|
1
|
Hou YX, Ren W, He QQ, Huang LY, Gao TH, Li H. Tetramethylpyrazine induces reactive oxygen species-based mitochondria-mediated apoptosis in colon cancer cells. World J Gastrointest Oncol 2025; 17:104922. [DOI: 10.4251/wjgo.v17.i4.104922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer is one of the most common malignancies worldwide, and chemotherapy is a widely used strategy in colon cancer clinical therapy. Chemotherapy resistance is the main cause of recurrence and progression in colon cancer. Thus, novel drugs for treatment are urgently needed. Tetramethylpyrazine (TMP), a component of the traditional Chinese medicine Chuanxiong Hort, has been proven to exhibit a beneficial effect in tumors.
AIM To investigate the potential anticancer activity of TMP in colon cancer and the underlying mechanisms.
METHODS Colon cancer cells were incubated with different concentrations of TMP. Cell viability was evaluated by crystal violet staining assay, and cell apoptosis was assessed by flow cytometry. Apoptosis-associated protein expression was measured using Western blot analysis. Intracellular reactive oxygen species (ROS) levels were assessed by flow cytometry using DCF fluorescence intensity. Xenografts were established by the subcutaneous injection of colon cancer cells into nude mice; tumor growth was monitored and intracellular ROS was detected in tumors by malondialdehyde assay.
RESULTS TMP induced apoptosis of colon cancer cells via the activation of the mitochondrial pathway. TMP increased the generation of intracellular ROS and triggered mitochondria-mediated apoptosis in a caspase-dependent manner.
CONCLUSION Our study demonstrates that TMP induces the apoptosis of colon cancer cells and increases the generation of intracellular ROS. TMP triggers mitochondria-mediated apoptosis in a caspase-dependent manner. The accumulation of intracellular ROS is involved in TMP-induced apoptosis. Our findings suggest that TMP may be a potential therapeutic drug for the treatment of colon cancer.
Collapse
Affiliation(s)
- Yan-Xu Hou
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Wei Ren
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Qing-Qiang He
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Li-Yan Huang
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Tian-Hua Gao
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| | - Hua Li
- The Second Department of Gastrointestinal Oncology Surgery, Xingtai People’s Hospital of Hebei Medical University, Xingtai 054001, Hebei Province, China
| |
Collapse
|
|
2
|
Lin Y, Itoh H, Dan S, Inoue M. Methyl scanning approach for enhancing the biological activity of the linear peptidic natural product, efrapeptin C. Chem Sci 2024; 15:19390-19399. [PMID: 39568880 PMCID: PMC11575625 DOI: 10.1039/d4sc04384g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/15/2024] [Indexed: 11/22/2024] Open
Abstract
Efrapeptin C (1a) is a large peptidic natural product comprising a 15-mer linear sequence and exerts potent anticancer activity by inhibiting mitochondrial FoF1-ATP synthase. Residues 1-6 and 9-15 of 1a fold into two 310-helical domains and interact with ATP synthase, while the central β-Ala-7-Gly-8 region functions as a flexible linker of the two domains. To enhance the function of 1a by minimally modifying its structure, we envisioned attaching one small methyl group to the β-Ala-7-Gly-8 and designed six methylated analogues 1b-1g, differing only in the position and configuration of the methyl group. We enabled the first solid-phase total synthesis of 1a and unified syntheses of 1b-1g. The growth inhibitory activities of 1a-1g against MCF-7 cells varied significantly: 1f with (S)-β3-hAla-7 and its epimer 1g with (R)-β3-hAla-7 were 4-fold more and 5-fold less potent, respectively, than 1a. Remarkably, the most potent 1f had the most stabilized 310-helical conformation and the highest hydrophobicity, which likely contributed to its effective transfer to the target protein within mitochondria. Moreover, 1f exhibited higher proteolytic stability than 1a. Therefore, the present methyl scanning approach provides a new strategy for changing the original properties of linear peptidic natural products to develop new pharmaceuticals.
Collapse
Affiliation(s)
- Yuanqi Lin
- Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan
| | - Hiroaki Itoh
- Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research 3-8-31 Ariake Koto-ku Tokyo 135-8550 Japan
| | - Masayuki Inoue
- Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-0033 Japan
| |
Collapse
|
|
3
|
Mohan S, Krishnan L, Madhusoodanan N, Sobha A, Jalaja R, Kumaran A, Vankadari N, Purushothaman J, Somappa SB. Linker-Based Pharmacophoric Design and Semisynthesis of Labdane Conjugates Active against Multi-Faceted Inflammatory Targets. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:6389-6401. [PMID: 38494644 DOI: 10.1021/acs.jafc.3c09536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Prolonged inflammation leads to the genesis of various inflammatory diseases such as atherosclerosis, cancer, inflammatory bowel disease, Alzheimer's, etc. The uncontrolled inflammatory response is characterized by the excessive release of pro-inflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1alpha (IL-1α), and inflammatory enzymes such as cyclooxygenase-2 (COX-2). Hence, the downregulation of these inflammatory mediators is an active therapy to control aberrant inflammation and tissue damage. To address this, herein, we present the rational design and synthesis of novel phytochemical entities (NPCEs) through strategic linker-based molecular hybridization of aromatic/heteroaromatic fragments with the labdane dialdehyde, isolated from the medicinally and nutritionally significant rhizomes of the plant Curcuma amada. To validate the anti-inflammatory potential, we employed a comprehensive in vitro study assessing its inhibitory effect on the COX-2 enzyme and other inflammatory mediators, viz., NO, TNF-α, IL-6, and IL-1α, in bacterial lipopolysaccharide-stimulated macrophages, as well as in-silico molecular modeling studies targeting the inflammation regulator COX-2 enzyme. Among the synthesized novel compounds, 5f exhibited the highest anti-inflammatory potential by inhibiting the COX-2 enzyme (IC50 = 17.67 ± 0.89 μM), with a 4-fold increased activity relative to the standard drug indomethacin (IC50 = 67.16 ± 0.17 μM). 5f also significantly reduced the levels of LPS-induced NO, TNF-α, IL-6, and IL-1α, much better than the positive control. Molecular mechanistic studies revealed that 5f suppressed the expression of COX-2 and pro-inflammatory cytokine release dose-dependently, which was associated with the inhibition of the NF-κB signaling pathway. This infers that the labdane derivative 5f is a promising lead candidate as an anti-inflammatory agent to further explore its therapeutic landscape.
Collapse
Affiliation(s)
- Sangeetha Mohan
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Lekshmy Krishnan
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
| | - Nithya Madhusoodanan
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Anjali Sobha
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Renjitha Jalaja
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
| | - Alaganandam Kumaran
- Agro Processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Naveen Vankadari
- Department of Biochemistry and Pharmacology, Bio21 Institute, The University of Melbourne, Melbourne, Victoria 3052, Australia
| | - Jayamurthy Purushothaman
- Agro Processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
| | - Sasidhar B Somappa
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
| |
Collapse
|
|
4
|
Rohilla S, Goyal G, Berwal P, Mathur N. A Review on Indole-triazole Molecular Hybrids as a Leading Edge in Drug Discovery: Current Landscape and Future Perspectives. Curr Top Med Chem 2024; 24:1557-1588. [PMID: 38766822 DOI: 10.2174/0115680266307132240509065351] [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: 02/24/2024] [Revised: 04/02/2024] [Accepted: 04/09/2024] [Indexed: 05/22/2024]
Abstract
Molecular hybridization is a rational design strategy used to create new ligands or prototypes by identifying and combining specific pharmacophoric subunits from the molecular structures of two or more known bioactive derivatives. Molecular hybridization is a valuable technique in drug discovery, enabling the modulation of unwanted side effects and the creation of potential dual-acting drugs that combine the effects of multiple therapeutic agents. Indole-triazole conjugates have emerged as promising candidates for new drug development. The indole and triazole moieties can be linked through various synthetic strategies, such as click chemistry or other coupling reactions, to generate a library of diverse compounds for biological screening. The achievable structural diversity with indole-triazole conjugates offers avenues to optimize their pharmacokinetic and pharmacodynamic attributes, amplifying their therapeutic efficacy. Researchers have extensively tailored both indole and triazole frameworks with diverse modifications to comprehend their impact on the drug's pharmacokinetic and pharmacodynamic characteristics. The current review article endeavours to explore and discuss various research strategies to design indoletriazole hybrids and elucidate their significance in a variety of pathological conditions. The insights provided herein are anticipated to be beneficial for the researchers and will likely encourage further exploration in this field.
