10'-Fluorovinblastine and 10'-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Jan 17

PMID 22247789

Citations 35

Authors

Hiroaki Gotoh

Katharine K Duncan

William M Robertson

Dale L Boger

Affiliations

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Abstract

A study on the impact of catharanthine C10 and C12 indole substituents on the biomimetic Fe(III)-mediated coupling with vindoline led to the discovery and characterization of two new and substantially more potent derivatives, 10'-fluorovinblastine and 10'-fluorovincristine. In addition to defining a pronounced and unanticipated substituent effect on the biomimetic coupling, fluorine substitution at C10', which minimally alters the natural products, was found to uniquely enhance the activity 8-fold against both sensitive (IC(50) = 800 pM, HCT116) and vinblastine-resistant tumor cell lines (IC(50) = 80 nM, HCT166/VM46). As depicted in the X-ray structure of vinblastine bound to tubulin, this site resides at one end of the upper portion of the T-shaped conformation of the tubulin-bound molecule, suggesting the 10'-fluorine substituent makes critical contacts with the protein at a hydrophobic site uniquely sensitive to steric interactions.

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