title: 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.affiliation: a Division of Food Science and Biotechnology , Graduate School of Agriculture, Kyoto University , Kyoto , Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kikumori
authors.affiliation: b Faculty of Agriculture, Department of Applied Biological Science , Kagawa University , Miki , Japan.
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.affiliation: c Department of Complementary and Alternative Medicine, Clinical R&D , Graduate School of Medical Science, Kanazawa University , Kanazawa , Japan.
authors.forename: Harukuni
authors.initials: H
authors.lastname: Tokuda
authors.affiliation: d Faculty of Science and Technology , Keio University , Yokohama , Japan.
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Suenaga
authors.affiliation: e Department of Ocean Sciences , Tokyo University of Marine Science and Technology , Tokyo , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagai
authors.affiliation: a Division of Food Science and Biotechnology , Graduate School of Agriculture, Kyoto University , Kyoto , Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002273:Carcinogens / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D008235:Lyngbya Toxins / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D007783:Lactones; D008235:Lyngbya Toxins; C017179:debromoaplysiatoxin
keywords: anti-proliferative; cancer; debromoaplysiatoxin; protein kinase C; tumor promoter