Collapse
Affiliation(s)
- Suman Rohilla
- Department of Pharmaceutical Chemistry, SGT College of Pharmacy, Shree Guru Gobind Singh Tricentenary University, Gurugram, Haryana, India
| | - Garima Goyal
- Department of Pharmaceutical Chemistry, SGT College of Pharmacy, Shree Guru Gobind Singh Tricentenary University, Gurugram, Haryana, India
| | - Paras Berwal
- Department of Pharmaceutical Chemistry, SGT College of Pharmacy, Shree Guru Gobind Singh Tricentenary University, Gurugram, Haryana, India
| | - Nancy Mathur
- Department of Pharmaceutical Chemistry, SGT College of Pharmacy, Shree Guru Gobind Singh Tricentenary University, Gurugram, Haryana, India
| |
Collapse
|
|
5
|
Liu S, Ma P, Zhang L, Shen S, Miao HJ, Liu L, Houk KN, Duan XH, Guo LN. A cheap metal catalyzed ring expansion/cross-coupling cascade: a new route to functionalized medium-sized and macrolactones. Chem Sci 2023; 14:5220-5225. [PMID: 37206389 PMCID: PMC10189895 DOI: 10.1039/d2sc06157k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 04/15/2023] [Indexed: 05/21/2023] Open
Abstract
An efficient alkoxyl radical-triggered ring expansion/cross-coupling cascade was developed under cheap metal catalysis. Through the metal-catalyzed radical relay strategy, a wide range of medium-sized lactones (9-11 membered) and macrolactones (12, 13, 15, 18, and 19-membered) were constructed in moderate to good yields, along with diverse functional groups including CN, N3, SCN, and X groups installed concurrently. Density functional theory (DFT) calculations revealed that reductive elimination of the cycloalkyl-Cu(iii) species is a more favorable reaction pathway for the cross-coupling step. Based on the results of experiments and DFT, a Cu(i)/Cu(ii)/Cu(iii) catalytic cycle is proposed for this tandem reaction.
Collapse
Affiliation(s)
- Shuai Liu
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
| | - Pengchen Ma
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
- Department of Chemistry and Biochemistry, University of California Los Angeles California 90095-1569 USA
| | - Lu Zhang
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
| | - Shenyu Shen
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
| | - Hong-Jie Miao
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
| | - Le Liu
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
| | - K N Houk
- Department of Chemistry and Biochemistry, University of California Los Angeles California 90095-1569 USA
| | - Xin-Hua Duan
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
| | - Li-Na Guo
- Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry and Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
| |
Collapse
|
|
6
|
Il’ina IV, Korchagina DV, Morozova EA, Tolstikova TG, Volcho KP, Salakhutdinov NF. Synthesis and analgesic activity of alkyl-substituted octahydro-2H-chromenols. Russ Chem Bull 2022. [DOI: 10.1007/s11172-022-3677-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
|
|
7
|
Guha S, Yussif El‐Deeb I, Yadav S, Das R, Dutta Dubey K, Baruah M, Ludovic G, Sen S. Capturing a Pentacyclic Fragment‐Based Library Derived from Perophoramidine: Their Design, Synthesis and Evaluation as Anticancer Compounds by DNA Double‐Strand Breaks (DSB) and PARP‐1 Inhibition. Chemistry 2022; 28:e202202405. [DOI: 10.1002/chem.202202405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Souvik Guha
- Department of Chemistry School of Natural Sciences Shiv Nadar University, Delhi NCR
| | | | - Shalini Yadav
- Department of Chemistry School of Natural Sciences Shiv Nadar University, Delhi NCR
| | - Ranajit Das
- Department of Chemistry School of Natural Sciences Shiv Nadar University, Delhi NCR
| | | | - Mousumi Baruah
- Department of Chemistry School of Natural Sciences Shiv Nadar University, Delhi NCR
| | - Gremaud Ludovic
- School of Engineering and Architecture Institute of Chemical Technology at University of Applied Sciences and Arts of Western Mumbai, Switzerland 1700 Fribourg Switzerland
| | - Subhabrata Sen
- Department of Chemistry School of Natural Sciences Shiv Nadar University, Delhi NCR
| |
Collapse
|
|
8
|
Phenolic compounds and antimicrobial properties of mint and thyme. J Herb Med 2022. [DOI: 10.1016/j.hermed.2022.100604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
|
|
9
|
Usami Y, Mizobuchi Y, Ijuin M, Yamada T, Morita M, Mizuki K, Yoneyama H, Harusawa S. Synthesis of 6-Halo-Substituted Pericosine A and an Evaluation of Their Antitumor and Antiglycosidase Activities. Mar Drugs 2022; 20:md20070438. [PMID: 35877731 PMCID: PMC9323573 DOI: 10.3390/md20070438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 06/25/2022] [Accepted: 06/28/2022] [Indexed: 11/16/2022] Open
Abstract
The enantiomers of 6-fluoro-, 6-bromo-, and 6-iodopericosine A were synthesized. An efficient synthesis of both enantiomers of pericoxide via 6-bromopericosine A was also developed. These 6-halo-substituted pericosine A derivatives were evaluated in terms of their antitumor activity against three types of tumor cells (p388, L1210, and HL-60) and glycosidase inhibitory activity. The bromo- and iodo-congeners exhibited moderate antitumor activity similar to pericosine A against the three types of tumor cell lines studied. The fluorinated compound was less active than the others, including pericosine A. In the antitumor assay, no significant difference in potency between the enantiomers was observed for any of the halogenated compounds. Meanwhile, the (−)-6-fluoro- and (−)-6-bromo-congeners inhibited α-glucosidase to a greater extent than those of their corresponding (+)-enantiomers, whereas (+)-iodopericosine A showed increased activity when compared to its (−)-enantiomer.
Collapse
Affiliation(s)
- Yoshihide Usami
- Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan; (Y.M.); (M.I.); (M.M.); (K.M.); (H.Y.); (S.H.)
- Correspondence: ; Tel.: +81-796-90-1087; Fax: +81-796-90-1005
| | - Yoshino Mizobuchi
- Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan; (Y.M.); (M.I.); (M.M.); (K.M.); (H.Y.); (S.H.)
| | - Mai Ijuin
- Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan; (Y.M.); (M.I.); (M.M.); (K.M.); (H.Y.); (S.H.)
| | - Takeshi Yamada
- Department of Medicinal Molecular Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan;
| | - Mizuki Morita
- Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan; (Y.M.); (M.I.); (M.M.); (K.M.); (H.Y.); (S.H.)
| | - Koji Mizuki
- Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan; (Y.M.); (M.I.); (M.M.); (K.M.); (H.Y.); (S.H.)
| | - Hiroki Yoneyama
- Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan; (Y.M.); (M.I.); (M.M.); (K.M.); (H.Y.); (S.H.)
| | - Shinya Harusawa
- Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara 4-20-1, Takatsuki 569-1094, Osaka, Japan; (Y.M.); (M.I.); (M.M.); (K.M.); (H.Y.); (S.H.)
| |
Collapse
|
|
10
|
Plastoquinone analogs: a potential antimicrobial lead structure intensely suppressing Staphylococcus epidermidis and Candida albicans growth. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02772-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
11
|
Li H, Hou YX, Yang Y, He QQ, Gao TH, Zhao XF, Huo ZB, Chen SB, Liu DX. Tetramethylpyrazine inhibits proliferation of colon cancer cells in vitro. World J Clin Cases 2021; 9:4542-4552. [PMID: 34222421 PMCID: PMC8223836 DOI: 10.12998/wjcc.v9.i18.4542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/27/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colon cancer is one of the most common malignancies worldwide, and chemotherapy is a widely used strategy in colon cancer clinical therapy. However, chemotherapy resistance is a major cause of disease recurrence and progression in colon cancer, and thus novel drugs for treatment are urgently needed. Tetramethylpyrazine (TMP), a component of the traditional Chinese medicine Chuanxiong Hort, has been proven to exhibit a beneficial effect in tumors.
AIM To investigate the potential anticancer activity of TMP in colon cancer and its underlying mechanisms.
METHODS Colon cancer cells were incubated with different concentrations of TMP. Cell viability was evaluated by crystal violet staining assay and cell counting kit-8 assay, and cell apoptosis and cell cycle were assessed by flow cytometry.
RESULTS TMP significantly inhibited the proliferation of colon cancer cells in a dose- and time-dependent manner. In addition, flow cytometry revealed that TMP induced cell cycle arrest at the G0/G1 phase. TMP treatment caused early stage apoptosis in SW480 cells, whereas it caused late stage apoptosis in HCT116 cells.
CONCLUSION Our studies demonstrated that TMP inhibits the proliferation of colon cancer cells in a dose- and time-dependent manner by inducing apoptosis and arresting the cell cycle at the G0/G1 phase. Our findings suggest that TMP might serve as a potential novel therapeutic drug in the treatment of human colon cancer.
