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.
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.
Sisco
J M
JM
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
Stella
V J
VJ
D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D010879:Piperazines / Q000737:chemistry; D011929:Razoxane / Q000737:chemistry*
D010879:Piperazines; D011929:Razoxane; C077079:4-methylpiperazine-2,6-dione