An Unexpected Hydrolysis pH-Rate Profile, at pH Values Less than 7, of the Labile Imide, ICRF-187: (+)-1,2-Bis-(3,5 -dioxopiperazin-1-yl)propane

Abstract

The hydrolysis of the cardioprotectant and anticancer agent, ICRF-187 (or ADR-529) and the structurally similar model compound, 4-methylpiperazine-2,6-dione (4-MP), was investigated in the acid to neutral pH range at 25°C and an ionic strength of 0.5 (sodium chloride). Their solution stability was shown to be compromised compared to 3-methylglutarimide (3-MG) and other imides. It appears that the tertiary piperazine nitrogens of ICRF-187 and 4-MP significantly contributed to the instability of these compounds over this pH range. Unexpectedly, bell-shaped curves were observed in the pH-rate profiles. A change in the rate-determining step from tetra-hedral intermediate formation in the weakly acidic pH region to breakdown of the tetrahedral intermediate in the more acidic pH regions was proposed as an explanation for the bell-shaped curves. The piperazine nitrogen was implicated in the hydrolytic pathways that occur within these pH regions; the mechanism of involvement was dependent on the state of ionization of the parent molecule and the tetrahedral intermediate.