Three-Carbon Linked Dihydroartemisinin-Isatin Hybrids: Design, Synthesis and Their Antiproliferative Anticancer Activity

Fifteen dihydroartemisinin-isatin hybrids (5a-e and 6a-j) linked with three-carbon were designed, synthesized. The antiproliferative activity against lung cancer cell lines including drug-sensitive A549, doxorubicin-resistant A549 (A549/DOX) and cisplatin-resistant A549 (A549/DDP) lung cancer cell lines was tested. The cytotocivity towards normal lung epithelial BEAS-2B cell line was also investigated. From the structure-activity relationship (SAR), it was found that hydrogen bond donors (especially hydroxime and thiosemicarbazide) at C-3 position and electron-withdrawing groups (fluoro and chloro) at C-5 position of isatin moiety were beneficial for the activity. A significant part of them (half maximal inhibitory concentration/IC50: 5.72-55.52 mu M) demonstrated considerable antiproliferative activity, and the activity was superior to that of dihydroartemisinin (IC50: 69.42-88.03 mu M) and artemisinin (IC50: >100 mu M). In particular, two hybrids 6a, e (IC50: 5.72-9.84 mu M) were not inferior to doxorubicin (IC50: 4.06 mu M) and cisplatin (IC50: 9.38 mu M) against drug-sensitive A549 cells and were more potent than doxorubicin (IC50: 54.32 and 15.10 mu M) and cisplatin (IC50: 19.74 and 66.89 mu M) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrids 6a, e (IC50: >100 mu M) showed no toxicity towards BEAS-2B cells, proving their excellent selectivity profile. Furthermore, hybrid 6a also possessed good stability in mouse and human microsomes, as well as excellent pharmacokinetic properties. Accordingly, hybrid 6a could serve as a promising anti-lung cancer chemotherapeutic candidate for further preclinical evaluations.

Automated summary

A series of dihydroartemisinin-isatin hybrids were designed and synthesized, and their antiproliferative activity against lung cancer cell lines was evaluated. The hybrids showed significant activity, surpassing the activity of dihydroartemisinin and artemisinin. In particular, hybrid 6a demonstrated comparable activity to common chemotherapeutic drugs and showed higher potency against multidrug-resistant lung cancer cell lines. Furthermore, hybrid 6a exhibited good selectivity and stability, making it a promising candidate for further development as an anti-lung cancer chemotherapeutic agent.