Synthesis and biological activity of fluorinated combretastatin analogues

  • J Med Chem. 2008 May 8;51(9):2708-21. doi: 10.1021/jm701362m.
Domenico Alloatti  1 ,  Giuseppe Giannini ,  Walter Cabri ,  Isabella Lustrati ,  Mauro Marzi ,  Andrea Ciacci ,  Grazia Gallo ,  M Ornella Tinti ,  Marcella Marcellini ,  Teresa Riccioni ,  Mario B Guglielmi ,  Paolo Carminati ,  Claudio Pisano
Affiliations
  • 1. R&D, Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30.400, 00040 Pomezia, Italy.
PMID: 18396857 DOI: 10.1021/jm701362m
Abstract

With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.