC76) from rat plasma. It was found that the calibration curve of the method had an excellent linearity (r2 ≥ 0.9993) for the analyte concentration ranging from 0.5 to 100 ng/mL with acceptable inter- and intra-assay, precision, accuracy and stability. The matrix effect and extraction recovery were in the range of 101.30-110.10% and 90.16- 105.00%, respectively. This LC-MS/MS method is simple and rapid and can be used in the future pharmaceutical studies of BMCL26.
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Affiliation(s)
| | - Xiang Zhou
- Department of Chemistry, Cleveland State University, USA
| | - Bin Su
- Department of Chemistry, Cleveland State University, USA
| | - Baochuan Guo
- Department of Chemistry, Cleveland State University, USA
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Nanavaty V, Lama R, Sandhu R, Zhong B, Kulman D, Bobba V, Zhao A, Li B, Su B. Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents. PLoS One 2016; 11:e0146289. [PMID: 26771307 PMCID: PMC4714897 DOI: 10.1371/journal.pone.0146289] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 12/15/2015] [Indexed: 11/21/2022] Open
Abstract
Objectives There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis. Methods We used Trypanosoma brucei brucei as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last, in vivo anti-parasite activities of these compounds were determined in T. brucei-infected mice. Results Three compounds were selected that are 100 fold more effective against the growth of T. brucei cells than mammalian cells. These compounds caused cell cycle progression defects in T. brucei cells. Western analyses indicated that these compounds decreased tubulin polymerization in T. brucei cells. The in vivo investigation revealed that these compounds, when admitted orally, inhibited T. brucei cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely. Conclusions These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR) was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds.
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Affiliation(s)
- Vishal Nanavaty
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Rati Lama
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Ranjodh Sandhu
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Bo Zhong
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Daniel Kulman
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Viharika Bobba
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Anran Zhao
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Bibo Li
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.,Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Bin Su
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.,Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
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Lu XY, Wang ZC, Wei T, Yan XQ, Wang PF, Zhu HL. Design, synthesis and evaluation of benzenesulfonamide-substituted 1,5-diarylpyrazoles containing phenylacetohydrazide derivatives as COX-1/COX-2 agents against solid tumors. RSC Adv 2016. [DOI: 10.1039/c6ra02168a] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Novel benzenesulfonamide-substituted 1,5-diarylpyrazoles containing phenylacetohydrazide derivatives have been synthesized. Among them, 48 showed best antiproliferative activity against A549 cells and was evaluated as a selective COX-2 inhibitor.
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Affiliation(s)
- Xiao-Yuan Lu
- State Key Laboratory of Pharmaceutical Biotechnology
- Nanjing University
- Nanjing 210023
- People's Republic of China
| | - Zhong-Chang Wang
- State Key Laboratory of Pharmaceutical Biotechnology
- Nanjing University
- Nanjing 210023
- People's Republic of China
| | - Ting Wei
- State Key Laboratory of Pharmaceutical Biotechnology
- Nanjing University
- Nanjing 210023
- People's Republic of China
| | - Xiao-Qiang Yan
- State Key Laboratory of Pharmaceutical Biotechnology
- Nanjing University
- Nanjing 210023
- People's Republic of China
| | - Peng-Fei Wang