Collapse
Affiliation(s)
- Hua Li
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Yan-Xu Hou
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Yu Yang
- School of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Qing-Qiang He
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Tian-Hua Gao
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Xiao-Feng Zhao
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Zhi-Bin Huo
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Shu-Bo Chen
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| | - Deng-Xiang Liu
- Institute of Cancer Control, Xingtai People’s Hospital, Xingtai 054001, Hebei Province, China
| |
Collapse
|
|
12
|
Porras G, Chassagne F, Lyles JT, Marquez L, Dettweiler M, Salam AM, Samarakoon T, Shabih S, Farrokhi DR, Quave CL. Ethnobotany and the Role of Plant Natural Products in Antibiotic Drug Discovery. Chem Rev 2021; 121:3495-3560. [PMID: 33164487 PMCID: PMC8183567 DOI: 10.1021/acs.chemrev.0c00922] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The crisis of antibiotic resistance necessitates creative and innovative approaches, from chemical identification and analysis to the assessment of bioactivity. Plant natural products (NPs) represent a promising source of antibacterial lead compounds that could help fill the drug discovery pipeline in response to the growing antibiotic resistance crisis. The major strength of plant NPs lies in their rich and unique chemodiversity, their worldwide distribution and ease of access, their various antibacterial modes of action, and the proven clinical effectiveness of plant extracts from which they are isolated. While many studies have tried to summarize NPs with antibacterial activities, a comprehensive review with rigorous selection criteria has never been performed. In this work, the literature from 2012 to 2019 was systematically reviewed to highlight plant-derived compounds with antibacterial activity by focusing on their growth inhibitory activity. A total of 459 compounds are included in this Review, of which 50.8% are phenolic derivatives, 26.6% are terpenoids, 5.7% are alkaloids, and 17% are classified as other metabolites. A selection of 183 compounds is further discussed regarding their antibacterial activity, biosynthesis, structure-activity relationship, mechanism of action, and potential as antibiotics. Emerging trends in the field of antibacterial drug discovery from plants are also discussed. This Review brings to the forefront key findings on the antibacterial potential of plant NPs for consideration in future antibiotic discovery and development efforts.
Collapse
Affiliation(s)
- Gina Porras
- Center for the Study of Human Health, Emory University, 1557 Dickey Dr., Atlanta, Georgia 30322
| | - François Chassagne
- Center for the Study of Human Health, Emory University, 1557 Dickey Dr., Atlanta, Georgia 30322
| | - James T. Lyles
- Center for the Study of Human Health, Emory University, 1557 Dickey Dr., Atlanta, Georgia 30322
| | - Lewis Marquez
- Molecular and Systems Pharmacology Program, Laney Graduate School, Emory University, 615 Michael St., Whitehead 115, Atlanta, Georgia 30322
| | - Micah Dettweiler
- Department of Dermatology, Emory University, 615 Michael St., Whitehead 105L, Atlanta, Georgia 30322
| | - Akram M. Salam
- Molecular and Systems Pharmacology Program, Laney Graduate School, Emory University, 615 Michael St., Whitehead 115, Atlanta, Georgia 30322
| | - Tharanga Samarakoon
- Emory University Herbarium, Emory University, 1462 Clifton Rd NE, Room 102, Atlanta, Georgia 30322
| | - Sarah Shabih
- Center for the Study of Human Health, Emory University, 1557 Dickey Dr., Atlanta, Georgia 30322
| | - Darya Raschid Farrokhi
- Center for the Study of Human Health, Emory University, 1557 Dickey Dr., Atlanta, Georgia 30322
| | - Cassandra L. Quave
- Center for the Study of Human Health, Emory University, 1557 Dickey Dr., Atlanta, Georgia 30322
- Emory University Herbarium, Emory University, 1462 Clifton Rd NE, Room 102, Atlanta, Georgia 30322
- Department of Dermatology, Emory University, 615 Michael St., Whitehead 105L, Atlanta, Georgia 30322
- Molecular and Systems Pharmacology Program, Laney Graduate School, Emory University, 615 Michael St., Whitehead 115, Atlanta, Georgia 30322
| |
Collapse
|
|
13
|
|
|
14
|
Motika SE, Hergenrother PJ. Re-engineering natural products to engage new biological targets. Nat Prod Rep 2020; 37:1395-1403. [PMID: 33034322 PMCID: PMC7720426 DOI: 10.1039/d0np00059k] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Covering: up to 2020 Natural products have a long history in drug discovery, with their inherent biological activity often tailored by medicinal chemists to arrive at the final drug product. This process is illustrated by numerous examples, including the conversion of epothilone to ixabepilone, erythromycin to azithromycin, and lovastatin to simvastatin. However, natural products are also fruitful starting points for the creation of complex and diverse compounds, especially those that are markedly different from the parent natural product and accordingly do not retain the biological activity of the parent. The resulting products have physiochemical properties that differ considerably when compared to traditional screening collections, thus affording an opportunity to discover novel biological activity. The synthesis of new structural frameworks from natural products thus yields value-added compounds, as demonstrated in the last several years with multiple biological discoveries emerging from these collections. This Highlight details a handful of these studies, describing new compounds derived from natural products that have biological activity and cellular targets different from those evoked/engaged by the parent. Such re-engineering of natural products offers the potential for discovering compounds with interesting and unexpected biological activity.
Collapse
Affiliation(s)
- Stephen E Motika
- Department of Chemistry, Institute for Genomic Biology, Cancer Center at Illinois, University of Illinois, Urbana-Champaign, USA.
| | - Paul J Hergenrother
- Department of Chemistry, Institute for Genomic Biology, Cancer Center at Illinois, University of Illinois, Urbana-Champaign, USA.
| |
Collapse
|
|
15
|
Relitti N, Saraswati AP, Chemi G, Brindisi M, Brogi S, Herp D, Schmidtkunz K, Saccoccia F, Ruberti G, Ulivieri C, Vanni F, Sarno F, Altucci L, Lamponi S, Jung M, Gemma S, Butini S, Campiani G. Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation. Eur J Med Chem 2020; 212:112998. [PMID: 33199154 DOI: 10.1016/j.ejmech.2020.112998] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/03/2020] [Accepted: 11/03/2020] [Indexed: 01/08/2023]
Abstract
In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.
Collapse
Affiliation(s)
- Nicola Relitti
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - A Prasanth Saraswati
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Giulia Chemi
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Margherita Brindisi
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy
| | - Daniel Herp
- Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104, Freiburg, Germany
| | - Karin Schmidtkunz
- Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104, Freiburg, Germany
| | - Fulvio Saccoccia
- Institute of Biochemistry and Cell Biology, CNR, Campus A. Buzzati-Traverso. Via E. Ramarini 32, 00015, Monterotondo, Rome, Italy
| | - Giovina Ruberti
- Institute of Biochemistry and Cell Biology, CNR, Campus A. Buzzati-Traverso. Via E. Ramarini 32, 00015, Monterotondo, Rome, Italy
| | - Cristina Ulivieri
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Francesca Vanni
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Federica Sarno
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Vico L. de Crecchio 7, 80138, Naples, Italy
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Vico L. de Crecchio 7, 80138, Naples, Italy
| | - Stefania Lamponi
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Manfred Jung
- Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104, Freiburg, Germany
| | - Sandra Gemma
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Stefania Butini
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Giuseppe Campiani
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.
| |
Collapse
|
|
16
|
Il’ina I, Morozova E, Pavlova A, Korchagina D, Tolstikova T, Volcho K, Salakhutdinov N. Synthesis and analgesic activity of aliphatic ketones-derived chiral hexahydro-2H-chromenes. Med Chem Res 2020. [DOI: 10.1007/s00044-020-02518-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
|
|
17
|
Nakayama A, Sato H, Nakamura T, Hamada M, Nagano S, Kameyama S, Furue Y, Hayashi N, Kamoshida G, Karanjit S, Oda M, Namba K. Synthesis and Antimicrobial Evaluation of Side-Chain Derivatives based on Eurotiumide A. Mar Drugs 2020; 18:E92. [PMID: 32019233 PMCID: PMC7074549 DOI: 10.3390/md18020092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 02/02/2023] Open
Abstract
Side-chain derivatives of eurotiumide A, a dihydroisochroman-type natural product, have been synthesized and their antimicrobial activities described. Sixteen derivatives were synthesized from a key intermediate of the total synthesis of eurotiumide A, and their antimicrobial activities against two Gram-positive bacteria, methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), and a Gram-negative bacterium, Porphyromonas gingivalis, were evaluated. The results showed that derivatives having an iodine atom on their aromatic ring instead of the prenyl moiety displayed better antimicrobial activity than eurotiumide A against MSSA and P. gingivalis. Moreover, we discovered that a derivative with an isopentyl side chain, which is a hydrogenated product of eurotiumide A, is the strongest antimicrobial agent against all three strains, including MRSA.
