NOTE: THE MATHEMATICAL SYMBOLS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. Nitrothienylprop-2-yl ether formation on the 3'-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized followingmodel kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promisingnew lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl a-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drugrel ease. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the a-carbon. Cellular and supersomal studies showed that this a-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.