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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.
- Authors
Fuwa, Haruhiko; Kawakami, Masato; Noto, Kenkichi; Muto, Takashi; Suga, Yuto; Konoki, Keiichi; Yotsu‐Yamashita, Mari; Sasaki, Makoto
- 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.
- Subjects
STEREOISOMERS; ISOMERISM; MACROCYCLIC compounds; HETEROCYCLIC compounds; STEREOCHEMISTRY
- Publication
Chemistry - A European Journal, 2013, Vol 19, Issue 25, p8100
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201300664