- State Key Laboratory of Pharmaceutical Biotechnology
- Nanjing University
- Nanjing 210023
- People's Republic of China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology
- Nanjing University
- Nanjing 210023
- People's Republic of China
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A New Ligustrazine Derivative-Selective Cytotoxicity by Suppression of NF-κB/p65 and COX-2 Expression on Human Hepatoma Cells. Part 3. Int J Mol Sci 2015; 16:16401-13. [PMID: 26193270 PMCID: PMC4519956 DOI: 10.3390/ijms160716401] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 07/03/2015] [Accepted: 07/13/2015] [Indexed: 01/14/2023] Open
Abstract
A new anticancer ligustrazine derivative, 3β-hydroxyolea-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methylester (T-OA, C38H58O3N2), was previously reported. It was synthesized via conjugating hepatoprotective and anticancer ingredients of traditional Chinese medicine. We found that T-OA exerted its anticancer activity by preventing the expression of nuclear transcription factor NF-κB/p65 and COX-2 in S180 mice. However, the selective cytotoxicity of T-OA on various kinds of cell lines has not been studied sufficiently. In the present study, compared with Cisplatin, T-OA was more toxic to human hepatoma cell line Bel-7402 (IC50 = 6.36 ± 1.56 µM) than other three cancer cell lines (HeLa, HT-29, BGC-823), and no toxicity was observed toward Madin–Darby canine kidney cell line MDCK (IC50 > 150 µM). The morphological changes of Bel-7402 cells demonstrated that T-OA had an apoptosis-inducing effect which had been substantiated using 4ʹ,6-diamidino-2-phenylindole (DAPI) staining, acridine orange (AO)/ethidium bromide (EB) staining, flow cytometry and mitochondrial membrane potential assay. Combining the immumohistochemical staining, we found T-OA could prevent the expression of NF-κB/p65 and COX-2 in Bel-7402 cells. Both of the proteins have been known to play roles in apoptosis and are mainly located in the nuclei. Moreover subcellular localization was performed to reveal that T-OA exerts in nuclei of Bel-7402 cells. The result was in accordance with the effects of down-regulating the expression of NF-κB/p65 and COX-2.
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Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors. Med Chem Res 2015. [DOI: 10.1007/s00044-014-1187-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Voggu RR, Alagandula R, Zhou X, Su B, Zhong B, Guo B. A rapid LC-MS/MS method for quantification of CSUOH0901, a novel antitumor agent, in rat plasma. Biomed Chromatogr 2014; 29:797-802. [PMID: 25424731 DOI: 10.1002/bmc.3365] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 09/03/2014] [Accepted: 09/25/2014] [Indexed: 12/25/2022]
Abstract
CSUOH0901, a novel anticancer derivative of nimesulide, exhibits very promising anticancer activities in various cancer cell lines. In order to support further pharmacological and toxicological studies of this promising anticancer drug candidate, an LC-MS/MS method was developed and validated in accordance with the US Food and Drug Administration guidelines. The drug molecules were extracted from plasma samples by protein precipitation and then analyzed with LC-ESI-MS/MS. An excellent analyte separation was achieved using a phenomenex C18 column with a mobile phase of 90% methanol and 5 m m of ammonium formate. The validated linear dynamic range was between 0.5 and 100 ng/mL and the achieved correlation coefficient (r(2)) was >0.9996. The results of inter- and intra-day precision and accuracy were satisfactory, that is, <12% for accuracy and within ±5% for precision at a low and high quality control concentrations, respectively. In addition, the analyte and internal standard (JCC76) were found to be stable under the storage conditions at -20°C for about 2 months. Hence, the acquired results proved that the LC-ESI-MS/MS method developed is precise, accurate and selective for the quantification of CSUOH0901 in plasma, and can be used for pharmacokinetic studies.