Collapse
Affiliation(s)
- Atsushi Nakayama
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| | - Hideo Sato
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| | - Tenta Nakamura
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| | - Mai Hamada
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| | - Shuji Nagano
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| | - Shuhei Kameyama
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| | - Yui Furue
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Misasaginakauchi-cho, Yamashita-Ku, Kyoto 607-8414, Japan; (Y.F.); (N.H.); (G.K.)
| | - Naoki Hayashi
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Misasaginakauchi-cho, Yamashita-Ku, Kyoto 607-8414, Japan; (Y.F.); (N.H.); (G.K.)
| | - Go Kamoshida
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Misasaginakauchi-cho, Yamashita-Ku, Kyoto 607-8414, Japan; (Y.F.); (N.H.); (G.K.)
| | - Sangita Karanjit
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| | - Masataka Oda
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Misasaginakauchi-cho, Yamashita-Ku, Kyoto 607-8414, Japan; (Y.F.); (N.H.); (G.K.)
| | - Kosuke Namba
- Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan; (H.S.); (T.N.); (M.H.); (S.N.); (S.K.); (S.K.)
| |
Collapse
|
|
18
|
Amer MM, Olaizola O, Carter J, Abas H, Clayden J. An Aliphatic Bischler-Napieralski Reaction: Dihydropyridones by Cyclocarbonylation of 3-Allylimidazolidin-4-ones. Org Lett 2020; 22:253-256. [PMID: 31846338 DOI: 10.1021/acs.orglett.9b04250] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The N-chloroformylimidazolidinone derivative of enantiopure l-alanine was deprotonated to form an enolate and functionalized with a series of allylic halides. Treatment of the resulting carbamoyl chlorides with potassium iodide led to cyclization of the allylic substituent onto the carbonyl group in an intramolecular aliphatic Friedel-Crafts-type acylation that corresponds to an aliphatic Bischler-Napieralski reaction. The product 3,4-dihydropyridinones were amenable to further functionalization, and finally hydrolysis, to deliver a series of enantio-enriched pipecolic acid derivatives.
Collapse
Affiliation(s)
- Mostafa M Amer
- School of Chemistry , University of Bristol , Cantock's Close, Bristol BS8 1TS , United Kingdom
| | - Olatz Olaizola
- School of Chemistry , University of Bristol , Cantock's Close, Bristol BS8 1TS , United Kingdom
| | - Jennifer Carter
- School of Chemistry , University of Bristol , Cantock's Close, Bristol BS8 1TS , United Kingdom
| | - Hossay Abas
- School of Chemistry , University of Bristol , Cantock's Close, Bristol BS8 1TS , United Kingdom
| | - Jonathan Clayden
- School of Chemistry , University of Bristol , Cantock's Close, Bristol BS8 1TS , United Kingdom
| |
Collapse
|
|
19
|
Synthesis, in-vitro antiprotozoal activity and molecular docking study of isothiocyanate derivatives. Bioorg Med Chem 2020; 28:115185. [DOI: 10.1016/j.bmc.2019.115185] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 10/12/2019] [Accepted: 10/25/2019] [Indexed: 11/22/2022]
|
|
20
|
Il'ina I, Morozova E, Korсhagina D, Volсho K, Tolstikova T, Salakhutdinov N. Synthesis and Analgesic Activity of Monoterpenoid Aldehyde-derived Hydro-2H-chromeneols. LETT DRUG DES DISCOV 2019. [DOI: 10.2174/1570180816666181114131220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Despite a variety of drugs used to stop acute pain, problems related to their
insufficient efficacy and undesirable side effects have remained unresolved. Therefore, the search for
analgesics of new structural types, which combine high activity with low toxicity, is a topical issue.
It is known that a number of compounds with a hydrogenated 2H-chromene skeleton exhibit
significant analgesic activity in in vivo tests.
Methods:
New hydro-2H-chromenols containing monoterpenoid moieties were obtained via one-pot
synthesis by the interaction between para-menthane alcohols and commercially available
monoterpene aldehydes: Citral, hydroxycitronellal, myrtenal, and perillaldehyde. The analgesic
activity of these compounds wаs studied in the acetic acid-induced writhing test and hot plate test.
Results:
The target compounds were characterized using NMR and HR-MS. Most of them exhibited
pronounced analgesic activity.
Conclusion:
Due to high analgesic activity, (2S,4aR,8R,8aR)-2-((E)-2,6-dimethylhepta-1,5-dien-1-
yl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol is considered as candidate compound
to participate in further research.
Collapse
Affiliation(s)
- Irina Il'ina
- N.N. Vorozhtsov Novosibirsk Institute of Organiс Сhemistry, Siberian Branсh, Russian Aсademy of Sсienсes, Lavrentjev Avenue, 9, 630090 Novosibirsk, Russian Federation
| | - Ekaterina Morozova
- N.N. Vorozhtsov Novosibirsk Institute of Organiс Сhemistry, Siberian Branсh, Russian Aсademy of Sсienсes, Lavrentjev Avenue, 9, 630090 Novosibirsk, Russian Federation
| | - Dina Korсhagina
- N.N. Vorozhtsov Novosibirsk Institute of Organiс Сhemistry, Siberian Branсh, Russian Aсademy of Sсienсes, Lavrentjev Avenue, 9, 630090 Novosibirsk, Russian Federation
| | - Konstantin Volсho
- N.N. Vorozhtsov Novosibirsk Institute of Organiс Сhemistry, Siberian Branсh, Russian Aсademy of Sсienсes, Lavrentjev Avenue, 9, 630090 Novosibirsk, Russian Federation
| | - Tat'yana Tolstikova
- N.N. Vorozhtsov Novosibirsk Institute of Organiс Сhemistry, Siberian Branсh, Russian Aсademy of Sсienсes, Lavrentjev Avenue, 9, 630090 Novosibirsk, Russian Federation
| | - Nariman Salakhutdinov
- N.N. Vorozhtsov Novosibirsk Institute of Organiс Сhemistry, Siberian Branсh, Russian Aсademy of Sсienсes, Lavrentjev Avenue, 9, 630090 Novosibirsk, Russian Federation
| |
Collapse
|
|
21
|
Arreaga-González HM, Rodríguez-García G, Del Río RE, Ferreira-Sereno JA, García-Gutiérrez HA, Cerda-García-Rojas CM, Joseph-Nathan P, Gómez-Hurtado MA. Configurational Variation of a Natural Compound within Its Source Species. The Unprecedented Case of Areolal in Piptothrix areolare. JOURNAL OF NATURAL PRODUCTS 2019; 82:3394-3400. [PMID: 31751133 DOI: 10.1021/acs.jnatprod.9b00734] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The exceptional case of a natural compound that shows drastic absolute configuration variations within the same species was examined. Sequential samples of areolal (1) isolated from Piptothrix areolare showed dextrorotatory (ee 32%), almost racemic (ee 4%), levorotatory (ee 82%), and again dextrorotatory (ee 10%) values. Enantiomeric compositions of this epoxythymol derivative were determined from individual plant specimens collected from the same geographical location over a 46-day period, which were processed using the same extraction and isolation methods. Detection of this unusual phenomenon was possible by analysis of NMR data recorded in the presence of BINOL as a chiral solvating agent. The absolute configuration of (-)-(8S)-areolal followed from vibrational circular dichroism data of an enantiomerically enriched sample, while single-crystal X-ray diffraction and supramolecular analyses revealed interactions that diminish the crystal entropy in rac-1. These results might be related with environmental factors and biochemical processes, suggesting the need of strict evaluations of enantiomeric composition of natural products that could be considered for human applications.
Collapse
Affiliation(s)
- Héctor M Arreaga-González
- Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo , Ciudad Universitaria , Morelia , Michoacán 58030 , Mexico
| | - Gabriela Rodríguez-García
- Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo , Ciudad Universitaria , Morelia , Michoacán 58030 , Mexico
| | - Rosa E Del Río
- Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo , Ciudad Universitaria , Morelia , Michoacán 58030 , Mexico
| | - José A Ferreira-Sereno
- Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo , Ciudad Universitaria , Morelia , Michoacán 58030 , Mexico
| | - Hugo A García-Gutiérrez
- Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo , Ciudad Universitaria , Morelia , Michoacán 58030 , Mexico
| | - Carlos M Cerda-García-Rojas
- Departamento de Química , Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional , Apartado 14-740 , Mexico City 07000 , Mexico
| | - Pedro Joseph-Nathan
- Departamento de Química , Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional , Apartado 14-740 , Mexico City 07000 , Mexico
| | - Mario A Gómez-Hurtado
- Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo , Ciudad Universitaria , Morelia , Michoacán 58030 , Mexico
| |
Collapse
|
|
22
|
Anand U, Jacobo-Herrera N, Altemimi A, Lakhssassi N. A Comprehensive Review on Medicinal Plants as Antimicrobial Therapeutics: Potential Avenues of Biocompatible Drug Discovery. Metabolites 2019; 9:E258. [PMID: 31683833 PMCID: PMC6918160 DOI: 10.3390/metabo9110258] [Citation(s) in RCA: 321] [Impact Index Per Article: 53.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/23/2019] [Accepted: 10/28/2019] [Indexed: 12/16/2022] Open
Abstract
The war on multidrug resistance (MDR) has resulted in the greatest loss to the world's economy. Antibiotics, the bedrock, and wonder drug of the 20th century have played a central role in treating infectious diseases. However, the inappropriate, irregular, and irrational uses of antibiotics have resulted in the emergence of antimicrobial resistance. This has resulted in an increased interest in medicinal plants since 30-50% of current pharmaceuticals and nutraceuticals are plant-derived. The question we address in this review is whether plants, which produce a rich diversity of secondary metabolites, may provide novel antibiotics to tackle MDR microbes and novel chemosensitizers to reclaim currently used antibiotics that have been rendered ineffective by the MDR microbes. Plants synthesize secondary metabolites and phytochemicals and have great potential to act as therapeutics. The main focus of this mini-review is to highlight the potential benefits of plant derived multiple compounds and the importance of phytochemicals for the development of biocompatible therapeutics. In addition, this review focuses on the diverse effects and efficacy of herbal compounds in controlling the development of MDR in microbes and hopes to inspire research into unexplored plants with a view to identify novel antibiotics for global health benefits.
