Organic Letters · 2005 · 47 citations · 6 references
MedicineMedicinal ChemistryPharmacologyCancer PharmacologyMolecular OncologyMolecular PharmacologyMicrotubule-associated ProteinsMicrotubule-targeting AgentsOncology PharmacologyPharmacodynamics Of Anticancer AgentsBinding Affinity To TubulinBiological Evaluation ReportDrug Binding Sites On TubulinMethyl Group ReplacementMicrotubule Inhibitor ResistanceTotal Synthesis-derived AnaloguesTubulin Binding InhibitionTubulin Binding Sites
[structure: see text] (-)-16-Normethyldictyostatin has been made by total synthesis and is a potent antitumor agent in cells expressing wild-type tubulin and in one mutant cell line that is resistant to paclitaxel, but it is much less active than dictyostatin in another paclitaxel-resistant cell line where Val is substituted for Phe270. This provides strong evidence that the C16 methyl group of the dictyostatins is oriented toward Phe270 in the paclitaxel-binding site on beta-tubulin.
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