Boronated nucleosides for neutron capture therapy of brain tumors

常规癌症治疗的进展尚未在以下治疗方面产生任何显著改善： 多形性胶质母细胞瘤（GBM）。因此，GBM新型治疗方式的进一步发展， 例如硼中子俘获疗法（BNCT），仍然是健康科学界的一项紧迫任务， 美国.本资助申请的主题是3-碳硼烷胸苷的继续开发 类似物（3CTA），一类新的BNCT药物用于治疗GBM。的作用机制 3CTA主要基于它们作为人胸苷激酶1（TK 1）的底物的能力， 在增殖细胞中活跃。接受N5- 2 OH（目前的铅）的荷瘤啮齿动物的BNCT 我们的3CTA文库的化合物，通过脑内（i. c.）或瘤内（i.t.）注射导致肿瘤缩小 生长和延长生存时间。另一方面，同样的研究揭示了两个主要的局限性 N5- 2 OH和其他3CTA。这些是（1）在200 ℃下与内源性胸苷（Thd）的次优竞争， TK 1的底物结合位点和（2）缺乏水溶性，这需要使用有机 用于生物学研究的溶解3CTA的溶剂。此外，重要的生物化学和生物学特征， 三是未知数。这些是（3）在单磷酸化步骤之后的3CTA的抑制， 包括它们可能与DNA的结合，以及（4）3CTA及其代谢产物 招募人员进出牢房为解决这些不足，制定了以下具体目标： (1)合成在TK 1的活性位点上具有改进的与Thd竞争的能力的3CTA，以评估它们的活性。 底物和抑制能力的酶试验与TK 1，并确定其物理化学 （2）合成N5- 2 OH的水溶性氨基酸前药并评价其应用性 对于i.c.（3）研究N5- 2 OH和3-CTA类药物的代谢， 特异性目的1和2在体外和使用核苷酸的酶测定中出现的酶性质 （4）研究N5- 2 OH，3CTAs在细胞内的内流和外流机制， 特异性目标1和2及其代谢产物的类药物和酶性质得到改善， （5）优化i.c.给予具有最大改善的药物样和 从特异性目的1- 4到携带RG 2神经胶质瘤的大鼠中出现的酶特性，并确定 可能的神经毒性。

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.