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 (5b) exhibited improved bioavailability
and significant antitumor activity, which suggests that 5b is a promising new anticancer agent. Our studies suggest that the
inhibition of cancer cell growth by 5b is associated
with the induction of G0/G1 cell cycle arrest via nicotinamide N-methyltransferase-dependent JNK activation in Caki-1 renal
cancer cells. In addition, compound 5b significantly
inhibited the migration and invasion of Caki-1 cancer cells by modulating
the p38 MAPK signaling pathway.