Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Bioorg Chem. 2020 Jun;99:103797. doi: 10.1016/j.bioorg.2020.103797. Epub 2020 Mar 30.
Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines includingliver (HePG2), colon (HCT116), breast (MCF7) and cervical (HeLa) carcinoma cell lines. Out of six valproic acid-amino acid conjugates 2a-f. Only cysteine containing conjugate 2f showed the significant activity (IC 9.10 µM against HePG2 and 6.81 µM against HCT116). However conjugate 2j showed broad-spectrum antitumor activity against all cell lines tested. In addition, conjugates 4j and 4k which contains phenyl hydrazide and hydroxamic acid group, respectively, also showed broad spectrum activity. Furthermore, six compounds were screened for HDAC 1-9 isozymes inhibitory activities. Compounds 2j, 4j and 4k manifested a higher inhibitory activity more than valproic acid but less than SAHA. In addition, the in vivo antitumor screening of 2j, 4j and 4k was done and the results have shown that 2j, 4j and 4k, particularly 4j, showed a significant decrease in tumor size and presented a considerable decrease in viable EAC count. Docking study of selectedcompound 4j revealed that it can bind nicely to the binding pocket of HDAC 1, 2, 3, 4 and HDAC 8. The results suggest that compounds 2j, 4j and 4k, particularly 4j, may be promising lead candidates for the development of novel targeted anti-tumor drug potentially via inhibiting HDACs.
已经设计和合成了 25 种丙戊酸缀合物。使用 MTT 法测定了所有目标化合物对四种人类癌细胞系（包括肝癌（HePG2）、结肠癌（HCT116）、乳腺癌（MCF7）和宫颈癌（HeLa））的体外增殖活性。在 6 种丙戊酸-氨基酸缀合物 2a-f 中，只有含半胱氨酸的缀合物 2f 显示出显著的活性（对 HePG2 的 IC 9.10 µM 和对 HCT116 的 6.81 µM）。然而，缀合物 2j 对所有测试的细胞系均表现出广谱抗肿瘤活性。此外，分别含有苯肼和羟肟酸基团的缀合物 4j 和 4k 也表现出广谱活性。此外，筛选了 6 种化合物对 HDAC 1-9 同工酶的抑制活性。化合物 2j、4j 和 4k 表现出比丙戊酸更高的抑制活性，但比 SAHA 低。此外，对 2j、4j 和 4k 的体内抗肿瘤筛选结果表明，2j、4j 和 4k，特别是 4j，显著减小了肿瘤体积，并使 EAC 活细胞计数有了相当大的减少。对选定化合物 4j 的对接研究表明，它可以很好地结合到 HDAC 1、2、3、4 和 HDAC 8 的结合口袋中。结果表明，化合物 2j、4j 和 4k，特别是 4j，可能是通过抑制 HDACs 开发新型靶向抗肿瘤药物的有前途的候选药物。
