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A new antimitotic substance, FR182877. III. Structure determination
S Yoshimura1, B Sato, T Kinoshita
1Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
The Journal of Antibiotics
|August 31, 2000
Summary
FR182877, a novel cell cycle inhibitor from Streptomyces, features a unique multi-ring structure. Its antitumor activity is linked to tubulin assembly, but epoxidation reduces efficacy.
Area of Science:
- Natural Product Chemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Screening for novel cell cycle inhibitors led to the isolation of FR182877 from Streptomyces sp. No.9885.
- FR182877 exhibited instability during structural elucidation, complicating initial analysis.
Purpose of the Study:
- To elucidate the structure of FR182877.
- To investigate the antitumor activities and mechanism of action of FR182877.
- To assess the impact of structural modifications on FR182877's activity.
Main Methods:
- Isolation from fermentation broth.
- Nuclear Magnetic Resonance (NMR) spectroscopy.
- Chemical correlations.
- In vitro antitumor assays.
- Tubulin assembly assays.
Main Results:
- FR182877 possesses an unprecedented multi-ring system with a strained double bond, susceptible to epoxidation by molecular oxygen.
- FR182877 demonstrated broad in vitro antitumor activities and promoted tubulin assembly, similar to taxol.
- Epoxidation of the strained double bond led to a significant decrease in antitumor activity.
Conclusions:
- FR182877 is a novel natural product with significant antitumor potential.
- The strained double bond and its epoxidation are critical for FR182877's biological activity.
- Further research into FR182877 analogs could lead to new cancer therapeutics.