Structure-activity studies on the spiroketal moiety of a simplified analogue of debromoaplysiatoxin with antiproliferative activity

Masayuki Kikumori, Ryo C. Yanagita, Harukuni Tokuda, Nobutaka Suzuki, Hiroshi Nagai, Kiyotake Suenaga, Kazuhiro Irie

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Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar K i values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.

Original languageEnglish
Pages (from-to)5614-5626
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number11
Publication statusPublished - 2012 Jun 14


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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