Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China.
Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China.
Molecules. 2020 Nov 21;25(22):5459. doi: 10.3390/molecules25225459.
Many sulfonamides show anticancer activity. Based on benzenesulfonylazaspirodienone (HL-X9) identified in our previous work, we optimized the lead compound for better efficacy, thereby synthesizing a series of novel 4-(aromatic sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-one derivatives through a key step of metal-catalyzed cascade cyclization. The preliminary antiproliferative tests have shown that the anticancer activities of acetyl-protected mannose-linked sulfonylazaspirodienone derivatives (-) have been greatly improved. Among them, is the most potent derivative, with IC values of 0.17 µM, 0.05 µM, and 0.07 µM for A549, MDA-MB-231, and HeLa cell lines, respectively. Flow cytometry analysis shows that arrests MDA-MB-231 cells in the G2/M phase and has a certain effect on the apoptosis of MDA-MB-231 cells. In addition, the acute toxicity of was lower than that of adriamycin.
许多磺胺类药物具有抗癌活性。基于我们之前工作中鉴定出的苯磺酰氮杂螺[4.5]癸-6,9-二烯-8-酮（HL-X9），我们对先导化合物进行了优化以提高疗效，从而通过关键的金属催化级联环化步骤合成了一系列新型的 4-（芳基磺酰基）-1-氧代-4-氮杂螺[4.5]癸-6,9-二烯-8-酮衍生物。初步的抗增殖测试表明，乙酰保护的甘露糖连接的磺酰氮杂螺[4.5]癸-6,9-二烯酮衍生物（-）的抗癌活性得到了极大的提高。其中，化合物 对 A549、MDA-MB-231 和 HeLa 细胞系的 IC 值分别为 0.17 µM、0.05 µM 和 0.07 µM，是最有效的衍生物。流式细胞术分析表明，化合物 使 MDA-MB-231 细胞停滞在 G2/M 期，并对 MDA-MB-231 细胞的凋亡有一定的影响。此外，化合物 的急性毒性低于阿霉素。
