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

Abstract

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.

• Authors: Masayuki Kikumori, Ryo C Yanagita, Harukuni Tokuda, Kiyotake Suenaga, Hiroshi Nagai, Kazuhiro Irie
• Journal: Bioscience, biotechnology, and biochemistry (Biosci Biotechnol Biochem) Vol. 80 Issue 2 Pg. 221-31 ( 2016) ISSN: 1347-6947 [Electronic] England
• PMID: 26452398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Carcinogens
• Lactones
• Lyngbya Toxins
• debromoaplysiatoxin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Carcinogens (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Lactones (chemical synthesis, pharmacology)
• Lyngbya Toxins (chemical synthesis, pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Papilloma (chemically induced, pathology)
• Skin Neoplasms (chemically induced, pathology)
• Structure-Activity Relationship