Hou Haodong, Qu Bin, Su Chen, Hou Guihua, Gao Feng
Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Pharmacol. 2021 Dec 16;12:801580. doi: 10.3389/fphar.2021.801580. eCollection 2021.
A series of 1,2,3-triazole tethered dihydroartemisinin-isatin hybrids 8a-c and 9a-k were designed and synthesized. Their antiproliferative activity against A549, doxorubicin-resistant A549 (A549/DOX) as well as cisplatin-resistant A549 (A549/DDP) lung cancer cell lines was also investigated in this study. All hybrids (half maximal inhibitory concentration/IC: 7.54-73.8 M) were more potent than the parent drug dihydroartemisinin (IC: 69.4-88.0 M) and also non-cytotoxic towards mouse embryonic fibroblast cells NIH/3T3 (IC: >100 M). The structure-activity relationships illustrated that the substituents on C-3 and C-5 position of isatin moiety influenced the activity significantly. Imine at C-3 position decreased the activity, whereas fluoro at C-5 position enhanced the activity. In particular, hybrids 8a,c (IC: 7.54-12.1 M) and 9i (IC: 9.10-15.9 M) were comparable to cisplatin (IC: 7.54-15.9 M 9.38-19.7 M) against A549 and A549/DOX, but 4.6-7.6 folds more potent than that of cisplatin (IC: 8.77-14.3 M 66.9 M) against A549/DDP cells. Moreover, hybrids 8a,c exhibited excellent stability (liver microsomes: 68-83%) in mouse/human microsomes and good pharmacokinetic properties, demonstrating their potential as a novel anti-lung cancer chemotherapeutic candidates.
设计并合成了一系列1,2,3-三唑连接的双氢青蒿素-异吲哚酮杂合物8a-c和9a-k。本研究还考察了它们对A549、多柔比星耐药的A549（A549/DOX）以及顺铂耐药的A549（A549/DDP）肺癌细胞系的抗增殖活性。所有杂合物（半数最大抑制浓度/IC：7.54-73.8 μM）均比母体药物双氢青蒿素（IC：69.4-88.0 μM）更有效，且对小鼠胚胎成纤维细胞NIH/3T3无细胞毒性（IC：>100 μM）。构效关系表明，异吲哚酮部分C-3和C-5位的取代基对活性有显著影响。C-3位的亚胺降低了活性，而C-5位的氟增强了活性。特别是，杂合物8a、c（IC：7.54-12.1 μM）和9i（IC：9.10-15.9 μM）对A549和A549/DOX的活性与顺铂（IC：7.54-15.9 μM 9.38-19.7 μM）相当，但对A549/DDP细胞的活性比顺铂（IC：8.77-14.3 μM 66.9 μM）高4.6-7.6倍。此外，杂合物8a、c在小鼠/人微粒体中表现出优异的稳定性（肝微粒体：68-83%）和良好的药代动力学性质，表明它们作为新型抗肺癌化疗候选药物的潜力。
