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Abbas N, Swamy PMG, Dhiwar P, Patel S, Giles D. Development of Fused and Substituted Pyrimidine Derivatives as Potent Anticancer Agents (A Review). Pharm Chem J 2021. [DOI: 10.1007/s11094-021-02346-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Sroor FM, Basyouni WM, Tohamy WM, Abdelhafez TH, El-awady MK. Novel pyrrolo[2,3-d]pyrimidine derivatives: Design, synthesis, structure elucidation and in vitro anti-BVDV activity. Tetrahedron 2019. [DOI: 10.1016/j.tet.2019.130749] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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3
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Vascular Endothelial Growth Factor Receptor (VEGFR-2)/KDR Inhibitors: Medicinal Chemistry Perspective. MEDICINE IN DRUG DISCOVERY 2019. [DOI: 10.1016/j.medidd.2019.100009] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Pathania S, Rawal RK. Pyrrolopyrimidines: An update on recent advancements in their medicinal attributes. Eur J Med Chem 2018; 157:503-526. [PMID: 30114661 DOI: 10.1016/j.ejmech.2018.08.023] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 08/06/2018] [Accepted: 08/08/2018] [Indexed: 01/09/2023]
Abstract
Fused heterocycles are reported to demonstrate variety of biological activities such as anticancer, antibacterial, antifungal and anti-inflammatory, and are thus exhaustively utilized in the field of medicinal chemistry. Pyrrolopyrimidines is one of the major classes of fused heterocycles which are extensively reported throughout the literature. Several reports suggest that pyrrolopyrimidine as fused scaffold possess more diverse and potent pharmacological profile than individual pyrrole and pyrimidine nucleus. Different pathological targets require different structural attributes reflected via varied substitutions, thus in recent years, researchers have employed various synthetic strategies to achieve desired substitutions on the pyrrolopyrimidine nucleus. In this review, authors highlight the recent advancement in this area, special focus was laid on the pharmacological profile and structure-activity relationship studies (SAR) of various synthesized pyrrolopyrimidine derivatives.
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Affiliation(s)
- Shelly Pathania
- Department of Pharmaceutical Chemistry, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga, 142001, India; Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, 151001, Punjab, India
| | - Ravindra K Rawal
- Department of Chemistry, Maharishi Markandeshwar (Deemed to be University), Mullana, 133207, Ambala, Haryana, India.
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Mostafa AS, Bayoumi WA, El-Mesery M, Elgaml A. Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity. Anticancer Agents Med Chem 2018; 19:310-322. [PMID: 30019649 DOI: 10.2174/1871520618666180717125906] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/30/2018] [Accepted: 07/02/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND Two series of 3,4-dihydropyrimidin-2(1H)-one derivatives were designed based on the main structural features characterizing reported anticancer compounds with potent VEGFR-2 inhibiting activity. METHODS All the target compounds were synthesized and investigated for their in vitro anticancer activity using MTT assay and NCI protocol. The most active compounds were further investigated for the VEGFR-2 inhibiting activity using enzyme inhibition assay. RESULT Of these derivatives, compound 8b possessed significant activity against Caco-2 (IC50 of 24.9 µM) and MCF7 (IC50 of 29.4 µM), compound 10 showed excellent potency against HCT-116 (IC50 of 32.6 µM), HEPG2 (IC50 of 16.4 µM) and MCF7 (IC50 of 32.8 µM), while compound 11b exhibited moderate anticancer activity towards MCF7 (IC50 of 41.7µM). Both 8b and 10 exhibited good potency regarding the inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), with an IC50 of 14.00 and 21.62 nM, respectively. CONCLUSION The activity was rationalized based on molecular docking study that supported their VEGFR-2 inhibitory activity; as indicated by their favorable binding with the active site.
