The anti-lung cancer activity of propylene tethered dihydroartemisinin-isatin hybrids

Nineteen propylene tethered dihydroartemisinin-isatin hybrids 5a-g and 6a-l were designed, synthesized, and screened for their in vitro antiproliferative activity against three lung cancer cell lines, inclusive of drug-sensitive (A549), doxorubicin-resistant A549 (A549/DOX) and cisplatin-resistant A549 (A549/DDP) cell lines. The cytotoxicity of the synthesized hybrids towards normal lung epithelial cell line (BEAS-2B) was also assessed to evaluate the selectivity. The structure-activity relationship (SAR) elucidated that (1) alkyloxylimino fragment at C-3 position of isatin moiety were more favorable than the carbonyl and benzoxylimino, and the relative contricution order was methoxylimino > ethoxylimino > carbonyl > benzoxylimino; halogen atom at C-5 or C-6 position of isatin fragment could enhance the activity. Among them, hybrid 6f (IC₅₀: 21.7–28.9 μM) showed promising activity against the three tested lung cancer cell lines, and the activity was not inferior to that of cisplatin (IC₅₀: 19.7 and 66.9 μM) and doxorubicin (IC₅₀: 54.3 and 15.1 μM) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrid 6f (IC₅₀: >100 μM) was non-cytotoxic towards normal lung epithelial cell line (BEAS-2B), and the RI values of hybrid 6f were 1.12 and 1.33. Further, hybrid 6f also possessed acceptable stability in mouse and human microsomes. Accordingly, hybrid 6a was a promising anti-lung cancer chemotherapeutic candidate and merited further evaluations.