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  • Title: Concise synthesis and biological assessment of (+)-neopeltolide and a 16-member stereoisomer library of 8,9-dehydroneopeltolide: identification of pharmacophoric elements.
    Author: Fuwa H, Kawakami M, Noto K, Muto T, Suga Y, Konoki K, Yotsu-Yamashita M, Sasaki M.
    Journal: Chemistry; 2013 Jun 17; 19(25):8100-10. PubMed ID: 23606326.
    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.
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