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Paper | Special issue | Vol 97, No. 1, 2018, pp.478-492
Published online, 5th April, 2018
DOI: 10.3987/COM-18-S(T)37
Synthesis and Biological Activities of Acetal Analogs at Position 3 of 10-Methyl-Aplog-1, a Potential Anti-Cancer Lead Derived from Debromoaplysiatoxin

Koutaro Hayakawa, Yusuke Hanaki, Harukuni Tokuda, Ryo C. Yanagita, Yu Nakagawa, Mutsumi Okamura, Shingo Dan, and Kazuhiro Irie*

*Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Oiwakecho, Kitasirakawa, Sakyo-Ku, Kyoto City, Kyoto 606-8502, Japan

Abstract

10-Methyl-Aplog-1 (1), a simplified analog of tumor-promoting debromoaplysiatoxin (DAT), is a potential anti-cancer lead because, unlike DAT, 1 is not tumor-promoting or proinflammatory. However, its synthesis required 23 linear steps with an overall yield of 1.1%. To develop a more synthetically accessible compound, we designed a new analog (2) whose carbon atom at position 4 was replaced with an oxygen atom. Simultaneous construction of the spiroketal at position 7, the acetal at position 3, and the macrolactone ring enabled us to reduce the synthetic steps to produce 2 and its 3-epimer (16) in 18 linear steps with overall yields of 0.30 and 0.67% respectively. Although both analogs retained anti-proliferative activity, it was weaker than that of 1.