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Affiliation(s)
- Ramakrishna R Voggu
- Department of Chemistry, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH, 44115, USA
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Ramos SS, Almeida SS, Leite PM, Boto RE, Silvestre S, Almeida P. VT-NMR and cytotoxic evaluation of some new ortho-(alkylchalcogen)acetanilides. Tetrahedron 2014. [DOI: 10.1016/j.tet.2014.09.055] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Dube PN, Bule SS, Mokale SN, Kumbhare MR, Dighe PR, Ushir YV. Synthesis and Biologic Evaluation of Substituted 5-methyl-2-phenyl-1H-pyrazol-3(2H)-one Derivatives as Selective COX-2 Inhibitors: Molecular Docking Study. Chem Biol Drug Des 2014; 84:409-19. [DOI: 10.1111/cbdd.12324] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 02/14/2014] [Accepted: 03/12/2014] [Indexed: 11/29/2022]
Affiliation(s)
- Pritam N. Dube
- Department of Pharmaceutical Chemistry; Y. B. Chavan College of Pharmacy; Dr. Rafiq Zakaria Campus; Aurangabad-431001 Maharashtra India
| | - Shweta S. Bule
- Department of Pharmaceutical Chemistry; S.M.B.T. College of Pharmacy; Dhamangaon Nashik-422403 Maharashtra India
| | - Santosh N. Mokale
- Department of Pharmaceutical Chemistry; Y. B. Chavan College of Pharmacy; Dr. Rafiq Zakaria Campus; Aurangabad-431001 Maharashtra India
| | - Manoj R. Kumbhare
- Department of Pharmaceutical Chemistry; S.M.B.T. College of Pharmacy; Dhamangaon Nashik-422403 Maharashtra India
| | - Pravin R. Dighe
- Department of Pharmaceutical Chemistry; S.M.B.T. College of Pharmacy; Dhamangaon Nashik-422403 Maharashtra India
| | - Yogesh V. Ushir
- Department of Pharmaceutical Chemistry; S.M.B.T. College of Pharmacy; Dhamangaon Nashik-422403 Maharashtra India
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Wu XL, Cheng B, Li PY, Huang HJ, Zhao Q, Dan ZL, Tian DA, Zhang P. MicroRNA-143 suppresses gastric cancer cell growth and induces apoptosis by targeting COX-2. World J Gastroenterol 2013; 19:7758-7765. [PMID: 24616567 PMCID: PMC3837276 DOI: 10.3748/wjg.v19.i43.7758] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 09/20/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the function of microRNA-143 (miR-143) in gastric cancer and explore the target genes of miR-143.
METHODS: A quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed to evaluate miR-143 expression in gastric cancer cell lines. After transfecting gastric cancer cells with miR-143-5p and miR-143-3p precursors, Alamar blue and apoptosis assays were used to measure the respective proliferation and apoptosis rates. Cyclooxygenase-2 (COX-2) expression was determined by real-time RT-PCR and Western blot assays after miR-143 transfection. Reporter plasmids were constructed, and a luciferase reporter assay was used to identify the miR-143 binding site on COX-2.
RESULTS: Both miR-143-5p and miR-143-3p were significantly downregulated in multiple gastric cancer cell lines. Forced miR-143-5p and miR-143-3p expression in gastric cancer cells produced a profound cytotoxic effect. MiR-145-5p transfection into gastric cancer cells resulted in a greater growth inhibitory effect (61.23% ± 3.16% vs 46.58% ± 4.28%, P < 0.05 in the MKN-1 cell line) and a higher apoptosis rate (28.74% ± 1.93% vs 22.13% ± 3.31%, P < 0.05 in the MKN-1 cell line) than miR-143-3p transfection. Further analysis indicated that COX-2 expression was potently suppressed by miR-143-5p but not by miR-143-3p. The activity of a luciferase reporter construct that contained the 3’-untranslated region (UTR) of COX-2 was downregulated by miR-143-5p (43.6% ± 4.86%, P < 0.01) but not by miR-143-3p. A mutation in the miR-145-5p binding site completely ablated the regulatory effect on luciferase activity, which suggests that there is a direct miR-145-5p binding site in the 3’-UTR of COX-2.
CONCLUSION: Both miR-143-5p and miR-143-3p function as anti-oncomirs in gastric cancer. However, miR-143-5p alone directly targets COX-2, and it exhibits a stronger tumor suppressive effect than miR-143-3p.
