Synthesis of Isocryptolepine-Triazole Adducts and Evaluation of Their Cytotoxic Activity.

Eighteen hybrid compounds between 8-bromo-2-fluoro-isocryptolepine (4) and 1,2,3-triazole were synthesized via azide rearrangement-annulation reaction. Compound 4 underwent regioselective N-propargylation and click reaction to form 8-bromo-2-fluoro-isocryptolepine-triazole hybrids 11 which were evaluated for cytotoxic activity. Compound 11c containing 1-anisyltriazole was the most effective in inhibiting HepG2, HuCCA-1 and A549 cell lines (IC50 values of 1.65-3.07 µM) while compounds 11a (1-phenyltriazole), 11j (1-para-CF3-benzyltriazole) and 11l (1-meta-Cl-benzyltriazole)  were potent inhibitors of HuCCA-1, HepG2 and A549 cell lines, respectively. Moreover, 11l showed the lowest cytotoxicity to normal human kidney cell line. Compounds 11c and 11l provided improvement of cytotoxic activity over 4. Compounds 4, 11c and 11l were selected to investigate their mechanisms of action. The results showed that 4 could induce G2/M cell cycle arrest and was involved in the upregulation of p53 and p21 proteins. However, the mechanisms of growth inhibition by 11c and 11l were associated with G0/G1 cell cycle arrest and mediated by induction of oxidative stress.