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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.
AuthorsHaruhiko Fuwa, Kana Mizunuma, Makoto Sasaki, Takaya Suzuki, Hiroshi Kubo
JournalOrganic & biomolecular chemistry (Org Biomol Chem) Vol. 11 Issue 21 Pg. 3442-50 (Jun 07 2013) ISSN: 1477-0539 [Electronic] England
PMID23538720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Macrolides
  • exiguolide
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Humans
  • Macrolides (chemical synthesis, chemistry, pharmacology)
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Neoplasms (drug therapy)
  • Structure-Activity Relationship

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