title: 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.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kikumori
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.forename: Harukuni
authors.initials: H
authors.lastname: Tokuda
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagai
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Suenaga
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002273:Carcinogens / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000378:metabolism; D008235:Lyngbya Toxins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D007527:Isoenzymes; D008235:Lyngbya Toxins; D013141:Spiro Compounds; C017179:debromoaplysiatoxin; D011493:Protein Kinase C