title: Synthesis and structure-activity relationship study of FD-891: importance of the side chain and C8-C9 epoxide for cytotoxic activity against cancer cells.
abstract: Unified synthesis of FD-891 analogs and their structure-activity relationship are described. By using stereoselective allylation/crotylation and Evans aldol chemistry, six side-chain fragments having different length and terminus were synthesized. These fragments were coupled with a macrolactone fragment, improved synthesis of which was also developed here, to generate FD-891 and five truncated analogs. These synthetic compounds as well as three analogs obtained from fermentation of gene-disrupted Streptomyces graminofaciens mutants were tested for in vitro cytotoxic activity against HeLa cells. As a result, coexistence of the C8-C9 epoxide and side-chain terminus was found to be critical for the cytotoxic activity.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Itagaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Kawamata
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hamada
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Iwabuchi
authors.affiliation: Graduate School of Science and Engineering, Tokyo Institute of Technology, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Eguchi
authors.affiliation: Graduate School of Science and Engineering, Tokyo Institute of Technology, Tokyo, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kudo
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanoh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004852:Epoxy Compounds / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D018942:Macrolides; C091118:FD 891
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