Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
Eur J Med Chem. 2013 Nov;69:498-507. doi: 10.1016/j.ejmech.2013.08.042. Epub 2013 Sep 12.
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.
新型杂环稠合嘧啶，即吡咯并[1,2-c]嘧啶 4-8、嘧啶并[5,4-e]吡咯并[1,2-c]嘧啶 9-14、嘧啶并[4',5':4,5]嘧啶并[1,6-a]氮杂环庚烷 16-18、吡咯并[1',2':1,6]嘧啶并[4,5-d][1,3]噻嗪 19a,b 和 1,3-噻嗪并[4',5':4,5]嘧啶并[1,6-a]-氮杂环庚烷 19c，被设计并合成作为潜在的抗癌药物。在这项研究中，所有新合成的化合物都被进行了细胞毒性筛选，以检测它们对 MCF-7 乳腺癌细胞系的作用。此外，对化合物 5、7、9 和 18 进行了激酶抑制试验，以检测它们对非受体和受体酪氨酸激酶 c-Src 和 VEGFR 的抑制作用。测试的化合物对 c-Src 的抑制作用强于 VEGFR，而化合物 18 的活性最高，对 c-Src 的抑制活性达到 81%。最后，通过分子对接技术与 c-Src 和 VEGFR 进行了对接实验，试图模拟和理解这些小分子与激酶酶 ATP 结合口袋必需氨基酸之间的结合相互作用。