Collapse
Affiliation(s)
- Uttpal Anand
- Department of Molecular and Cellular Engineering (MCE), Jacob Institute of Biotechnology and Bioengineering (JIBB), Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj (Allahabad), Uttar Pradesh 211007, India.
| | - Nadia Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Av. Vasco de Quiroga 15. Col. Belisario Domínguez Sección XVI. C.P. Tlalpan, Ciudad de México 14080, Mexico.
| | - Ammar Altemimi
- Department of Food Science, College of Agriculture, University of Basrah, Basrah 61004, Iraq.
| | - Naoufal Lakhssassi
- Department of Plant, Soil and Agricultural Systems, Southern Illinois University, Carbondale, IL 62901, USA.
| |
Collapse
|
|
23
|
Gatadi S, Gour J, Nanduri S. Natural product derived promising anti-MRSA drug leads: A review. Bioorg Med Chem 2019; 27:3760-3774. [DOI: 10.1016/j.bmc.2019.07.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/07/2019] [Accepted: 07/11/2019] [Indexed: 12/20/2022]
|
|
24
|
Novel steroidal 1,3,4-thiadiazines: Synthesis and biological evaluation in androgen receptor-positive prostate cancer 22Rv1 cells. Bioorg Chem 2019; 91:103142. [PMID: 31400555 DOI: 10.1016/j.bioorg.2019.103142] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/17/2019] [Accepted: 07/19/2019] [Indexed: 12/20/2022]
Abstract
A flexible approach to previously unknown spirofused and linked 1,3,4-thiadiazine derivatives of steroids with selective control of heterocyclization patterns is disclosed. (N-Arylcarbamoyl)spiroandrostene-17,6' [1,3,4]thiadiazines and (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes, novel types of heterosteroids, were prepared from 16β,17β-epoxypregnenolone and 21-bromopregna-5,16-dien-20-one in good to high yields by the treatment with oxamic acid thiohydrazides. The synthesized compounds were screened for antiproliferative activity against the human androgen receptor-positive prostate cancer cell line 22Rv1. Most of (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes exhibit better antiproliferative potency (IC50 = 2.1-6.6 µM) than the antiandrogen bicalutamide. Compounds 7d with IC50 = 3.0 μM and 7j with IC50 = 2.1 μM proved to be the most active in the series under study. Lead synthesized compound 7j downregulates AR expression and activity in 22Rv1 cells. NF-κB activity is also blocked in 7j-treated 22Rv1 cells. Apoptosis is considered as a possible mechanism of 7j-induced cell death.
Collapse
|
|
25
|
N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis, antiparasitic activity and molecular docking study. Bioorg Chem 2019; 91:103116. [PMID: 31377384 DOI: 10.1016/j.bioorg.2019.103116] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 07/03/2019] [Accepted: 07/10/2019] [Indexed: 11/21/2022]
Abstract
Novel N-substituted noscapine derivatives were synthesized by a three-component Strecker reaction of cyclic ether of N-nornoscapine with varied aldehydes, in the presence of cyanide ion. Moreover, the corresponding amides were synthesized by the oxidation of cyanide moieties in good yields. The in vitro antiprotozoal activity of the products was also investigated. Interestingly, some analogues did put on display promising antiparasitic activity against Trypanosoma brucei rhodesiense with IC50 values between 2.5 and 10.0 µM and selectivity index (SI) ranged from 0.8 to 13.2. Eight compounds exhibited activity against Plasmodium falciparum K1 strain with IC50 ranging 1.7-6.4 µM, and SI values between 2.8 and 10.5 against L6 rat myoblast cell lines. Molecular docking was carried out on trypanothione reductase (TbTR, PDB ID: 2WOW) and UDP-galactose 4' epimerase (TbUDPGE PDB: 1GY8) as targets for studying the envisaged mechanism of action. Compounds 6j2 and 6b2 displayed excellent docking scores with -8.59 and -8.86 kcal/mol for TbTR and TbUDPGE, respectively.
Collapse
|
|
26
|
Li J, Nie C, Qiao Y, Hu J, Li Q, Wang Q, Pu X, Yan L, Qian H. Design, synthesis and biological evaluation of novel 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole triazole derivatives as potent TRPV1 antagonists. Eur J Med Chem 2019; 178:433-445. [PMID: 31202991 DOI: 10.1016/j.ejmech.2019.06.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/03/2019] [Accepted: 06/03/2019] [Indexed: 10/26/2022]
Abstract
Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as A-region and triazole as B-region. The SAR analysis indicated that 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed better potency compared to the corresponding dihydroindole analogues. Optimization of this design led to the eventual identification of 2-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6g), a potent TRPV1 antagonist. In vitro, using cells expressing recombinant human TRPV1 channels, 6g displayed potent antagonism activated by capsaicin (IC50 = 0.075 μM) and only partially blocked acid activation of TRPV1. In vivo, 6g exhibited good efficacy in capsaicin-induced and heat-induced pain models and had almost no hyperthermia side-effect. Furthermore, pharmacokinetic studies revealed that compound 6g had a superior oral exposure after oral administration in rats. To understand its binding interactions with the receptor, the docking study of 6g was performed in rTRPV1 model and showed an excellent fit to the binding site. On the basis of its superior profiles, 6g could be considered as the lead candidate for the further development of antinociceptive drugs.
Collapse
Affiliation(s)
- Jinyu Li
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China
| | - Cunbin Nie
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China
| | - Yue Qiao
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China
| | - Jing Hu
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China
| | - Qifei Li
- State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China
| | - Qiang Wang
- School of Pharmaceutical Sciences, South-Central University for Nationalities, 182 Minyuan Road, Wuhan, Hubei, 430074, China
| | - Xiaohui Pu
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China
| | - Lin Yan
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China.
| | - Hai Qian
- State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China.
| |
Collapse
|
|
27
|
Kiefer A, Bader CD, Held J, Esser A, Rybniker J, Empting M, Müller R, Kazmaier U. Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards
Mycobacterium Tuberculosis
and
Plasmodium Falciparum. Chemistry 2019; 25:8894-8902. [DOI: 10.1002/chem.201901640] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Indexed: 01/03/2023]
Affiliation(s)
- Alexander Kiefer
- Organic ChemistrySaarland University Campus C4.2 66123 Saarbrücken Germany
| | - Chantal D. Bader
- Department Microbial Natural Products (MINS)Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)–Helmholtz Centre for Infection Research (HZI) Campus E8.1 66123 Saarbrücken Germany
| | - Jana Held
- Department of Tropical MedicineUniversity of Tübingen Wilhelmstraße 27 72074 Tübingen Germany
| | - Anna Esser
- Center for Molecular Medicine CologneUniversity of Cologne Robert Koch Str. 21 50931 Cologne Germany
| | - Jan Rybniker
- Department I of Internal MedicineUniversity of Cologne 50937 Cologne (Germany) and German Center for Infection Research (DZIF), Partner Site Bonn-Cologne Germany
| | - Martin Empting
- Department of Drug Design and Optimization (DDOP)Helmholtz-Institute for Pharmaceutical Research Saarland, (HIPS)–Helmholtz Centre for Infection Research (HZI) Campus E8.1 66123 Saarbrücken Germany
| | - Rolf Müller
- Department Microbial Natural Products (MINS)Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)–Helmholtz Centre for Infection Research (HZI) Campus E8.1 66123 Saarbrücken Germany
- Department of PharmacySaarland University Campus E8.1 66123 Saarbrücken Germany
| | - Uli Kazmaier
- Organic ChemistrySaarland University Campus C4.2 66123 Saarbrücken Germany
| |
Collapse
|
|
28
|
Okolo C, Ali MA, Newman M, Chambers SA, Whitt J, Alsharif ZA, Day VW, Alam MA. Hexafluoroisopropanol-Mediated Domino Reaction for the Synthesis of Thiazolo-androstenones: Potent Anticancer Agents. ACS OMEGA 2018; 3:17991-18001. [PMID: 30613817 PMCID: PMC6312635 DOI: 10.1021/acsomega.8b02840] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 12/12/2018] [Indexed: 05/02/2023]
Abstract
A cascade reaction of thioamides with 6β-bromoandrostenedione in hexafluoroisopropanol formed substituted thiazolo-androstenones. This is a simple and mild protocol to synthesize novel molecules by using readily available reagents and substrates. Feasibility of the reaction has been rationalized by density functional theory calculations. Moreover, these compounds are potent growth inhibitors of colon, central nervous system, melanoma, ovarian, and renal cancer cell lines with 50% growth inhibition values as low as 1.04 μM.