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Paul AG, Chandran B, Sharma-Walia N. Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies. Transl Res 2013; 162:77-92. [PMID: 23567332 PMCID: PMC7185490 DOI: 10.1016/j.trsl.2013.03.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 02/13/2013] [Accepted: 03/15/2013] [Indexed: 12/28/2022]
Abstract
The role of cyclooxygenase-2 (COX-2), its lipid metabolite prostaglandin E2 (PGE2), and Eicosanoid (EP) receptors (EP; 1-4) underlying the proinflammatory mechanistic aspects of Burkitt's lymphoma, nasopharyngeal carcinoma, cervical cancer, prostate cancer, colon cancer, and Kaposi's sarcoma (KS) is an active area of investigation. The tumorigenic potential of COX-2 and PGE2 through EP receptors forms the mechanistic context underlying the chemotherapeutic potential of nonsteroidal anti-inflammatory drugs (NSAIDs). Although role of the COX-2 is described in several viral associated malignancies, the biological significance of the COX-2/PGE2/EP receptor inflammatory axis is extensively studied only in Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) associated malignancies such as KS, a multifocal endothelial cell tumor and primary effusion lymphoma (PEL), a B cell-proliferative disorder. The purpose of this review is to summarize the salient findings delineating the molecular mechanisms downstream of COX-2 involving PGE2 secretion and its autocrine and paracrine interactions with EP receptors (EP1-4), COX-2/PGE2/EP receptor signaling regulating KSHV pathogenesis and latency. KSHV infection induces COX-2, PGE2 secretion, and EP receptor activation. The resulting signal cascades modulate the expression of KSHV latency genes (latency associated nuclear antigen-1 [LANA-1] and viral-Fas (TNFRSF6)-associated via death domain like interferon converting enzyme-like- inhibitory protein [vFLIP]). vFLIP was also shown to be crucial for the maintenance of COX-2 activation. The mutually interdependent interactions between viral proteins (LANA-1/vFLIP) and COX-2/PGE2/EP receptors was shown to play key roles in the biological mechanisms involved in KS and PEL pathogenesis such as blockage of apoptosis, cell cycle regulation, transformation, proliferation, angiogenesis, adhesion, invasion, and immune-suppression. Understanding the COX-2/PGE2/EP axis is very important to develop new safer and specific therapeutic modalities for KS and PEL. In addition to COX-2 being a therapeutic target, EP receptors represent ideal targets for pharmacologic agents as PGE2 analogues and their blockers/antagonists possess antineoplastic activity, without the reported gastrointestinal and cardiovascular toxicity observed with few a NSAIDs.
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MESH Headings
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Antineoplastic Agents/pharmacology
- Cyclooxygenase 2/metabolism
- Dinoprostone/metabolism
- Gene Expression Regulation, Viral
- Herpesvirus 8, Human/genetics
- Herpesvirus 8, Human/pathogenicity
- Humans
- Lymphoma, Primary Effusion/drug therapy
- Lymphoma, Primary Effusion/metabolism
- Receptors, Eicosanoid/metabolism
- Sarcoma, Kaposi/drug therapy
- Sarcoma, Kaposi/metabolism
- Sarcoma, Kaposi/virology
- Signal Transduction
- Virus Latency/genetics
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Affiliation(s)
- Arun George Paul
- H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Ill
| | - Bala Chandran
- H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Ill
| | - Neelam Sharma-Walia
- H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Ill
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43
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Zhong B, Chennamaneni S, Lama R, Yi X, Geldenhuys WJ, Pink JJ, Dowlati A, Xu Y, Zhou A, Su B. Synthesis and anticancer mechanism investigation of dual Hsp27 and tubulin inhibitors. J Med Chem 2013; 56:5306-20. [PMID: 23767669 DOI: 10.1021/jm4004736] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development.
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Affiliation(s)
- Bo Zhong
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University , 2121 Euclid Avenue, Cleveland, Ohio 44115, United States
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44
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Mendanha da Cunha CR, Mendanha Neto SA, Carlos da Silva C, Cortez AP, Gomes MDN, Martins FI, Alonso A, Rezende KR, Menegatti R, de Magalhães MTQ, Valadares MC. 4-Nerolidylcatechol and its synthetic analogues: Antioxidant activity and toxicity evaluation. Eur J Med Chem 2013; 62:371-8. [DOI: 10.1016/j.ejmech.2012.12.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 11/02/2012] [Accepted: 12/12/2012] [Indexed: 02/06/2023]
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45
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Nimesulide Based Novel Glycolamide Esters: Their Design, Synthesis, and Pharmacological Evaluation. J CHEM-NY 2013. [DOI: 10.1155/2013/816769] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The nimesulide based novel glycolamide esters were designed and synthesized for the first timeviaa three-step method starting from nimesulide. Structures of the synthesized compounds were confirmed by spectroscopic analysis. All the synthesized compounds were examined for their cytotoxic effectsin vitro,some of which showed significant cytotoxic activities against HCT-15 human colon cancer cell line.
