Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), PO box 29, Nasr City, Cairo, Egypt.
Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Bioorg Chem. 2018 Oct;80:276-287. doi: 10.1016/j.bioorg.2018.06.010. Epub 2018 Jun 5.
Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC values of 20.4, 18.3 and 26.3 µM, respectively compared to E7070 IC 36.3 µM. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC of 2.53, 1.79 and 2.92 µM, respectively compared to roscovitine IC 0.43 µM. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme.
设计并合成了两个系列的含有 4-甲基苯磺酰胺部分的 2-氨基吡啶衍生物 6-17 和 tyrphostin AG17 类似物 18-22，作为抗癌化合物。对合成的化合物进行了细胞毒性活性测试，以评估其对人乳腺癌 MCF-7 细胞系的抑制作用。在 2-氨基吡啶和 tyrphostin AG17 系列中，化合物 14、16 和 20 的活性最好，IC 值分别为 20.4、18.3 和 26.3µM，而 E7070 的 IC 值为 36.3µM。进一步对 14、16 和 20 进行了对细胞周期蛋白依赖性激酶-2（CDK2）的抑制活性测试，结果显示，其 IC 值分别为 2.53、1.79 和 2.92µM，而 roscovitine 的 IC 值为 0.43µM。此外，研究了 γ 辐射对 14、16 和 20 的细胞毒性活性的增强作用，结果显示在照射后较低浓度下，细胞杀伤效果显著增加。通过对接研究了化合物 14、16 和 20 在 CDK2 酶活性位点中的可能结合模式。
