debromoaplysiatoxin and Skin-Neoplasms

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 (1) 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 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.

Topics: Animals; Antineoplastic Agents; Carcinogens; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Female; Humans; Lactones; Lyngbya Toxins; Male; Mice; Mice, Inbred ICR; Papilloma; Skin Neoplasms; Structure-Activity Relationship

Topics: Alkaloids; Animals; Carcinogens; Cell Adhesion; Cell Differentiation; Cocarcinogenesis; Enzyme Induction; Female; Lactones; Lyngbya Toxins; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Skin Neoplasms