Evading Pgp activity in drug-resistant cancer cells: a structural and functional study of antitubulin furan metotica compounds.

ABSTRACT: Tumor resistance to antitubulin drugs resulting from P-glycoprotein (Pgp) drug-efflux activity, increased expression of the βIII tubulin isotype, and alterations in the drug-binding sites are major obstacles in cancer therapy. Consequently, novel antitubulin drugs that overcome these challenges are of substantial interest. Here, we study a novel chemotype named furan metotica that localizes to the colchicine-binding site in β-tubulin, inhibits tubulin polymerization, and is not antagonized by Pgp. To elucidate the structure-activity properties of this chiral chemotype, the enantiomers of its most potent member were separated and their absolute configurations determined by X-ray crystallography. Both isomers were active and inhibited all 60 primary cancer cell lines tested at the U.S. Natio

SUBMITTER: Nguyen TL 

PROVIDER: S-EPMC3349764 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature