Novel nitroimidazole alkylsulfonamides as hypoxic cell radiosensitisers

被引:20
作者
Bonnet, Muriel [1 ]
Hong, Cho Rong [1 ]
Gu, Yongchuan [1 ]
Anderson, Robert F. [1 ]
Wilson, William R. [1 ]
Pruijn, Frederik B. [1 ]
Wang, Jingli [1 ]
Hicks, Kevin O. [1 ]
Hay, Michael P. [1 ]
机构
[1] Univ Auckland, Auckland Canc Soc Res Ctr, Auckland 1142, New Zealand
关键词
Nitroimidazole; Radiosensitiser; Sulfonamide; Hypoxia; STEREOTACTIC ABLATIVE RADIOTHERAPY; RADIATION-THERAPY; AQUEOUS-SOLUTION; NECK CARCINOMAS; TUMOR HYPOXIA; CANCER; HEAD; MISONIDAZOLE; TRIAL; ETANIDAZOLE;
D O I
10.1016/j.bmc.2014.02.039
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A novel class of nitroimidazole alkylsulfonamides have been prepared and evaluated as hypoxia-selective cytotoxins and radiosensitisers. The sulfonamide side chain markedly influences the physicochemical properties of the analogues: lowering aqueous solubility and raising the electron affinity of the nitroimidazole group. The addition of hydroxyl or basic amine groups increased aqueous solubility, with charged amine groups contributing to increased electron affinity. The analogues covered the range of electron affinity for effective radiosensitisation with one-electron reduction potentials ranging from -503 to -342 mV. Cytotoxicity under normoxia or anoxia against a panel of human tumour cell lines was determined using a proliferation assay. 2-Nitroimidazole sulfonamides displayed significant hypoxia-selective cytotoxicity ( 6 to 64-fold), while 4- and 5-nitroimidazole analogues did not display hypoxia-selective cytotoxicity. All analogues sensitised anoxic HCT-116 human colorectal cells to radiation at non-toxic concentrations. 2-Nitroimidazole analogues provided modest sensitisation due to the relatively low concentrations used while several 5-nitroimidazole analogues provided equivalent sensitisation to misonidazole and etanidazole at similar molar concentrations. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2123 / 2132
页数:10
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