Collapse
Affiliation(s)
- ChrisTina Okolo
- Department
of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas 72467, United States
| | - Mohamad Akbar Ali
- Department
of Chemistry, Sejong University, Seoul 143-747, Republic of Korea
| | - Matthew Newman
- Department
of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas 72467, United States
| | - Steven A. Chambers
- Department
of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas 72467, United States
| | - Jedidiah Whitt
- Department
of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas 72467, United States
| | - Zakeyah A. Alsharif
- Department
of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas 72467, United States
| | - Victor W. Day
- Department
of Chemistry, Integrated Science Building, University of Kansas, Lawrence, Kansas 66046, United States
| | - Mohammad A. Alam
- Department
of Chemistry and Physics, College of Science and Mathematics, Arkansas State University, Jonesboro, Arkansas 72467, United States
- E-mail:
| |
Collapse
|
|
29
|
Salam AM, Quave CL. Opportunities for plant natural products in infection control. Curr Opin Microbiol 2018; 45:189-194. [PMID: 30218951 DOI: 10.1016/j.mib.2018.08.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023]
Abstract
The continued spread of antimicrobial resistance represents one of the most serious infectious disease threats to global health. There is consensus that a key component of addressing this threat is to replenish the waning pipeline of antimicrobials, with attention being paid to novel mechanisms of action. This includes the development of new classes of classic bacteriostatic and bactericidal antibiotics as well as antivirulence drugs, and it is especially in these areas where plant natural products demonstrate great potential. To this end, we discuss the unique characteristics of plant natural products, the advantages of plants as a resource for anti-infective drug discovery, and recent technologies that have further enabled this path of inquiry. As a result of emerging realization of their advantages, plant natural products have recently enjoyed increased scrutiny in antimicrobial lead discovery, and they will continue to serve as a source of leads. We conclude that plant natural products represent a promising and largely untapped source of new chemical entities from which novel anti-infectives can be discovered.
Collapse
Affiliation(s)
- Akram M Salam
- Molecular and Systems Pharmacology Program, Laney Graduate School, Emory University, Atlanta, GA, United States
| | - Cassandra L Quave
- Center for the Study of Human Health, Emory University College of Arts and Sciences, Atlanta, GA, United States; Department of Dermatology, Emory University School of Medicine, Atlanta, GA, United States; Antibiotic Resistance Center, Emory University, Atlanta, GA, United States; Emory University Herbarium, Atlanta, GA, United States.
| |
Collapse
|
|
30
|
Ali MA, Okolo C, Alsharif ZA, Whitt J, Chambers SA, Varma RS, Alam MA. Benign Synthesis of Thiazolo-androstenone Derivatives as Potent Anticancer Agents. Org Lett 2018; 20:5927-5932. [PMID: 30204455 DOI: 10.1021/acs.orglett.8b02587] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
An unprecedented reaction of thiourea derivatives with 6β-bromoandrostenedione has been discovered for the formation of aminothiazolo-androstenones via a simple, safer, cascade protocol that enables the syntheses of novel molecules by using readily available reagents. The reaction mechanism of product formation has been rationalized by density functional theory calculations. This benign methodology accentuates a domino protocol deploying a renewable solvent, ethanol, while generating novel compounds that display potent growth inhibitory effects in in vitro studies for several cancer cell lines at submicromolar concentrations.
Collapse
Affiliation(s)
- Mohamad Akbar Ali
- Department of Chemistry , Sejong University , Seoul 143-747 , Republic of Korea
| | - ChrisTina Okolo
- Department of Chemistry and Physics, College of Science and Mathematics , Arkansas State University , Jonesboro , Arkansas 72467 , United States
| | - Zakeyah A Alsharif
- Department of Chemistry and Physics, College of Science and Mathematics , Arkansas State University , Jonesboro , Arkansas 72467 , United States
| | - Jedidiah Whitt
- Department of Chemistry and Physics, College of Science and Mathematics , Arkansas State University , Jonesboro , Arkansas 72467 , United States
| | - Steven A Chambers
- Department of Chemistry and Physics, College of Science and Mathematics , Arkansas State University , Jonesboro , Arkansas 72467 , United States
| | - Rajender S Varma
- Regional Center of Advanced Technologies and Materials, Faculty of Science , Palacký University , Olomouc, Šlechtitelů 27 , 783 71 Olomouc , Czech Republic
| | - Mohammad A Alam
- Department of Chemistry and Physics, College of Science and Mathematics , Arkansas State University , Jonesboro , Arkansas 72467 , United States
| |
Collapse
|
|
31
|
Takahashi K, Fukushima K, Seto M, Togashi A, Arai Y, Tsubuki M, Honda T. Studies on Instructive Construction of exo-Olefin Terminated Five- and Six-Membered Nitrogen Heterocycles: SmI 2-Mediated Intramolecular Cyclization of Haloalkynals. J Org Chem 2018; 83:10636-10645. [PMID: 30044913 DOI: 10.1021/acs.joc.8b01440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Stereoselective construction of exo-olefin terminated pyrrolidine and piperidine frameworks was developed by employing SmI2-mediated intramolecular radical cyclization of haloalkynaks. The radical cyclization affording 2,3-disubstituted pyrrolidines and piperidines proceeded in a highly stereoselective manner. However, decreasing stereoselectivety was observed in the preparation of 2,4-disubstituted pyrrolidine and 3,4-disubstituted piperidine derivatives in the cyclization.
Collapse
Affiliation(s)
| | - Kei Fukushima
- Hoshi University , 2-4-41 Ebara , Shinagawa-ku , Tokyo 142-8501 , Japan
| | - Marina Seto
- Hoshi University , 2-4-41 Ebara , Shinagawa-ku , Tokyo 142-8501 , Japan
| | - Azusa Togashi
- Hoshi University , 2-4-41 Ebara , Shinagawa-ku , Tokyo 142-8501 , Japan
| | - Yuichi Arai
- Hoshi University , 2-4-41 Ebara , Shinagawa-ku , Tokyo 142-8501 , Japan
| | - Masayoshi Tsubuki
- Hoshi University , 2-4-41 Ebara , Shinagawa-ku , Tokyo 142-8501 , Japan
| | - Toshio Honda
- Hoshi University , 2-4-41 Ebara , Shinagawa-ku , Tokyo 142-8501 , Japan
| |
Collapse
|
|
32
|
Shang J, Hu B, Wang J, Zhu F, Kang Y, Li D, Sun H, Kong DX, Hou T. Cheminformatic Insight into the Differences between Terrestrial and Marine Originated Natural Products. J Chem Inf Model 2018; 58:1182-1193. [PMID: 29792805 DOI: 10.1021/acs.jcim.8b00125] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This is a new golden age for drug discovery based on natural products derived from both marine and terrestrial sources. Herein, a straightforward but important question is "what are the major structural differences between marine natural products (MNPs) and terrestrial natural products (TNPs)?" To answer this question, we analyzed the important physicochemical properties, structural features, and drug-likeness of the two types of natural products and discussed their differences from the perspective of evolution. In general, MNPs have lower solubility and are often larger than TNPs. On average, particularly from the perspective of unique fragments and scaffolds, MNPs usually possess more long chains and large rings, especially 8- to 10-membered rings. MNPs also have more nitrogen atoms and halogens, notably bromines, and fewer oxygen atoms, suggesting that MNPs may be synthesized by more diverse biosynthetic pathways than TNPs. Analysis of the frequently occurring Murcko frameworks in MNPs and TNPS also reveals a striking difference between MNPs and TNPs. The scaffolds of the former tend to be longer and often contain ester bonds connected to 10-membered rings, while the scaffolds of the latter tend to be shorter and often bear more stable ring systems and bond types. Besides, the prediction from the naïve Bayesian drug-likeness classification model suggests that most compounds in MNPs and TNPs are drug-like, although MNPs are slightly more drug-like than TNPs. We believe that MNPs and TNPs with novel drug-like scaffolds have great potential to be drug leads or drug candidates in drug discovery campaigns.
