title: Total synthesis and biological evaluation of (-)-exiguolide analogues: importance of the macrocyclic backbone.
abstract: (-)-Exiguolide (1), isolated from the marine sponge Geodia exigua, has been shown to inhibit the growth of the A549 human lung adenocarcinoma and NCI-H460 human lung large cell carcinoma cells in vitro. In this study, we synthesized structural analogues of 1 to explore its skeletal structure-activity relationships and found that the C18 methyl group and the configuration of the C16-C17 double bond of 1 are important for the potent antiproliferative activity. Furthermore, we prepared a series of side-chain analogues of 1 by diversification of a late-stage intermediate of our total synthesis, and found that the triene side chain of 1 could be modified to some extent without significant loss of activity, provided a Lewis basic heteroatom is placed at the terminus.
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan. hfuwa@m.tohoku.ac.jp
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Fuwa
authors.forename: Kana
authors.initials: K
authors.lastname: Mizunuma
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Takaya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018942:Macrolides; C527475:exiguolide