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

Abstract	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.
Authors	Masayuki Kikumori, Ryo C Yanagita, Harukuni Tokuda, Nobutaka Suzuki, Hiroshi Nagai, Kiyotake Suenaga, Kazuhiro Irie
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 11 Pg. 5614-26 (Jun 14 2012) ISSN: 1520-4804 [Electronic] United States
PMID	22625994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Carcinogens Isoenzymes Lyngbya Toxins Spiro Compounds debromoaplysiatoxin Protein Kinase C
Topics	Animals Antineoplastic Agents (chemical synthesis, pharmacology, toxicity) Carcinogens (chemical synthesis, pharmacology, toxicity) Cell Line, Tumor Drug Screening Assays, Antitumor Enzyme Activation Humans Hydrophobic and Hydrophilic Interactions Isoenzymes (metabolism) Lyngbya Toxins (chemical synthesis, pharmacology, toxicity) Male Mice Mice, Inbred ICR Protein Binding Protein Kinase C (metabolism) Spiro Compounds (chemical synthesis, pharmacology, toxicity) Structure-Activity Relationship

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