cardiovascular-agents and 1-2-bis(3-5-dioxopiperazin-1-yl)ethane

This study investigates the solution thermodynamics of the iron complexes of dexrazoxane (ICRF-187, (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane), [Fe(ADR-925)](+/0), and its desmethyl derivative ICRF-154, [Fe(ICRF-247)H2O](+/0). The solid state structure of [Fe(ICRF-247)H2O]+ is also reported. [Fe(ICRF-247)H2O]Br x 0.5NaBr x H2O crystallizes in the P42(1)2 space group with Z = 4, a = 14.9851(8), b = 14.9851(8), c = 8.0825(9) A and R = 0.03(2) for 1839 reflections and exhibits a pentagonal bipyramidal geometry with a labile water molecule occupying the seventh coordination site. Potentiometric titrations (FeL = 8.5 mM, 0.1 M NaNO3, 25 degrees C) reveal stable monomeric complexes (log Kf = 18.2 +/- 0.1, [Fe(ADR-925)]+, and 17.4 +/- 0.1, [Fe(ICRF-247)H2O]+) exist in solution at relatively low pH. Upon addition of base, the iron-bound water is deprotonated; the pKa values for [Fe(ICRF-247)H2O]+ and [Fe(ADR-925)]+ are 5.63 +/- 0.07 and 5.84 +/- 0.07, respectively. At higher pH both complexes undergo mu-oxo dimerization characterized by log Kd values of 2.68 +/- 0.07 for [Fe(ICRF-247)H2O]+ and 2.23 +/- 0.07 for [Fe(ADR-925)]+. In the presence of an oxidant and reductant, both [Fe(ICRF-247)H2O]+ and [Fe(ADR-925)]+ produce hydroxyl radicals that cleave pBR322 plasmid DNA at pH 7 in a metal complex concentration-dependent manner. At low metal complex concentrations (approximately 10(-5) M) where the monomeric form predominates, cleavage by both FeICRF complexes is efficient while at higher concentrations (approximately 5 x 10(-4) M) DNA cleavage is hindered. This change in reactivity is in part accounted for by dimer formation.

Topics: Cardiovascular Agents; Crystallography, X-Ray; DNA; Hydrolysis; Iron; Magnetic Resonance Spectroscopy; Molecular Structure; Razoxane; Solutions; Thermodynamics

Histologic and biochemical studies were carried out to compare the protective activity of various bisdiketopiperazines against the cardiac and renal toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR), a well-established animal model of this disorder, with: (1) the rates of hydrolysis of these agents to form the iron-chelating derivatives (which are considered to cause a decrease in the formation of reactive oxygen intermediates) and (2) the ability of these derivatives to bind iron. SHR were given 12 weekly injections of doxorubicin, 1 mg/kg i.v. either alone or 30 min after the administration of ICRF-154, ICRF-187, ICRF-192, ICRF-197, ICRF-198, ICRF-239 and ADR-559. Semiquantitative grading of the severity of the resulting cardiac and renal lesions showed that ICRF-187, ICRF-154 and ADR-559 were the most protective, whereas ICRF-197 and ICRF-239 provided intermediate degrees of protection, and ICRF-192 and ICRF-198 were not protective. Quantitative measurements in vitro revealed only relatively small differences in the rates of opening of the two diketopiperazine rings of the various agents to form the corresponding iron-chelating diacid diamide derivatives, and in the ability of these various derivatives to remove iron from the iron-doxorubicin complex. Such differences showed no relationship with cardioprotective activity. Some bisdiketopiperazines (including ICRF-154 and ICRF-187) with cardioprotective activity also are inhibitors of DNA topoisomerase II; however, the significance of this relationship remains uncertain, since ADR-925, the open-ring derivative of ICRF-187, does not inhibit DNA topoisomerase II.

Topics: Animals; Antibiotics, Antineoplastic; Cardiovascular Agents; Chelating Agents; Diketopiperazines; DNA Topoisomerases, Type II; Doxorubicin; Ethylenediamines; Glycine; Heart; Hydrolysis; Iron; Male; Myocardium; Piperazines; Rats; Rats, Inbred SHR; Razoxane