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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. 1992

J M Sisco, and V J Stella
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.

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 degrees 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 tetrahedral 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.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D010879 Piperazines Compounds that are derived from PIPERAZINE.
D011929 Razoxane An antimitotic agent with immunosuppressive properties. ICRF-159,ICRF-186,NSC-129943,Razoxane Mesylate, (R)-Isomer,Razoxane, (R)-Isomer,Razoxin,ICRF 159,ICRF 186,ICRF159,ICRF186,NSC 129943,NSC129943
D004355 Drug Stability The chemical and physical integrity of a pharmaceutical product. Drug Shelf Life,Drugs Shelf Lives,Shelf Life, Drugs,Drug Stabilities,Drugs Shelf Life,Drugs Shelf Live,Life, Drugs Shelf,Shelf Life, Drug,Shelf Live, Drugs,Shelf Lives, Drugs
D006863 Hydrogen-Ion Concentration The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH pH,Concentration, Hydrogen-Ion,Concentrations, Hydrogen-Ion,Hydrogen Ion Concentration,Hydrogen-Ion Concentrations
D006868 Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water.

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