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Affiliation(s)
- Amany S Mostafa
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Waleed A Bayoumi
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamassa, Egypt
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Abdelaziz Elgaml
- Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Bayat M, Nasri S. Synthesis and dynamic 1 H NMR study of pyrazolo substituted pyrrolo[2,3- d ]pyrimidines via a regioselective heterocyclization. J Mol Struct 2018. [DOI: 10.1016/j.molstruc.2017.10.056] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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8
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Kambappa V, Chandrashekara GK, Rekha ND, Shivaramu PD, Palle K. Synthesis, anti-angiogenic and DNA cleavage studies of novel N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)piperidine-4-carboxamide derivatives. Chem Cent J 2017; 11:122. [PMID: 29189954 PMCID: PMC5709256 DOI: 10.1186/s13065-017-0354-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 11/20/2017] [Indexed: 01/13/2023] Open
Abstract
A series of novel N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)piperidine-4-carboxamide derivatives 10(a-f), 12(a-c) and 14(a-c) were synthesized and characterized by FTIR, 1H-NMR, mass spectral and elemental analysis. The efficacy of these derivatives to inhibit in vivo angiogenesis was evaluated using chick chorioallantoic membrane (CAM) model and their DNA cleavage abilities were evaluated after incubating with calf thymus DNA followed by gel electrophoresis. These novel piperidine analogues efficiently blocked the formation of blood vessels in vivo in CAM model and exhibited differential migration and band intensities in DNA binding/cleavage assays. Among the tested compounds 10a, 10b, 10c, 12b, 14b and 14c showed significant anti-angiogenic and DNA cleavage activities compared to their respective controls and the other derivatives used in this study. These observations suggest that the presence of electron donating and withdrawing groups at positions 2, 3 and 4 of the phenyl ring of the side chain may determine their potency and as anticancer agents by exerting both anti-angiogenic and cytotoxic effects .
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Affiliation(s)
- Vinaya Kambappa
- Department of Chemistry, Government First Grade College, Kadur, 577 548, India. .,Department of Oncological Sciences, Mitchell Cancer Institute, USA Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL, 36604, USA.
| | - G K Chandrashekara
- Department of Chemistry, Government First Grade College, Kadur, 577 548, India
| | - N D Rekha
- Department of Studies in Biotechnology, JSS College of Arts, Commerce & Science, Ooty Road, Mysore, 570 025, India
| | - Prasanna D Shivaramu
- Department of Nanotechnology, Visvesvaraya Technological University, Center for Postgraduate Studies, Bengaluru Region, Muddenahalli, Ckikkaballapur, 562 101, India
| | - Komaraiah Palle
- Department of Oncological Sciences, Mitchell Cancer Institute, USA Mitchell Cancer Institute, 1660 Springhill Avenue, Mobile, AL, 36604, USA
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Kurup S, McAllister B, Liskova P, Mistry T, Fanizza A, Stanford D, Slawska J, Keller U, Hoellein A. Design, synthesis and biological activity of N 4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase. J Enzyme Inhib Med Chem 2017; 33:74-84. [PMID: 29115879 PMCID: PMC6009956 DOI: 10.1080/14756366.2017.1376666] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1-18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1-18 allow for a structure-activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition. Compound 6, a 4-methoxyphenylpyrrolo[2,3-d]pyrimidin-4-amine, demonstrates single-digit micromolar inhibition of both AURKA and EGFR and provides evidence of a single molecule with dual activity against EGFR and AURKA. Compound 2, the most potent inhibitor of EGFR and AURKA from this series, has been further evaluated in four different squamous cell head and neck cancer cell lines for downstream effects resulting from AURKA and EGFR inhibition.
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Affiliation(s)
- Sonali Kurup
- a College of Pharmacy , Roosevelt University , Schaumburg , IL , USA
| | | | - Pavlina Liskova
- a College of Pharmacy , Roosevelt University , Schaumburg , IL , USA
| | - Trusha Mistry
- a College of Pharmacy , Roosevelt University , Schaumburg , IL , USA
| | - Anthony Fanizza
- b Department of Chemistry , Harper College , Palatine , IL , USA
| | - Dan Stanford
- b Department of Chemistry , Harper College , Palatine , IL , USA
| | - Jolanta Slawska
- c III. Medical Department , Technische Universität München , Munich , Germany
| | - Ulrich Keller
- c III. Medical Department , Technische Universität München , Munich , Germany.,d German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | - Alexander Hoellein
- c III. Medical Department , Technische Universität München , Munich , Germany
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Fekete B, Palkó M, Haukka M, Fülöp F. Synthesis of Pyrrolo[1,2-a]pyrimidine Enantiomers via Domino Ring-Closure followed by Retro Diels-Alder Protocol. Molecules 2017; 22:molecules22040613. [PMID: 28406463 PMCID: PMC6154686 DOI: 10.3390/molecules22040613] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 04/04/2017] [Accepted: 04/06/2017] [Indexed: 01/14/2023] Open
Abstract
From 2-aminonorbornene hydroxamic acids, a simple and efficient method for the preparation of pyrrolo[1,2-a]pyrimidine enantiomers is reported. The synthesis is based on domino ring-closure followed by microwave-induced retro Diels-Alder (RDA) protocols, where the chirality of the desired products is transferred from norbornene derivatives. The stereochemistry of the synthesized compounds was proven by X-ray crystallography. The absolute configuration of the product is determined by the configuration of the starting amino hydroxamic acid.
