Anderson R F, Denny W A, Ware D C, Wilson W R
Department of Chemistry, University of Auckland, New Zealand.
Br J Cancer Suppl. 1996 Jul;27:S48-51.
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.
已使用脉冲辐解研究了钴（III）-氮芥配合物SN 24771（NSC 675352）体外缺氧选择性细胞毒性（HSC）的动力学基础。模型还原剂对SN 24771进行单电子还原的速率常数对还原剂的单电子还原电位表现出显著依赖性，其值比硝基咪唑药物米索硝唑慢几个数量级。单电子还原形成钴（II）配合物（物种I）后，会以120±10 s⁻¹和10±2 s⁻¹的一级速率常数连续转化为其他瞬态物种（II和III），且与配体释放有关。在添加浓度高达0.5 mmol l⁻¹的O₂时，这些后续过程均未受到抑制，这表明SN 24771的HSC作用最有可能源于一种不同于O₂使钴（III）和钴（II）形式之间简单氧化还原循环的机制。如果SN 24771的模型还原剂单电子还原的低速率常数（与硝基芳烃的还原相比）能被生物还原剂反映出来，那么有人提出HSC可能是通过SN 24771和O₂对这些还原剂的竞争而发生的。
