Spin labelled nitrosoureas and triazenes and their non-labelled clinically used analogues - a comparative study on their physicochemical properties and antimelanomic effects
Spin labelled nitrosoureas and triazenes and their non-labelled clinically used analogues - a comparative study on their physicochemical properties and antimelanomic effects
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DOI：
10.1016/s0378-5173(00)00611-6
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发表时间：
2001-01-16
影响因子：
5.8
通讯作者：
Gadjeva, VG
中科院分区：
文献类型：
--
作者：
Zheleva, AM;Gadjeva, VG
研究了本实验室合成的自旋标记（含硝基自由基部分）氨基酸亚硝基脲的理化性质，如半衰期（tau(0.5)）、烷基化和氨基酰基化活性以及体内抗黑素瘤B16的作用，并与抗肿瘤药物N'-环己基-N-（2-氯乙基）-N-亚硝基脲（洛莫斯汀，CCNU）进行了比较。我们已经证明，与CCNU相比，引入氨基酸部分和用硝基部分取代环己胺，可以更快地分解，更高的烷基化，更低的氨基酰基化活性，更好的抗黑素活性和更低的一般毒性。我们之前合成的自旋标记的三氮杂烯在磷酸盐盐中比未标记的类似物5-（3,3-二甲基三氮杂-1-基）-咪唑-4-carboxamide （dacarbazine， DTTC）更稳定。与DTIC相比，所有自旋标记三氮杂烯对B16黑色素瘤细胞的细胞毒性高于对YAC-1和淋巴细胞的细胞毒性。一个假设被用来解释自旋标记亚硝基脲的一般毒性比CCNU低。基于上述结果，我们认为合成选择性更强、毒性更小的亚硝基脲和三氮杂烯衍生物可能成为潜在的抗黑色素瘤药物。(C) 2001 Elsevier Science B.V.版权所有
Physicochemical properties, such as half life time (tau (0.5)), alkylating and carbamoylating activity and in vivo antimelanomic effects against B16 melanoma of spin labeled (containing nitroxyl free radical moiety) amino acid nitrosoureas, synthesized in our laboratory, have been studied and compared to those of the antitumor drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). We have shown that the introduction of amino acid moieties and the replacement of cyclohexylamine with nitroxyl moiety leads to a faster decomposition, higher alkylating, lower carbamoylating activity, better antimelanomic activity and lower general toxicity, when compared to those of CCNU. It was also established that spin labeled triazenes, previously synthesized by us: were more stable in phosphate saline than their nonlabeled analogue, 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (dacarbazine, DTTC). A higher cytotoxicity to B16 melanoma cells than to YAC-1 and lymphocytes was demonstrated for all spin labeled triazenes, in comparison with DTIC. An assumption has been made to explain the lower general toxicity of the spin labeled nitrosoureas compared to that of CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea and triazene derivatives as potential antimelanomic drugs might be developed. (C) 2001 Elsevier Science B.V. All rights reserved.