Structural optimization of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, as an anticancer lead

Aplog-1 is a simplified analog of debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (<b>1</b>) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (<b>2</b>, <b>3</b>) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (<b>2</b>) had stronger inhibitory effects on the growth of several human cancer cell lines than <b>1</b> and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (<b>3)</b> displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of <b>1</b> and DAT. Compound <b>2</b> would be the optimized seed for anticancer drugs among the simplified analogs of DAT.