Design, Synthesis, and Biological Activity of Sulfonamide Analogues of Antofine and Cryptopleurine as Potent and Orally Active Antitumor Agents

Due to their profound antiproliferative activity and unique mode of action, phenanthro­indolizidine and phenanthro­quinolizidine alkaloids, represented by antofine and cryptopleurine, have attracted attention recently as potential therapeutic agents. We have designed, synthesized, and evaluated the methanesulfonamide analogues of these natural alkaloids with the hope of improving their druglikeness. The analogues showed enhanced growth inhibition of human cancer cells compared with the parent natural products. In particular, a methanesulfonamide analogue of cryptopleurine (<b>5b</b>) exhibited improved bioavailability and significant antitumor activity, which suggests that <b>5b</b> is a promising new anticancer agent. Our studies suggest that the inhibition of cancer cell growth by <b>5b</b> is associated with the induction of G0/G1 cell cycle arrest via nicotinamide <i>N</i>-methyltransferase-dependent JNK activation in Caki-1 renal cancer cells. In addition, compound <b>5b</b> significantly inhibited the migration and invasion of Caki-1 cancer cells by modulating the p38 MAPK signaling pathway