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Affiliation(s)
- Beáta Fekete
- Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös utca 6, Szeged H-6720, Hungary.
| | - Márta Palkó
- Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös utca 6, Szeged H-6720, Hungary.
| | - Matti Haukka
- Department of Chemistry, University of Jyväskylä, FIN-40014 Turku, Finland.
| | - Ferenc Fülöp
- Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös utca 6, Szeged H-6720, Hungary.
- MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eötvös utca 6, Szeged H-6720, Hungary.
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De Coen LM, Heugebaert TSA, García D, Stevens CV. Synthetic Entries to and Biological Activity of Pyrrolopyrimidines. Chem Rev 2015; 116:80-139. [DOI: 10.1021/acs.chemrev.5b00483] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Laurens M. De Coen
- Department of Sustainable
Organic Chemistry and Technology, Ghent University, Coupure links
653, B-9000 Ghent, Belgium
| | - Thomas S. A. Heugebaert
- Department of Sustainable
Organic Chemistry and Technology, Ghent University, Coupure links
653, B-9000 Ghent, Belgium
| | - Daniel García
- Department of Sustainable
Organic Chemistry and Technology, Ghent University, Coupure links
653, B-9000 Ghent, Belgium
| | - Christian V. Stevens
- Department of Sustainable
Organic Chemistry and Technology, Ghent University, Coupure links
653, B-9000 Ghent, Belgium
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Discovery of novel tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives as VEGFR-2 inhibitors. Bioorg Chem 2015; 60:1-12. [PMID: 25899678 DOI: 10.1016/j.bioorg.2015.03.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 03/28/2015] [Accepted: 03/30/2015] [Indexed: 12/17/2022]
Abstract
In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a novel series of tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives were designed and synthesized. These compounds were characterized by IR, (1)H NMR, (13)C NMR, elemental and mass spectral analyses. Docking studies have given a partial insight into the molecular determinants of the activity of this novel series in VEGFR-2 kinase active site. Moreover, these compounds were assessed at 10μM for their selective inhibitory activities over a panel of 6 human kinases, namely VEGFR-1/Flt-1, VEGFR-2/KDR, EGFR, CDK5/p25, GSK3α and GSK3β. Compound N-(4,6-dimethylthieno[2,3-b]pyridine)-7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (9d) exhibited the most potent and selective inhibitory activity against VEGFR-2/KDR over the six human kinases, with an IC50 value 2.6μM. The identification of this hit candidate could aid the design of new tricyclic-based VEGFR-2 kinase modulators.
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Prieur V, Heindler N, Rubio-Martínez J, Guillaumet G, Pujol MD. One-pot synthesis of 4-aminated pyrrolo[2,3-d]pyrimidines from alkynylpyrimidines under metal-catalyst-free conditions. Tetrahedron 2015. [DOI: 10.1016/j.tet.2015.01.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Ramírez J, Svetaz L, Quiroga J, Abonia R, Raimondi M, Zacchino S, Insuasty B. Synthesis of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as potential antitumor and antifungal agents. Eur J Med Chem 2015; 92:866-75. [PMID: 25638570 DOI: 10.1016/j.ejmech.2015.01.053] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Revised: 01/22/2015] [Accepted: 01/24/2015] [Indexed: 12/24/2022]
Abstract
A new series of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines 6a-g and 7a-g were obtained with high regioselectivity from the reaction of triamino- or tetraaminopyrimidines 4 and 5 with α,β-unsaturated carbonyl compounds 3a-g based on 2,4-dichlorothiazol-5-carbaldehyde 1. Twelve of the synthesized compounds were selected and tested by US National Cancer Institute (NCI) for their antitumor activity against 60 different human tumor cell lines. Compounds 7d and 7g showed important GI50 ranges of 1.28-2.98 μM and 0.35-2.78 μM respectively under in vitro assays. In addition, 6a-g and 7a-g were tested for antifungal properties against the clinical important fungi Candida albicans and Cryptococcus neoformans. Although these compounds showed moderate activities against C. albicans, the 2-amino derivatives 7a-g and mainly 7a and 7b, showed high activity against standardized and clinical isolates of C. neoformans with MIC50 = 7.8-31.2 μg/mL, MIC80 = 15.6-31.2 μg/mL and MIC100 = 15.6-62.5 μg/mL. In addition, since both compounds were fungicide rather than fungistatic these thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines appear as good candidates for further development not only as antifungal but also as antitumor drugs.
