Design, synthesis, and biological evaluation of novel 7-substituted 10,11-methylenedioxy-camptothecin derivatives against drug-resistant small-cell lung cancer in vitro and in vivo

A series of novel 7-substituted 10,11-methylenedioxy-camptothecin (FL118) derivatives were designed, syn-thesized, and biologically evaluated. All the FL118 analogues showed significant cytotoxic activities in vitro with IC50 values in the nanomolar range and were more potent than topotecan. The most active compound 9c exhibited more significant anti-tumor activity against small-cell lung cancer (NCI-H446, H69, drug-resistant H69AR cells, drug-resistant NCI-H446/Irinotecan cells and drug-resistant NCI-H446/EP cells) in vitro. Addi-tionally, 9c could also induce the expression of apoptosis proteins such as caspase-3, caspase-9, and PARP in small-cell lung cancer. Further studies showed that 9c induced apoptosis by inhibiting the expression of Mcl-1, Bcl-2, XIAP and survivin in small-cell lung cancer. In vivo 9c also showed better anti-tumor efficacy, with the tumor growth inhibition rates were 40.4% (0.75 mg/kg), 73.7% (1.5 mg/kg), and 95.5% (3 mg/kg). It is noteworthy that 9c also demonstrated potent inhibition of drug-resistant tumor growth in NCI-H446/Irinotecan and NCI-H446/EP xenograft models, the tumor growth inhibition rates were 93.42% and 84.46%, respectively. Taken together, these findings indicated that compound 9c displays outstanding antitumor activity and drug -resistance in small-cell lung cancer both in vivo and in vitro, which could be worth further research as a novel anti-tumor drug against small-cell lung cancer.