Novel heterocyclic-fused pyrimidine derivatives: Synthesis, molecular modeling and pharmacological screening
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Date
2013
Authors
Journal Title
Journal ISSN
Volume Title
Type
Article
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Series Info
European Journal of Medicinal Chemistry
69
69
Scientific Journal Rankings
Abstract
Novel heterocyclic-fused pyrimidines viz pyrrolo[1,2-c]pyrimidines 4-8, pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 9-14, pyrimido[4?,5?:4,5] pyrimido[1,6-a]azepines 16-18, pyrrolo[1?,2?:1,6]pyrimido[4,5-d][1, 3]thiazines 19a,b and 1,3-thiazino[4?,5?:4,5]pyrimido[1,6-a]-azepine 19c were designed and synthesized as potential anticancer agents. In this investigation all the newly synthesized compounds were subjected to cytotoxic screening against MCF-7 breast cancer cell line. Moreover, kinase inhibitory assay was done for compounds 5, 7, 9 and 18 against the non-receptor and receptor tyrosine kinases c-Src and VEGFR, respectively. The tested compounds were more potent against c-Src than VEGFR, and the highest activity was observed for 18 showing 81% c-Src activity inhibition. Finally, molecular docking was performed with c-Src and VEGFR in an attempt to simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. � 2013 Elsevier Masson SAS. All rights reserved.
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Scopus
Keywords
Antiproliferative agents, c-Src and VEGFR inhibition, Fused pyrimidines, MCF-7 breast cancer cell line, 1 amino 5 phenyl 3 thioxo 3,5,8,9,10,10a hexahydropyrimido[5,4 e]pyrrolo[1,2 c] pyrimidin 6(4h) one, 1 amino 5 phenyl 3 thioxo 3,5,8,9,10,11,12,12a octahydropyrimido[4',5':4,5] pyrimido[1,6 a]azepin 6(4h) one, 1 amino 5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 3,6(4h,5h) dithione, 1 chloro 5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 6(5h) one, 1 hydrazino 5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 6(5h) one, 1 imino 2,5 diphenyl 1,5,8,9,10,10a hexahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 3,6(2h,4h) dione, 1 oxo 2 phenyl 3 (2,4,5 trioxo 3 phenylimidazolidin 1 yl) 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile, 1 oxo 2 phenyl 3 (2,5 dioxo 3 phenylimidazolidin 1 yl) 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile, 1 oxo 2 phenyl 3 (n p tolylcarbamoylmethyl)amino 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile, 1 oxo 3 (3 phenylthioureido) 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile, 1 oxo 3 (3 phenylureido) 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile, 1[(4 chlorobenzylidene)amino] 5 phenyl 3 thioxo 3,5,8,9,10,10a hexahydro pyrimido[5,4 e]pyrrolo[1,2 c] pyrimidin 6(4h) one, 1[(4 chlorobenzylidene)amino] 5 phenyl 3 thioxo 3,5,8,9,10,10a octahydropyrimido[5,4 e]pyrrolo[1,2 c] pyrimidin 6(4h) one, 2 phenyl 3 (n p tolylcarbamoylmethyl)amino 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile, 3 (2 cyano 1 oxoethyl)amino 1 oxo 2 phenyl 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile, 3 (3 phenylureido) 1 thioxo 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile, 3 phenylthioureido 1 thioxo 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile, 5 phenyl 3 thioxo 3,4,8,9,10,10a hexahydro 1h [1,3] thiazino[4',5':4,5] pyrimido[1,6 a]azepine 1,6(5h) dione, 5 phenyl 3 thioxo 3,4,8,9,10,10a hexahydro 1h pyrrolo[1',2':1,6] pyrimido[4,5 d][1,3]thiazine 1,6(5h) dione, 5 phenyl 3,6 dithioxo 3,4,5,6,8,9,10,10a octahydro 1h pyrrolo[1',2':1,6] pyrimido[4,5 d][1,3]thiazine 1 one, 5 phenyl 6 thioxo 5,6,8,9,10,10a hexahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidin 1(2h) one, 5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 1,6(2h,5h) dione, 5 phenyl 8,9,10,11,12,12a tetrahydropyrimido[4',5':4,5]pyrimido[1,6 a]azepine 1,6(2h,5h) dione, antineoplastic agent, doxorubicin, pyrimidine derivative, unclassified drug, antiproliferative activity, article, breast cancer, cancer cell culture, controlled study, drug cytotoxicity, drug screening, drug synthesis, hydrophilicity, IC 50, molecular docking, molecular model, oncogene src, structure activity relation, Antiproliferative agents, c-Src and VEGFR inhibition, Fused pyrimidines, MCF-7 breast cancer cell line, Antineoplastic Agents, Cell Proliferation, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor, Heterocyclic Compounds, Humans, MCF-7 Cells, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors, Pyrimidines, Receptors, Vascular Endothelial Growth Factor, src-Family Kinases, Structure-Activity Relationship