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Affiliation(s)
- Juan Ramírez
- Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia
| | - Laura Svetaz
- Área Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
| | - Jairo Quiroga
- Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia
| | - Rodrigo Abonia
- Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia
| | - Marcela Raimondi
- Área Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
| | - Susana Zacchino
- Área Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
| | - Braulio Insuasty
- Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, AA 25360 Cali, Colombia.
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Dasari R, Kornienko A. Multicomponent Synthesis of the Medicinally Important Pyrrolo[2,3-d]Pyrimidine Scaffold (Minireview). Chem Heterocycl Compd (N Y) 2014. [DOI: 10.1007/s10593-014-1456-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Frolova LV, Magedov IV, Romero AE, Karki M, Otero I, Hayden K, Evdokimov NM, Banuls LMY, Rastogi SK, Smith WR, Lu SL, Kiss R, Shuster CB, Hamel E, Betancourt T, Rogelj S, Kornienko A. Exploring natural product chemistry and biology with multicomponent reactions. 5. Discovery of a novel tubulin-targeting scaffold derived from the rigidin family of marine alkaloids. J Med Chem 2013; 56:6886-900. [PMID: 23927793 DOI: 10.1021/jm400711t] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
We developed synthetic chemistry to access the marine alkaloid rigidins and over 40 synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine, and 7-deazahypoxanthine skeletons. Analogues based on the 7-deazahypoxanthine skeleton exhibited nanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases, and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerization and disorganized microtubules in live HeLa cells. Experiments evaluating the effects of the 7-deazahypoxanthines on the binding of [(3)H]colchicine to tubulin identified the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7-deazahypoxanthine rigidin analogues have significant potential as new anticancer agents.
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Affiliation(s)
- Liliya V Frolova
- Department of Chemistry and ‡Department of Biology, New Mexico Institute of Mining and Technology , Socorro, New Mexico 87801, United States
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Acetamidines and acetamidoximes containing an electron-withdrawing group at the α-carbon atom: their use in the synthesis of nitrogen heterocycles (review)*. Chem Heterocycl Compd (N Y) 2013. [DOI: 10.1007/s10593-013-1277-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Elassar AZA, Alsughayer A, Sagheer FA. Convenient Synthesis and Antibacterial Activity of Tricyclic Azine Derivatives. JOURNAL OF CHEMICAL RESEARCH 2013. [DOI: 10.3184/174751913x13640546938841] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
1,4-Phenylenediamine reacted readily with 2 mol of ethyl acetoacetate to give diethyl ( 2Z,2′Z)-3,3′-[(1,4-phenylene)-bisimino]dibut-2-enoate, which reacted with dimethylformamide dimethylacetal, activated methylene nitriles, ylidenemalononitriles and phenyl and benzoyl isothiocyanate to give, respectively, a 4,7-phenanthroline-2,9-dicarb-oxylate-1,10-diol, and tricyclic bispyridine and bispyrimidine derivatives. Two compounds showed strong antibacterial activity against several microorganisms, while six others showed high to moderate activity.
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Affiliation(s)
- Abdel-Zaher A. Elassar
- Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969-Safat-13060, Kuwait
- Chemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt
| | - Abdulhakeem Alsughayer
- Pharmaceutical Science Department, College of Health Science, The Public Authority for Applied Education and Training, Kuwait
| | - Fakhreia Al Sagheer
- Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969-Safat-13060, Kuwait
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Musumeci F, Radi M, Brullo C, Schenone S. Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. J Med Chem 2012; 55:10797-822. [PMID: 23098265 DOI: 10.1021/jm301085w] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this Perspective we briefly report the inhibitors that are in clinical use, while we dedicate two wider sections to the compounds that are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic and report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past 5 years.
