Abstract |
We describe herein an enantioselective total synthesis of (-)- exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)- exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)- exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.
|
Authors | Haruhiko Fuwa, Takaya Suzuki, Hiroshi Kubo, Takao Yamori, Makoto Sasaki |
Journal | Chemistry (Weinheim an der Bergstrasse, Germany)
(Chemistry)
Vol. 17
Issue 9
Pg. 2678-88
(Feb 25 2011)
ISSN: 1521-3765 [Electronic] Germany |
PMID | 21264972
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Chemical References |
- Antineoplastic Agents
- Biological Products
- Macrolides
- exiguolide
|
Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Biological Products
(chemical synthesis, chemistry, pharmacology)
- Drug Screening Assays, Antitumor
- Geodia
(chemistry)
- Humans
- Macrolides
(chemical synthesis, chemistry, pharmacology)
- Molecular Structure
- Nuclear Magnetic Resonance, Biomolecular
- Stereoisomerism
- Structure-Activity Relationship
|