The 3-N-phenyl amide of all-cis-cyclopentane-1,2,3,4-tetracarboxylic acid as a potential pH-sensitive amine-releasing prodrug; intervention of imide formation around neutral pH.

Abstract

To assess the potential utility of the new amide [(1S,2R,3R,4R)-3-(phenylaminocarbonyl)cyclopentane-1,2,4-tricarboxylic acid] (10) as a pH-sensitive amine-releasing prodrug aimed at selective activation at the low extracellular pH of solid tumours, its reactivity in D2O was studied between pD 5 and 6.5. Neighbouring group catalysis of amide hydrolysis by unionised carboxylic acid groups was expected up to neutral pH, with this decreasing with increasing levels of ionisation. Rate measurements on 10 in D2O by UV at 27 o C gave k1 7.3 x 10 -5 s -1 (half-life ca 2.5 h) at pD 5.02 and 3.0 x 10 -5 s -1 (half-life ca 6.5 h) at pD 6.53. However, NMR monitoring of 10 in D2O showed that at pD 5 and above, formation of the 2,3- and 3,4-Nphenylimides of cyclopentane-1,2,3,4-tetracarboxylic acid (13 and 16) unexpectedly predominates over amide hydrolysis, thwarting the potential prodrug application. The rates together with variations in the product ratios with pD show that the rate of formation of 13 from 10 is only marginally reduced between pD 5 and 6.5 while the rates of formation of 16 and of hydrolysis products both decrease sharply. We report syntheses of 10 and the new imide 16, Xray crystal structure determinations of imides 13 and 16, as well as NMR data for their solutions in D2O at different levels of ionization.