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Affiliation(s)
- Francesca Musumeci
- Dipartimento di Farmacia, University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy
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Jakubkiene V, Cepla V, Burbuliene MM, Vainilavicius P. Synthesis and Functionalization of 8-Methyl-2h-pyrimido [2,1-c][1,2,4]triazine-3,6(1h,4h)-dione. J Heterocycl Chem 2012. [DOI: 10.1002/jhet.844] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Virginija Jakubkiene
- Department of Organic Chemistry, Faculty of Chemistry; Vilnius University; LT-03225; Vilnius; Lithuania
| | - Vytautas Cepla
- Department of Organic Chemistry, Faculty of Chemistry; Vilnius University; LT-03225; Vilnius; Lithuania
| | - Milda M. Burbuliene
- Department of Organic Chemistry, Faculty of Chemistry; Vilnius University; LT-03225; Vilnius; Lithuania
| | - Povilas Vainilavicius
- Department of Organic Chemistry, Faculty of Chemistry; Vilnius University; LT-03225; Vilnius; Lithuania
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Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol 2012; 3:32-42. [PMID: 22442756 PMCID: PMC3309891 DOI: 10.5306/wjco.v3.i3.32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/12/2012] [Accepted: 03/05/2012] [Indexed: 02/06/2023] Open
Abstract
Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3’-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.
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Affiliation(s)
- Murielle Mimeault
- Murielle Mimeault, Surinder K Batra, Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, United States
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Atapour-Mashhad H, Tayarani-Najaran Z, Davoodnia A, Moloudi R, Mousavi SH. Antitumor activity of novel pyrrolo[2,3-d]pyrimidin-4-ones. Drug Chem Toxicol 2011; 34:271-6. [PMID: 21649481 DOI: 10.3109/01480545.2010.545066] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Pyrrolo[2,3-d]pyrimidine is known to have a broad spectrum of biological activities, including antitumor activity. The cytotoxic properties of six novel pyrrolo[2,3-d]pyrimidin-4-ones in vitro were investigated on four different human cancer cell lines. Meanwhile, the role of apoptosis was explored. Malignant cells were cultured in RPMI medium and incubated with different concentrations. Cell viability was quantitated by MTT assay. Apoptotic cells were determined using DAPI (4'-6-diamidino-2-phenylindole) and propidium iodide staining of DNA fragmentation by flow cytometry (sub-G1 peak). We have identified new analogs as a novel class of antiproliferative agents by a cell-based screening method. All compounds inhibited the growth of malignant cells in a dose-dependent manner. The IC₅₀ of compounds 4 and 5 as the two most potent analogs was determined as 122.4 and 106.7 μM in HeLa cells, respectively. Compounds 4 and 5 induced a sub-G1 peak in the flow-cytometry histogram of treated cells, compared to control, indicating that apoptotic cell death is involved in compound 4- and 5-induced toxicity. In conclusion, compounds 4 and 5 exert cytotoxic effects in different cancer cell lines in which apoptosis plays an important role. Thus, compounds 4 and 5 could be considered as potential chemotherapeutic agents.
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Aly AA, Behalo MS. Synthesis of New Peptidyl- and Glycosylpyrimidine Derivatives. JOURNAL OF CHEMICAL RESEARCH 2011. [DOI: 10.3184/174751911x13083314900282] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A new series of 2- N-(phthalyl- or tosylamino acid)pyrimidines have been synthesised from the coupling of pyrimidine derivatives with phthalyl- or tosylamino acids. Hydrazinolysis of 2- N-phthalyl derivatives afforded unprotected amino acid derivatives. New derivatives of peptidylpyrimidines have been synthesised from the reaction of pyrimidine derivatives with α-amino acids methyl ester hydrochloride viz different routes. Also, new glycosides have been prepared from the reaction of pyrimidine derivatives with α-D-glucopyranosyl bromide. Most of the synthesised compounds showed a significant antimicrobial activity.
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Affiliation(s)
- Aly A. Aly
- Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
| | - Mohamed S. Behalo
- Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
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