Design and synthesis of 3′- and 5′-O-(3-benzenesulfonylfuroxan-4-yl)-2′-deoxyuridines:: Biological evaluation as hybrid nitric oxide donor-nucleoside anticancer agents
Design and synthesis of 3′- and 5′-O-(3-benzenesulfonylfuroxan-4-yl)-2′-deoxyuridines:: Biological evaluation as hybrid nitric oxide donor-nucleoside anticancer agents
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DOI：
10.1021/jm030544m
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发表时间：
2004-03-25
影响因子：
7.3
通讯作者：
Knaus, EE
中科院分区：
文献类型：
--
作者：
Moharram, S;Zhou, A;Knaus, EE
合成了一组在核苷部分的 C-5 位具有多种取代基（H、Me、1、F、CF3）的 3'-O- 和 5'-O-（3-苯磺酰基呋喃氧烷-4-基）-2'-脱氧尿苷，用于评估作为能够同时释放细胞毒性一氧化氮的混合抗癌剂 （（NO）-N-。）。在 18 MM L-半胱氨酸存在下孵育这些一氧化氮供体-核苷缀合物，释放出高百分比的 (NO)-N-。 （1 小时时为 21-48%；16 小时时为 37-86%）。 (NO)-N-的释放。在没有硫醇辅助因子的情况下可以忽略不计。这些杂合体(NO)-N-。供体核苷对一系列肿瘤细胞系（143B-LTK、14313、EMT-6、KBALB-STK 和 KBALB）和正常人成纤维细胞（Hs578Bst）表现出高细胞毒性（CC50 = 10(-6)-10(-8) M 范围）。未观察到具有 1 型单纯疱疹病毒 (HSV-1) 胸苷激酶基因 (TK+) 的未转染 (143B、KBALB) 和相应转染 (143B-LTK、KBALB-STK) 癌细胞系之间的细胞毒性差异，表明病毒 TK 酶的表达没有提供基因治疗效果。
A group of 3'-O- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines possessing a variety of substituents (H, Me, 1, F, CF3) at the C-5 position of the nucleoside moiety were synthesized for evaluation as hybrid anticancer agents that have the ability to simultaneously release cytotoxic nitric oxide ((NO)-N-.). Incubation of these nitric oxide donor-nucleoside conjugates in the presence of 18 MM L-cysteine released a high percentage of (NO)-N-. (21-48% at 1 h; 37-86% at 16 h). The release of (NO)-N-. in the absence of the thiol cofactor was negligible. These hybrid (NO)-N-. donor-nucleosides exhibited high cellular toxicity (CC50 = 10(-6)-10(-8) M range) against a battery of tumor cell lines (143B-LTK, 14313, EMT-6, KBALB-STK, and KBALB) and normal human fibroblasts (Hs578Bst). No differences in cytotoxicity between nontransfected (143B, KBALB) and the corresponding transfected (143B-LTK, KBALB-STK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+) were observed, indicating that expression of the viral TK enzyme did not provide a gene therapeutic effect.