Substituent effects on the hydrolysis of analogues of nitracrine {9-[3-(N,N-dimethylamino)propylamino]-1-nitroacridine}

Abstract

Studies of the hydrolysis of the hypoxia-selective cytotoxic agent 9-[3-(N,N-dimethylamino)-propylamino]-1-nitroacridine (nitracrine) and several of its 4-substituted analogues and nitro-positional isomers have been carried out. Examination of the effects of pH and temperature on the hydrolysis of nitracrine itself shows that the reaction is subject to acid catalysis. The value of ΔH^‡ increases from 46 to 63 kJ mol^–1 as the pH falls from 6 to 3, while the value of ΔS^‡ increases from –195 to –138 J K^–1 mol^–1. The rate constants for hydrolysis and the acid dissociation constants have been measured at pH 5 and 60 °C. Both the rate constants of hydrolysis, corrected for the substrate–protonation equilibrium, and the substrate–acid association constants are well fitted by the Ehrenson–Brownlee–Taft dual-substituent–parameter σ_R^– relationship. The Swain–Unger–Rosenquist–Swain relationship shows weak correlation but the linear free-energy relationships of Hammett and Yukawa–Tsuno are not fitted. The results are discussed in terms of the resonance interactions of the possible intermediates in the hydrolysis pathways.