Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 2014, Aljouf, Saudi Arabia.
Bioorg Chem. 2019 Oct;91:103127. doi: 10.1016/j.bioorg.2019.103127. Epub 2019 Jul 18.
A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation.
设计、合成并评价了一系列新型 5,6,7,8-四氢[1]苯并噻吩[2,3-d]嘧啶-4(3H)-酮衍生物，这些衍生物带有作为锌结合基团（ZBG）的羟肟酸、2-氨基苯甲酰胺和酰肼部分。大多数测试的化合物表现出强到中等的 HDAC 抑制活性。其中一些化合物对人 HepG2、MCF-7 和 HCT-116 细胞系表现出很强的抗增殖活性。特别是化合物 IVa、IVb、IXa 和 IXb 与作为参比的 SAHA 相比，对三种测试的细胞系表现出显著的抗增殖活性。化合物 IVb 对 HDAC1 和 HDAC2 的抑制活性与 SAHA 相当。显然，游离羟肟酸基团的存在对于锌结合亲和力是必需的，其最大活性与 6 个碳原子的脂肪族连接子有关。对接研究结果表明，化合物 IVb 可以占据 HDAC2 的结合位点，并有可能通过 HDAC 抑制发挥抗肿瘤活性，这值得进一步研究。
