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Published on: June 13, 2022
Amphidinolide B: total synthesis, structural investigation, and biological evaluation
Liang Lu1, Wei Zhang, Sangkil Nam
1Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States.
The Journal of Organic Chemistry
|February 15, 2013
Summary
Total syntheses of amphidinolide B1 and B2 were achieved, revealing potent anticancer activities. Epoxide stereochemistry significantly influences the efficacy of these marine natural products against various cancer cells.
Area of Science:
- Organic Chemistry
- Natural Product Synthesis
- Medicinal Chemistry
Background:
- Amphidinolides are marine natural products with known biological activities.
- The total synthesis of complex natural products is crucial for structure confirmation and analog development.
Purpose of the Study:
- To achieve the total synthesis of amphidinolide B1 and the proposed structure of amphidinolide B2.
- To evaluate the antitumor activities of amphidinolide B2 and its stereoisomers.
- To investigate the role of epoxide stereochemistry in anticancer activity.
Main Methods:
- Development of a non-transition-metal-mediated method for C13-C15 diene construction.
- Utilizing α-chelation and dipole minimization models for diastereoselective aldol reactions.
- Employing a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy.
- Establishing a novel late-stage method for allylic epoxide moiety construction.
Main Results:
- Successful total syntheses of amphidinolide B1 and amphidinolide B2.
- Amphidinolide B2 and its diastereomers exhibit potent antitumor activity (IC50: 3.3–94.5 nM) against human tumor cells.
- The proposed structure of amphidinolide B2 is over 12-fold more potent than its epimers in DU145 prostate cancer cells.
Conclusions:
- The total synthesis provides access to amphidinolides B1 and B2.
- Epoxide stereochemistry is a critical determinant of anticancer potency for amphidinolide B2.
- These findings support further investigation of amphidinolides as anticancer drug leads.
