Design, Synthesis and Anti-Lung Cancer Evaluation of 1, 2, 3-Triazole Tethered Dihydroartemisinin-Isatin Hybrids

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/IC50: 7.54-73.8 mu M) were more potent than the parent drug dihydroartemisinin (IC50: 69.4-88.0 mu M) and also non-cytotoxic towards mouse embryonic fibroblast cells NIH/3T3 (IC50: >100 mu 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 (IC50: 7.54-12.1 mu M) and 9i (IC50: 9.10-15.9 mu M) were comparable to cisplatin (IC50: 7.54-15.9 mu M vs 9.38-19.7 mu M) against A549 and A549/DOX, but 4.6-7.6 folds more potent than that of cisplatin (IC50: 8.77-14.3 mu M vs 66.9 mu 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.

Automated summary

The designed and synthesized hybrids showed higher antiproliferative activity against lung cancer cell lines compared to the parent drug, while exhibiting no cytotoxicity towards normal cells. The structure-activity relationships revealed the significant influence of substituents on the isatin moiety on the activity of the hybrids.