Structure-based design of a novel synthetic spiroketal pyran as a pharmacophore for the marine natural product spongistatin 1.
SPIKET-P, a novel synthetic spiroketal pyran, was rationally designed as a pharmocophore for the tubulin depolymerizing marine natural product Spongistatin 1. SPIKET-P was prepared from the commercially available benzyl (R)-(-)-glycidyl ether using a versatile 11-step synthetic scheme in a stereocontrolled fashion. At nanomolar concentrations, SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells.
Uckun
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Drug Discovery Program and Parker Hughes Cancer Center, Parker Hughes Institute, St. Paul, MN 55113, USA.
Mao
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Vassilev
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Huang
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Jan
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D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004988:Ethers, Cyclic / Q000737:chemistry*; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D018942:Macrolides; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D009391:Nephelometry and Turbidimetry; D011161:Porifera / Q000737:chemistry; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D000095702:Polyether Toxins
D000970:Antineoplastic Agents; D004988:Ethers, Cyclic; D007783:Lactones; D018942:Macrolides; D011714:Pyrans; D013141:Spiro Compounds; D014404:Tubulin; C409002:SPIKET-P; C083856:spongistatin 1; D000095702:Polyether Toxins