title: Concise synthesis and biological assessment of (+)-neopeltolide and a 16-member stereoisomer library of 8,9-dehydroneopeltolide: identification of pharmacophoric elements.
abstract: We describe herein a concise synthesis of (+)-neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond-forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross-metathesis reaction directed by H-bonding, and a ring-closing metathesis conducted under non-high dilution conditions. Moreover, we developed a 16-member stereoisomer library of 8,9-dehydroneopeltolide to systematically explore the stereostructure-activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HT-1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure-activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency.
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: Masato
authors.initials: M
authors.lastname: Kawakami
authors.forename: Kenkichi
authors.initials: K
authors.lastname: Noto
authors.forename: Takashi
authors.initials: T
authors.lastname: Muto
authors.forename: Yuto
authors.initials: Y
authors.lastname: Suga
authors.forename: Keiichi
authors.initials: K
authors.lastname: Konoki
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000599260:8,9-dehydroneopeltolide; D000970:Antineoplastic Agents; D018942:Macrolides; D010080:Oxazoles; C519136:neopeltolide