Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogs for boron neutron capture therapy of cancer.
Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogs for boron neutron capture therapy of cancer.
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DOI：
10.1016/j.ejmech.2015.05.042
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发表时间：
2015-07-15
影响因子：
6.7
通讯作者：
Tjarks W
中科院分区：
文献类型：
--
作者：
Agarwal HK;Khalil A;Ishita K;Yang W;Nakkula RJ;Wu LC;Ali T;Tiwari R;Byun Y;Barth RF;Tjarks W
合成了16种第二代氨基和氨基取代碳硼酰嘧啶核苷类似物，作为胸苷激酶1 （TK1）的底物和抑制剂，有望用于癌症的硼中子俘获治疗（BNCT），并在酶动力学-、酶抑制-、代谢组学-和生物分布研究中进行了评估。这些第二代碳硼基嘧啶核苷类似物之一（YB18A[3]），其氨基直接连接到通过乙烯间隔物连接到胸腺嘧啶3位的碳硼烷笼上，作为hTK1的底物和抑制剂，其性能大约是第一代碳硼基嘧啶核苷类似物N5-2OH(2)的3- 4倍。在体外和体内，2和3在TK1(+) RG2细胞中都出现了5 ' -单磷酸化。在脑内RG2胶质瘤大鼠的生物分布研究中发现3选择性肿瘤摄取，瘤内浓度约为2的4倍。获得的结果显著推进了对TK1与碳烷嘧啶核苷类似物之间结合相互作用的理解，并将深刻影响这些药物的未来设计策略。
A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogues, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2nd generation carboranyl pyrimidine nucleoside analogues (YB18A [3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3–4 times superior as a substrate and inhibitor of hTK1 than N5-2OH (2), a 1st generation carboranyl pyrimidine nucleoside analogue. Both 2 and 3 appeared to be 5′-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of 3 with an intratumoral concentration that was approximately 4 times higher than that of 2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogues and will profoundly impact future design strategies for these agents.