College of Pharmacy, Guilin Medical University, Guilin 541199, China; The First People's Hospital of Fangchenggang, Fangchenggang 538021, China.
College of Pharmacy, Guilin Medical University, Guilin 541199, China.
Bioorg Med Chem Lett. 2022 Sep 15;72:128880. doi: 10.1016/j.bmcl.2022.128880. Epub 2022 Jul 7.
A series of novel pentanediamide derivatives were designed, synthesized and evaluated as S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitors in this study. Some compounds showed good inhibitory activity against SAHase. The optimal compound 7i showed good inhibitory activity against SAHase with IC value of 3.58 ± 0.19 μM, cytotoxicity with IC values ranging from 13.16 ± 1.44 to 21.23 ± 0.73 μM against four tumor cell lines (MCF-7, A549, MGC-803, Hela) and very weak cytotoxicity (IC = 84.22 ± 1.89 μM) on normal LO2 cells. In addition, compound 7i showed potency against respiratory syncytial virus with EC value of 27.4 μM and selectivity index of 6.84. Further molecular simulation study suggested that compound 7i had good ADMET properties, and strongly binds to the active site of SAHase. In summary, compound 7i could serve as a new lead compound for further screening novel non-adenosine SAHase inhibitors.
本研究设计、合成并评价了一系列新型戊二酰胺衍生物作为 S-腺苷-L-同型半胱氨酸水解酶（SAHase）抑制剂。一些化合物对 SAHase 表现出良好的抑制活性。最优化合物 7i 对 SAHase 表现出良好的抑制活性，IC 值为 3.58 ± 0.19 μM，对四种肿瘤细胞系（MCF-7、A549、MGC-803、Hela）的细胞毒性 IC 值范围为 13.16 ± 1.44 至 21.23 ± 0.73 μM，对正常 LO2 细胞的细胞毒性非常弱（IC = 84.22 ± 1.89 μM）。此外，化合物 7i 对呼吸道合胞病毒具有 EC 值为 27.4 μM 和选择性指数为 6.84 的活性。进一步的分子模拟研究表明，化合物 7i 具有良好的 ADMET 性质，并能与 SAHase 的活性部位强烈结合。综上所述，化合物 7i 可以作为进一步筛选新型非腺苷 SAHase 抑制剂的新先导化合物。
