Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy.
Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy.
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DOI：
10.1021/jm0491896
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发表时间：
2005-01
影响因子：
7.3
通讯作者：
Youngjoo Byun;Junhua Yan;A. S. Al-Madhoun;Jayaseharan Johnsamuel;Weilian Yang;R. Barth;S. Eriksson;W. Tjarks
中科院分区：
文献类型：
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作者：
Youngjoo Byun;Junhua Yan;A. S. Al-Madhoun;Jayaseharan Johnsamuel;Weilian Yang;R. Barth;S. Eriksson;W. Tjarks
合成了一种新型的3-碳硼基胸苷类似物（3cta），作为硼中子俘获治疗（BNCT）的潜在硼递送剂。该文库包括6个两性离子nh3 (+)-nido-m-碳硼烷取代胸苷类似物（Thds）和相应的中性nh2 -相近-m-碳硼烷取代胸苷类似物。该文库的所有化合物都是重组人胸苷激酶1 （TK1）的良好底物，相对于Thd的磷酸化率高达89%。该文库中的一个化合物3-[3-(7-NH（3)(+)-nido-m-碳硼-1-基）丙烷-1-基]胸苷（19b）在生物分布研究中在表达TK1的小鼠L929野生型肿瘤和L929 TK1（-）肿瘤中表现出选择性保留。两性离子NH(3)(+)-nido-m-碳硼烷取代Thds的生物学评价表明，与不同类别的3cta相比，它们具有更好的水溶性和相似甚至更优的BNCT潜力（Cancer Res. 2004,64, 6280-6286和6287-6295）。为了完成之前的构效关系（SAR）研究，我们还合成了3-[（近邻碳硼基）甲基]胸苷(4)并对其进行了评价。
Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH(3)(+)-nido-m-carborane-substituted thymidine analogues (Thds) and the corresponding neutral NH(2)-closo-m-carborane-substituted counterparts. All compounds of this library were good substrates for recombinant human thymidine kinase 1 (TK1) with phosphorylation rates up to 89% relative to that of Thd. One compound out of this library, 3-[3-(7-NH(3)(+)-nido-m-carboran-1-yl)propan-1-yl]thymidine (19b), showed selective retention in TK1-expressing murine L929 wild-type tumors versus L929 TK1 (-) tumors in biodistribution studies. The biological evaluation of the zwitterionic NH(3)(+)-nido-m-carborane-substituted Thds indicated improved aqueous solubility and similar or even superior potential as BNCT agents compared with different classes of 3CTAs (Cancer Res. 2004, 64, 6280-6286 and 6287-6295). To complete previous structure-activity relationship (SAR) studies, 3-[(closo-o-carboranyl)methyl]thymidine (4) was also synthesized and evaluated.