Abstract
The kinetic basis for the in vitro hypoxia-selective cytotoxicity (HSC) of the Co(III)-nitrogen mustard complex SN 24771 (NSC 675352) has been investigated using pulse radiolysis. The rate constants for the one-electron reduction of SN 24771 by model reductants exhibited a marked dependence on the one-electron reduction potential of the reductant, with values up to several orders of magnitude slower than for the nitroimidazole drug misonidazole. Following one-electron reduction to form the Co(II) complex (species I) consecutive conversion to further transient species (II and III) occurs with first order rate constants of 120 +/- 10 s-1 and 10 +/- 2 s-1 and are associated with release of ligands. Neither of these subsequent processes are inhibited by the addition of O2 up to a concentration of 0.5 mmol l-1 suggesting that the HSC action of SN 24771 most likely arises from a mechanism other than simple redox cycling between the Co(III) and Co(II) forms by O2. If the measured low rate constants of one-electron reduction by model reductants of SN 24771 (as compared to the reduction of nitroaromatics), is mirrored by biological reductants, then it is proposed that HSC may occur through competition between SN 24771 and O2 for these reductants.
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Selected References
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