The hydrolysis activation of the doxorubicin cardioprotective agent ICRF-187 [+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane).
ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] has shown promise [Speyer et al., N. Engl. J. Med. 319, 745 (1988)] as a cardioprotective agent against what may be an iron-based doxorubicin (Adriamycin)-induced cardiotoxicity. ICRF-187 likely exerts its action through its rings-opened hydrolysis product, a compound that has an EDTA-type structure and, likewise, strongly binds metal ions. The hydrolysis of ICRF-187 was followed spectrophotometrically in the ultraviolet and was shown to be pseudo-first-order over a wide pH range. The hydrolysis mechanism was shown to have a hydroxide-catalyzed path and a pH-independent path similar to the hydrolysis of other imides. The anionic form of ICRF-187 (with a pKa of 9.6 at 37 degrees C) was resistant to hydroxide attack. The kinetically, spectroscopically and potentiometrically determined pKa values were all in excellent agreement and thus provided a test of the mechanism. Each imide group underwent hydrolysis and ionization independently of the other. The rate of ICRF-187 hydrolysis was also followed by observation of the removal of Cu2+ from a Cu2(+)-doxorubicin complex by the ICRF-187 hydrolysis product.
Hasinoff
B B
BB
Department of Chemistry, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
D055598:Chemical Phenomena; D002621:Chemistry; D003300:Copper; D004317:Doxorubicin / Q000032:analysis*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D010879:Piperazines / Q000032:analysis*; D011199:Potentiometry; D011929:Razoxane / Q000032:analysis*; D013056:Spectrophotometry, Ultraviolet
D010879:Piperazines; D011929:Razoxane; D003300:Copper; D004317:Doxorubicin