Collapse
Affiliation(s)
- Jun Shang
- College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China.,State Key Laboratory of Agricultural Microbiology and Agricultural Bioinformatics, Key Laboratory of Hubei Province, College of Informatics , Huazhong Agricultural University , Wuhan 430070 , China.,State Key Lab of CAD&CG , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - Ben Hu
- State Key Laboratory of Agricultural Microbiology and Agricultural Bioinformatics, Key Laboratory of Hubei Province, College of Informatics , Huazhong Agricultural University , Wuhan 430070 , China
| | - Junmei Wang
- Department of Pharmaceutical Sciences , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States
| | - Feng Zhu
- College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - Yu Kang
- College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - Dan Li
- College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - Huiyong Sun
- College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| | - De-Xin Kong
- State Key Laboratory of Agricultural Microbiology and Agricultural Bioinformatics, Key Laboratory of Hubei Province, College of Informatics , Huazhong Agricultural University , Wuhan 430070 , China
| | - Tingjun Hou
- College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China.,State Key Lab of CAD&CG , Zhejiang University , Hangzhou , Zhejiang 310058 , China
| |
Collapse
|
|
33
|
Fuentes-Aguilar A, Romero-Hernández LL, Arenas-González A, Merino-Montiel P, Montiel-Smith S, Meza-Reyes S, Vega-Báez JL, Plata GB, Padrón JM, López Ó, Fernández-Bolaños JG. New selenosteroids as antiproliferative agents. Org Biomol Chem 2018; 15:5041-5054. [PMID: 28574071 DOI: 10.1039/c7ob00458c] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Starting from natural steroids (diosgenin, hecogenin, smilagenin, estrone), we have prepared a wide panel of selenoderivatives, including benzoselenazolones, selenosemicarbazones, isoselenocyanates, selenoureas, selenocyanates and diselenides, with the aim of developing new families of potential chemotherapeutic agents. The modification of the organoselenium moieties, and their position on the steroid provided valuable information concerning the antiproliferative activities. Among all the families accessed herein, the best profile was achieved for selenoureas on the A ring of estrone, which exhibited GI50 values in the range 2.0-4.1 μM for all the tested tumor cell lines, with increased potency compared with commonly used chemotherapeutic agents, like 5-fluorouracil and cisplatin. Cell cycle analysis revealed that selenoureas induced accumulation of cells in the G1 phase of the cell cycle in the breast cancer cell lines HBL-100 and T-47D; therefore, a different mechanism than cisplatin, that induces cell cycle accumulation in the S phase as a result of DNA damage, must be involved. In the rest of the tumor cells, a slight increase of the S compartment was observed. Moreover, selenosteoids turned out to be excellent glutathione peroxidase (GPx) mimics for the catalytic removal of deleterious H2O2 (t1/2 8.0-22.5 min) and alkyl peroxides (t1/2 23.0-38.9 min) when used in substoichiometric amounts (1% molar ratio), thus providing a valuable tool for reducing the intrinsic oxidative stress in tumor progression.
Collapse
Affiliation(s)
- Alma Fuentes-Aguilar
- Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, PUE, Mexico.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Kim J, Kim I. Design and synthesis of a hybrid framework of indanone and chromane: total synthesis of a homoisoflavanoid, brazilane. Org Biomol Chem 2017; 16:89-100. [PMID: 29192699 DOI: 10.1039/c7ob02758c] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
A chemical backbone of tetracyclic homoisoflavanoid natural products such as brazilin inspired us to design a new chemical scaffold, 6a,11b-dihydroindeno[2,1-c]chromen-7(6H)-one, which is a hybrid structure of indanone and chromane. Pd-catalyzed Suzuki-Miyaura cross-coupling of 4-chloro-2H-chromene-3-carbaldehydes with (hetero)aryl boronic acids was employed as a means to introduce a wide variety of (hetero)aryl groups as the D ring and intramolecular Friedel-Crafts acylation was utilized to construct the C ring of this skeleton. Total synthesis of the natural product, brazilane, was also demonstrated via this new chemical framework.
Collapse
Affiliation(s)
- Jinwoo Kim
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
| | | |
Collapse
|
|
35
|
von Delius M, Le CM, Ellinger B, Kuzikov M, Gul S, Dong VM. Synthesis and Biological Activity of Octaketides from the Cytosporone Family. Isr J Chem 2017. [DOI: 10.1002/ijch.201700023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Max von Delius
- Institute of Organic Chemistry and Advanced Materials; University of Ulm; Albert-Einstein-Allee 11 89081 Ulm Germany
| | - Christine M. Le
- Department of Chemistry; University of Toronto; 80 St. George Street Toronto, Ontario M5S 3H6 Canada
| | - Bernhard Ellinger
- Fraunhofer Institute for Molecular Biology and Applied Ecology - ScreeningPort (Fraunhofer-IME SP); Schnackenburgallee 114 D-22525 Hamburg Germany
| | - Maria Kuzikov
- Fraunhofer Institute for Molecular Biology and Applied Ecology - ScreeningPort (Fraunhofer-IME SP); Schnackenburgallee 114 D-22525 Hamburg Germany
| | - Sheraz Gul
- Fraunhofer Institute for Molecular Biology and Applied Ecology - ScreeningPort (Fraunhofer-IME SP); Schnackenburgallee 114 D-22525 Hamburg Germany
| | - Vy M. Dong
- Department of Chemistry; University of California Irvine; 4403 Natural Sciences 1 Irvine, California 92697 USA
| |
Collapse
|
|
36
|
Brown TK, Alper K. Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2017; 44:24-36. [PMID: 28541119 DOI: 10.1080/00952990.2017.1320802] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. OBJECTIVES To study outcomes following opioid detoxification with ibogaine. METHODS In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respective amounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes of treatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 months were evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity Index Composite (ASIC) scores, respectively. RESULTS SOWS scores decreased from 31.0 ± 11.6 pretreatment to 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatment follow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use and Legal and Family/Social Status scores were improved relative to pretreatment baseline at all posttreatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, and subsequently sustained from 3 to 12 months at levels that did not reach equivalence to the effect at 1 month. CONCLUSION Ibogaine was associated with substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful, and may provide a useful prototype for discovery and development of innovative pharmacotherapy of addiction.
Collapse
Affiliation(s)
| | - Kenneth Alper
- b Departments of Psychiatry and Neurology , New York University School of Medicine , New York , NY , USA
| |
Collapse
|
|
37
|
Abstract
Covering: July 2012 to June 2015. Previous review: Nat. Prod. Rep., 2013, 30, 869-915The structurally diverse imidazole-, oxazole-, and thiazole-containing secondary metabolites are widely distributed in terrestrial and marine environments, and exhibit extensive pharmacological activities. In this review the latest progress involving the isolation, biological activities, and chemical and biogenetic synthesis studies on these natural products has been summarized.
Collapse
Affiliation(s)
- Zhong Jin
- State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
| |
Collapse
|
|
38
|
Il’ina I, Pavlova A, Korchagina D, Ardashov O, Tolstikova T, Volcho K, Salakhutdinov N. Synthesis and analgesic activity of monoterpenoid-derived alkyl-substituted chiral hexahydro-2H-chromenes. Med Chem Res 2017. [DOI: 10.1007/s00044-017-1847-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
39
|
Hemmaragala NM, Abrahamse H, George BP. Effect of GNP functionalisation and multiple
N
‐methylation of
β
‐amyloid residue (32–37) on Gram‐positive bacterium. IET Nanobiotechnol 2017; 11:377-382. [DOI: 10.1049/iet-nbt.2016.0083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
| | - Heidi Abrahamse
- Laser Research CentreFaculty of Health SciencesUniversity of JohannesburgP.O. Box 17011Doornfontein 2028South Africa
| | - Blassan P. George
- Laser Research CentreFaculty of Health SciencesUniversity of JohannesburgP.O. Box 17011Doornfontein 2028South Africa
| |
Collapse
|
|
40
|
Kotoku N, Ito A, Shibuya S, Mizuno K, Takeshima A, Nogata M, Kobayashi M. Short-step synthesis and structure-activity relationship of cortistatin A analogs. Tetrahedron 2017. [DOI: 10.1016/j.tet.2017.01.042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
|
|
41
|
Ren Y, Yu J, Kinghorn AD. Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones. Curr Med Chem 2017; 23:2397-420. [PMID: 27160533 DOI: 10.2174/0929867323666160510123255] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 04/26/2016] [Accepted: 05/09/2016] [Indexed: 12/24/2022]
Abstract
Sesquiterpene lactones are of considerable interest due to their potent bioactivities, including cancer cell cytotoxicity and antineoplastic efficacy in in vivo studies. Among these compounds, artesunate, dimethylaminoparthenolide, and L12ADT peptide prodrug, a derivative of thapsigargin, are being evaluated in the current cancer clinical or preclinical trials. Based on the structures of several antitumor sesquiterpene lactones, a number of analogues showing greater potency have been either isolated as natural products or partially synthesized, and some potential anticancer agents that have emerged from this group of lead compounds have been investigated extensively. The present review focuses on artemisinin, parthenolide, thapsigargin, and their naturally occurring or synthetic analogues showing potential anticancer activity. This provides an overview of the advances in the development of these types of sesquiterpene lactones as potential anticancer agents, including their structural characterization, synthesis and synthetic modification, and antitumor potential, with the mechanism of action and structure-activity relationships also discussed. It is hoped that this will be helpful in stimulating the further interest in developing sesquiterpene lactones and their derivatives as new anticancer agents.