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46
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Lama R, Zhang L, Naim JM, Williams J, Zhou A, Su B. Development, validation and pilot screening of an in vitro multi-cellular three-dimensional cancer spheroid assay for anti-cancer drug testing. Bioorg Med Chem 2012; 21:922-31. [PMID: 23306053 DOI: 10.1016/j.bmc.2012.12.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 11/29/2012] [Accepted: 12/06/2012] [Indexed: 11/28/2022]
Abstract
It has been demonstrated that two-dimensional (2D) monolayer cancer cell proliferation assay for anti-cancer drug screening is a very artificial model and cannot represent the characteristics of three-dimensional (3D) solid tumors. The multi-cellular in vitro 3D tumor spheroid model is of intermediate complexity, and can provide a bridge to the gap between the complex in vivo tumors and simple in vitro monolayer cell cultures. In this study, a simple and cost-effective cancer 3D spheroid assay suitable for small molecule anti-cancer compound screening was developed, standardized and validated on H292 non-small lung cancer cell line. A pilot screening with this assay was performed utilizing a compound library consisting of 41 anti-cancer agents. The traditional 2D monolayer cell proliferation assay was also performed with the same cell line and compounds. A correlational study based on the IC(50) values from the 2D and 3D assays was conducted. There is low correlation with the two sets of biological data, suggesting the two screening methods provide different information regarding the potency of the tested drug candidates.
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Affiliation(s)
- Rati Lama
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
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47
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Chennamaneni S, Zhong B, Lama R, Su B. COX inhibitors Indomethacin and Sulindac derivatives as antiproliferative agents: synthesis, biological evaluation, and mechanism investigation. Eur J Med Chem 2012; 56:17-29. [PMID: 22940705 DOI: 10.1016/j.ejmech.2012.08.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Revised: 07/23/2012] [Accepted: 08/02/2012] [Indexed: 02/08/2023]
Abstract
Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC(50)s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC(50)s around 0.5 μM-3 μM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation.
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Affiliation(s)
- Snigdha Chennamaneni
- Department of Chemistry and Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
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48
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Lama R, Sandhu R, Zhong B, Li B, Su B. Identification of selective tubulin inhibitors as potential anti-trypanosomal agents. Bioorg Med Chem Lett 2012; 22:5508-16. [PMID: 22850214 DOI: 10.1016/j.bmcl.2012.07.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 07/05/2012] [Accepted: 07/06/2012] [Indexed: 11/16/2022]
Abstract
The potency of a series of sulfonamide tubulin inhibitors against the growth of Trypanosoma brucei (T. brucei), as well as human cancer and primary fibroblast cells were evaluated with the aim of determining whether compounds that selectively inhibit parasite proliferation could be identified. Several compounds showed excellent selectivity against T. brucei growth, and have the potential to be used for the treatment of Human African trypanosomiasis. A T. brucei tubulin protein homology model was built based on the crystal structure of the bovine tubulin. The colchicine-binding domain, which is also the binding site of the tested sulfonamide tubulin inhibitors, showed clear differences between the tubulin structures and presumably explained the selectivity of the compounds.
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Affiliation(s)
- Rati Lama
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
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49
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Yi X, Zhong B, Smith KM, Geldenhuys WJ, Feng Y, Pink JJ, Dowlati A, Xu Y, Zhou A, Su B. Identification of a Class of Novel Tubulin Inhibitors. J Med Chem 2012; 55:3425-35. [DOI: 10.1021/jm300100d] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
| | | | | | - Werner J. Geldenhuys
- Department
of Pharmaceutical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, Ohio 44272, United States
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