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基于吡啶并[2,3-d]嘧啶骨架的多靶点激酶抑制剂的抗癌评估与分子建模

Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold.

作者信息

Elzahabi Heba S A, Nossier Eman S, Khalifa Nagy M, Alasfoury Rania A, El-Manawaty May A

机构信息

a Department of Pharmaceutical Chemistry , Faculty of Pharmacy (Girls), Al-Azhar University , Cairo , Egypt.

b Drug Exploration & Development Chair (DEDC), Department of Pharmaceutical Chemistry , College of Pharmacy, King Saud University , Riyadh , Saudi Arabia.

出版信息

J Enzyme Inhib Med Chem. 2018 Dec;33(1):546-557. doi: 10.1080/14756366.2018.1437729.

DOI:10.1080/14756366.2018.1437729
PMID:29482389
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6009920/
Abstract

An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC: 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC: 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR β, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.

摘要

进行了取代吡啶并[2,3 - d]嘧啶的高效合成，并对其针对五种癌细胞系，即肝癌（HepG - 2）、前列腺癌（PC - 3）、结肠癌（HCT - 116）、乳腺癌（MCF - 7）和肺癌（A - 549）细胞系的体外抗癌活性进行了评估。对于HepG - 2、PC - 3、HCT - 116癌细胞系，7 -（4 - 氯苯基）- 2 -（3 - 甲基 - 5 - 氧代 - 2,3 - 二氢 - 1H - 吡唑 - 1 - 基）- 5 -（对甲苯基）- 吡啶并[2,3 - d]嘧啶 - 4(3H) - 酮（5a）相对于标准阿霉素（IC：0.6、6.8和12.8 μM）分别表现出较强、更有效的抗癌活性（IC：0.3、6.6和7 μM）。5a的激酶抑制评估显示，在单次测量中，在50和100 μM这两个浓度下，对三种激酶即血小板衍生生长因子受体β（PDGFR β）、表皮生长因子受体（EGFR）和细胞周期蛋白依赖性激酶4/细胞周期蛋白D1（CDK4/cyclin D1）具有有前景的抑制活性。此外，对化合物5a进行了分子对接研究，以验证其与EGFR和CDK4/cyclin D1激酶的结合模式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/74b08d08552e/IENZ_A_1437729_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/18c2ebe6e1d6/IENZ_A_1437729_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/4e8c0fe5c5b1/IENZ_A_1437729_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/86140811fca3/IENZ_A_1437729_SCH0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/60e773d49f6b/IENZ_A_1437729_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/14b406fc2afb/IENZ_A_1437729_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/4ac48c84349e/IENZ_A_1437729_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/74b08d08552e/IENZ_A_1437729_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/18c2ebe6e1d6/IENZ_A_1437729_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/4e8c0fe5c5b1/IENZ_A_1437729_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/86140811fca3/IENZ_A_1437729_SCH0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/60e773d49f6b/IENZ_A_1437729_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/14b406fc2afb/IENZ_A_1437729_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/4ac48c84349e/IENZ_A_1437729_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adad/6009920/74b08d08552e/IENZ_A_1437729_F0005_C.jpg

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