Radiolytic and cellular reduction of a novel hypoxia-activated cobalt(III) prodrug of a chloromethylbenzindoline DNA minor groove alkylator

被引:65
作者
Ahn, G-One [1 ]
Botting, K. Jane [1 ]
Patterson, Adam V. [1 ]
Ware, David C. [1 ]
Tercel, Moana [1 ]
Wilson, William R. [1 ]
机构
[1] Univ Auckland, Auckland Canc Soc Res Ctr, Auckland, New Zealand
关键词
tumour hypoxia; prodrug; ionising radiation; Co(III) complex; CBI; DNA minor groove alkylator;
D O I
10.1016/j.bcp.2006.03.007
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Metabolic reduction can be used to activate prodrugs in hypoxic regions of tumours, but reduction by ionising radiation is also theoretically attractive. Previously, we showed that a cobalt(III) complex containing 8-hydroxyquinoline (8-HQ) and cyclen ligands releases 8-HQ efficiently on irradiation in hypoxic solutions [Ahn G-O, Ware DC, Denny WA, Wilson WR. optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs. Radiat Res 2004;162:315-25]. Here we investigate an analogous Co(III) complex containing the potent DNA minor groove alkylator azachloromethylbenzindoline (azaCBI, (1) under bar) to determine whether it releases (1) under bar on radiolytic and/or enzymatic reduction under hypoxia. Monitoring by HPLC, the azaCBI ligand in the Co(III)(cyclen)(azaCBI) complex M slowly hydrolysed in aqueous solution, in contrast to the free ligand 1 which readily converted to its reactive cyclopropyl form. Irradiation of 2 (3050 mu M) in hypoxic solutions released (1) under bar with yields of 0.57 mu mol/J in formate buffer and 0.13 mu mol/J in human plasma. Using bioassay methods, cytotoxic activation by irradiation of at 1 mu M in hypoxic plasma was readily detectable at clinically relevant doses (>= 1 Gy), with a estimated yield of (1) under bar of 0.075 mu mol/J. Release of 1 from 2 was also observed in hypoxic HT29 cultures without radiation, with subsequent conversion of 1 to its O-glucuronide. Surprisingly, overexpression of human cytochrome P450 reductase in A549 cells did not increase the rate of metabolic reduction of 2, suggesting that other reductases and/or non-enzymatic reductants are responsible. Thus the cobalt(III) complex 2 is a promising prodrug capable of being activated to release a very potent cytotoxin when reduced by either ionising radiation or cells under hypoxic conditions. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:1683 / 1694
页数:12
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