Boronated nucleosides for neutron capture therapy of brain tumors

传统癌症治疗的进展并没有在治疗上产生任何显著的改善 多形性胶质母细胞瘤(GBM)。因此，对于GBM的新的治疗方式的进一步开发， 例如硼中子俘获疗法(BNCT)，仍然是#年健康科学界的一项紧迫任务。 美国。目前拨款申请的主题是3-Carboranyl胸苷的继续开发 类似物(3CTA)，一类治疗GBM的新型BNCT药物。其作用机制 3CTA主要是基于它们作为人胸苷激酶1(TK1)底物的能力，而TK1只是 活跃在增殖的细胞中。接受了N5-2OH的荷瘤啮齿动物的BNCT，目前的铅 我们的3CTA文库的化合物，通过脑内(I.C.)或瘤内(I.T.)注射导致肿瘤减少 生长和延长存活时间。另一方面，同样的研究揭示了两个主要的局限性 N5-2OH和其他3CTA。这些是(1)与内源性胸腺嘧啶核苷(THD)的次优竞争 TK1的底物结合部位和(2)缺乏水溶性，这需要使用有机 为生物研究增溶3CTA的溶剂。此外，重要的生化和生物学特性 3CTA尚不清楚。这些是(3)单磷酸化步骤以外的3CTA的合成代谢， 包括它们可能与DNA结合，以及(4)3CTA及其代谢物的作用机制 招募人员进入和退出单元格。为解决这些缺点，制定了以下具体目标： (1)合成在TK1活性部位与THD竞争能力增强的3CTA，并对其进行评价 TK1在酶测定中的底物和抑制能力及其物理化学测定 性质，(2)合成N5-2OH的水溶性氨基酸前药并评价其适用性 为了国际刑事法院。给药，(3)研究N5-2OH和3CTA的代谢，改进的类药物和 特异性AIMS 1和2在体外和核苷酸酶分析中的酶学性质 激酶和DNA聚合酶，(4)研究N5-2OH、3CTAS的细胞内流和外流机制。 从特定目标1和2及其代谢物中产生的改善的类药物和酶性质 体外实验；(5)优化I.C.用3CTA给药改善最多的类药物和 特异性AIMS 1-4对荷RG2胶质瘤大鼠的酶学性质及测定 可能有神经毒性。

Advances in conventional cancer therapy have not produced any significant improvement in the treatment of glioblastoma multiforme (GBM). Therefore, the further development of novel treatment modalities for GBM, such as boron neutron capture therapy (BNCT), remains a pressing task for the health science community in the USA. Subject of the present grant application is the continued development of 3-carboranyl thymidine analogues (3CTAs), a novel class of BNCT agents for the treatment of GBM. The mechanism of action of 3CTAs is primarily based on their ability to function as substrates of human thymidine kinase 1 (TK1), which is only active in proliferating cells. BNCT of tumor-bearing rodents that had received N5-2OH, the current lead compound of our 3CTA library, via intracerebral (i.c.) or intratumoral (i.t.) injection resulted in reduced tumor growth and prolonged survival times. On the other hand, the same studies have revealed two major limitations of N5-2OH and other 3CTAs. These are (1) the suboptimal competition with endogenous thymidine (Thd) at the substrate-binding site of TK1 and (2) the lack of water-solubility, which necessitated the use of organic solvents to solubilize 3CTAs for biological studies. In addition crucial biochemical and biological features of 3CTAs are still unknown. These are (3) the anabolism of 3CTAs beyond the monophosphorylation step, including their possible incorporation into DNA, and (4) the mechanisms that 3CTAs and their metabolites recruit to enter and exit cells. To address these shortcomings, the following SPECIFIC AIMS were developed: (1) To synthesize 3CTAs with improved ability to compete with Thd at the active site of TK1, to evaluate their substrate and inhibitory capacities in enzyme assays with TK1, and to determine their physicochemical properties, (2) to synthesize water-soluble amino acid prodrugs of N5-2OH and to evaluate their applicability for i.c. administration, (3) To study the metabolism of N5-2OH and 3CTAs with improved drug-like and enzymatic properties that emerged from Specific Aims 1 and 2 in vitro and in enzyme assays with nucleotide kinases and DNA polymerase, (4) to study the mechanisms of cellular influx and efflux of N5-2OH, 3CTAs with improved drug-like and enzymatic properties that emerged from Specific Aims 1 and 2, and their metabolites in vitro, and (5) to optimize parameters for i.c. administration of the 3CTA with the most improved drug-like and enzymatic properties that emerged from Specific Aims 1- 4 to RG2 glioma bearing rats and to determine possible neurotoxicity.