Synthesis of 5-(carboranylalkylmercapto)-2'-deoxyuridines and 3-(carboranylalkyl)thymidines and their evaluation as substrates for human thymidine kinases 1 and 2.
Synthesis of 5-(carboranylalkylmercapto)-2'-deoxyuridines and 3-(carboranylalkyl)thymidines and their evaluation as substrates for human thymidine kinases 1 and 2.
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5-(碳硼烷基烷基巯基)-2-脱氧尿苷和 3-(碳硼烷基烷基)胸苷的合成及其作为人胸苷激酶 1 和 2 底物的评估。
DOI：
10.1021/jm990125i
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Tjarks,W
中科院分区：
文献类型：
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作者：
Lunato,AJ;Wang,J;Woollard,JE;Anisuzzaman,AK;Ji,W;Rong,FG;Ikeda,S;Soloway,AH;Eriksson,S;Ives,DH;Blue,TE;Tjarks,W
合成了N-3位含邻碳硼烷烷基的胸苷衍生物和C-5位含邻碳硼烷烷基巯基的2 ′-脱氧尿苷衍生物。烷基间隔基由4 - 8个亚甲基单元组成。前一种化合物的合成需要3 - 4个反应步骤，总产率高达75%，后一种化合物的合成需要9 - 10个反应步骤，总产率明显较低。胸苷衍生物取代carboranylalkyl取代基在N-3位和短间隔被磷酸化的重组和纯化的胞质胸苷激酶（TK 1）到一个相对较高的程度。在C-5位具有碳硼烷基取代基的测试的2 ′-脱氧尿苷衍生物均未被重组或纯化的TK 1磷酸化。用重组线粒体胸苷激酶（TK 2）检测到的一些C-5取代核苷的磷酸化产物的量较低，但显着，并且随着烷基间隔基长度的增加而减少。本研究中获得的数据似乎不支持在合成新的C-5-和N-3-取代的碳硼烷核苷中应用的系链概念，该概念旨在减少碳硼烷核苷与脱氧核苷激酶结合中可能的空间干扰。相反，看起来大体积碳硼烷部分与核苷支架的更接近导致更好的底物特性。
Derivatives of thymidine containingo-carboranylalkyl groups at the N-3 position and derivatives of 2‘-deoxyuridine containingo-carboranylalkylmercapto groups at the C-5 position were synthesized. The alkyl spacers consist of 4−8 methylene units. The synthesis of the former compounds required 3−4 reaction steps in up to 75% overall yield and that of the latter 9−10 reaction steps with significantly lower overall yield. Derivatives of thymidine substituted with carboranylalkyl substituents at the N-3 position and short spacers were phosphorylated by both recombinant and purified cytosolic thymidine kinase (TK1) to a relatively high degree. None of the tested 2‘-deoxyuridine derivatives possessing carboranyl substituents at the C-5 position were phosphorylated by either recombinant or purified TK1. The amounts of phosphorylation product detected for some of the C-5-substituted nucleosides with recombinant mitochondrial thymidine kinase (TK2) were low but significant and decreased with increasing lengths of the alkyl spacer. The data obtained in this study do not seem to support the tether concept applied in the synthesis of the new C-5- and N-3-substituted carboranyl nucleosides intended to reduce possible steric interference in the binding of carboranyl nucleosides with deoxynucleoside kinases. Instead, it appeared that a closer proximity of the bulky carborane moiety to the nucleoside scaffold resulted in better substrate characteristics.