Collapse
Affiliation(s)
| | | | - A Douglas Kinghorn
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States
| |
Collapse
|
|
42
|
Dey A, Mukherjee A, Chaudhury M. Alkaloids From Apocynaceae. STUDIES IN NATURAL PRODUCTS CHEMISTRY 2017. [DOI: 10.1016/b978-0-444-63931-8.00010-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
43
|
|
|
44
|
Yao H, Liu J, Xu S, Zhu Z, Xu J. The structural modification of natural products for novel drug discovery. Expert Opin Drug Discov 2016; 12:121-140. [DOI: 10.1080/17460441.2016.1272757] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Hong Yao
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China
| | - Junkai Liu
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China
| | - Shengtao Xu
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China
| | - Zheying Zhu
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, Nottingham, UK
| | - Jinyi Xu
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China
| |
Collapse
|
|
45
|
Sarkar S, Laha RM, Mitra RN, Maiti DK. Pd II-Catalyzed Oxidative Aldehyde-sp 2C-H Functionalization and Cyclization Using NHC with Mild Oxidant DMSO for the Selective Synthesis of Esters, Sugar-Based Analogues, and β-Hydroxy Chromanones: An 18O-Labeling Study. ACS OMEGA 2016; 1:981-995. [PMID: 30023497 PMCID: PMC6044719 DOI: 10.1021/acsomega.6b00261] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 11/04/2016] [Indexed: 06/08/2023]
Abstract
We assume formation of acyl-PdII-N-heterocyclic-carbene (NHC) organometalics for diverse C-O/O-C and C-C/C-O coupling catalysis of direct functionalization and cyclization reactions. We report the first use of dimethyl sulfoxide (DMSO) as an oxidant under an inert atmosphere to O2-sensitive NHC for oxidative transformations. In situ generated imidazolium halides are utilized as a precursor of NHC and as a source of alkyl group for the sp2C-H functionalization of aldehydes to esters under mild conditions. In contrast to the reported NHC-catalyzed esterification strategies, the outstanding substrate scope of this mild catalysis approach is established through synthesis of thermally labile sugar-based chiral esters. Our competition experiments using various unsymmetrical imidazolium halides revealed an ascending rate of migratory aptitude among methyl ≪ allyl < crotyl < cinnamyl < benzyl moiety. DMSO is used as an oxidant for both esterification and cyclization reactions, and the transfer of the DMSO-oxygen to ester is confirmed using an 18O-labeling experiment. The diverse activity using DMSO-oxygen to acyl-PdII-NHC is verified by developing a unique C-C-coupled cyclization with side-chain hydroxylation of olefin to achieve valuable β-hydroxy chromanones.
Collapse
|
|
46
|
Liao L, Zhou J, Xu Z, Ye T. Concise Total Synthesis of Nannocystin A. Angew Chem Int Ed Engl 2016; 55:13263-13266. [DOI: 10.1002/anie.201606679] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 08/17/2016] [Indexed: 12/27/2022]
Affiliation(s)
- Linping Liao
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| | - Jingjing Zhou
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| | - Zhengshuang Xu
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| | - Tao Ye
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| |
Collapse
|
|
47
|
Affiliation(s)
- Linping Liao
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| | - Jingjing Zhou
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| | - Zhengshuang Xu
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| | - Tao Ye
- Laboratory of Chemical Genomics; Engineering Laboratory for Chiral Drug Synthesis; School of Chemical Biology and Biotechnology; Peking University Shenzhen Graduate School; Xili, Nanshan District Shenzhen 518055 China
| |
Collapse
|
|
48
|
Huang J, Wang Z. Total Syntheses of Nannocystins A and A0, Two Elongation Factor 1 Inhibitors. Org Lett 2016; 18:4702-5. [PMID: 27598405 DOI: 10.1021/acs.orglett.6b02352] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Asymmetric total syntheses of nannocystins A and A0 were achieved in a convergent route starting from simple materials. Nannocystin family natural products bear potent anticancer activity as elongation factor 1 inhibitors. In this synthesis, the challenging tertiary amide bond was constructed by peptide coupling between an acyl chloride and a secondary amine. A late-stage ring-closing metathesis reaction successfully rendered the macrocycle. This efficient synthetic strategy should be applicable to other nannocystins and analogues and therefore should benefit future structure-activity relationship studies.
Collapse
Affiliation(s)
- Jun Huang
- Department of Chemistry, University at Albany, State University of New York , Albany, New York 12222, United States
| | - Zhang Wang
- Department of Chemistry, University at Albany, State University of New York , Albany, New York 12222, United States
| |
Collapse
|
|
49
|
Pérez de Vega MJ, Gómez-Monterrey I, Ferrer-Montiel A, González-Muñiz R. Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer. J Med Chem 2016; 59:10006-10029. [PMID: 27437828 DOI: 10.1021/acs.jmedchem.6b00305] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
TRPM8 ion channels, the primary cold sensors in humans, are activated by innocuous cooling (<28 °C) and cooling compounds (menthol, icilin) and are implicated in sensing unpleasant cold stimuli as well as in mammalian thermoregulation. Overexpression of these thermoregulators in prostate cancer and in other life-threatening tumors, along with their contribution to an increasing number of pathological conditions, opens a plethora of medicinal chemistry opportunities to develop receptor modulators. This Perspective seeks to describe current known modulators for this ion channel because both agonists and antagonists may be useful for the treatment of most TRPM8-mediated pathologies. We primarily focus on SAR data for the different families of compounds and the pharmacological properties of the most promising ligands. Furthermore, we also address the knowledge about the channel structure, although still in its infancy, and the role of the TRPM8 protein signalplex to channel function and dysfunction. We finally outline the potential future prospects of the challenging TRPM8 drug discovery field.
Collapse
Affiliation(s)
| | - Isabel Gómez-Monterrey
- Dipartimento di Farmacia, Università "Federico II" de Napoli , Via D. Montesano 49, 80131, Naples, Italy
| | - Antonio Ferrer-Montiel
- Instituto de Biología Molecular y Celular. Universitas Miguel Hernández . 03202 Alicante, Spain
| | | |
Collapse
|
|
50
|
Kawai S, Sasaki H, Okada N, Kanie K, Yokoshima S, Fukuyama T, Honda H, Kato R. Morphological Evaluation of Nonlabeled Cells to Detect Stimulation of Nerve Growth Factor Expression by Lyconadin B. ACTA ACUST UNITED AC 2016; 21:795-803. [DOI: 10.1177/1087057116645500] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 03/30/2016] [Indexed: 01/30/2023]
Abstract
The success of drug development is greatly influenced by the efficiency of drug screening methods. Recently, phenotype-based screens have raised expectations, based on their proven record of identifying first-in-class drugs at a higher rate. Although fluorescence images are the data most commonly used in phenotype-based cell-based assays, nonstained cellular images have the potential to provide new descriptive information about cellular responses. In this study, we applied morphology-based evaluation of nonlabeled microscopic images to a phenotype-based assay. As a study case, we attempted to increase the efficiency of a cell-based assay for chemical compounds that induce production of nerve growth factor (NGF), using lyconadin B as a model compound. Because the total synthesis of lyconadin B was accomplished very recently, there is no well-established cell-based assay scheme for further drug screening. The conventional cell-based assay for evaluating NGF induction requires two types of cells and a total of 5 days of cell culture. The complexity and length of this assay increase both the risk of screening errors and the cost of screening. Our findings show that analysis of cellular morphology enables evaluation of NGF induction by lyconadin B within only 9 h.
Collapse
Affiliation(s)
- Shun Kawai
- Division of Bioscience, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
| | - Hiroto Sasaki
- Department of Biotechnology, Graduate School of Engineering, Nagoya University, Nagoya, Japan
| | - Norihiro Okada
- Division of Bioscience, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
| | - Kei Kanie
- Division of Bioscience, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
| | - Satoshi Yokoshima
- Division of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
| | - Tohru Fukuyama
- Division of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
| | - Hiroyuki Honda
- Department of Biotechnology, Graduate School of Engineering, Nagoya University, Nagoya, Japan
| | - Ryuji Kato
- Division of Bioscience, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
| |
Collapse
|