Mourier N S, Eleuteri A, Hurwitz S J, Tharnish P M, Schinazi R F
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Bioorg Med Chem. 1999 Dec;7(12):2759-66. doi: 10.1016/s0968-0896(99)00222-9.
Base-modified carborane-containing nucleosides such as 5-o-carboranyl-2'-deoxyuridine (CDU) when combined with neutrons have potential for the treatment of certain malignancies. Lack of toxicity in various cells, high accumulation in cancer cells and intracellular phosphorylation are desirable characteristics for modified nucleosides used in boron neutron capture therapy (BNCT) for brain tumors and other malignancies. The aim of this work was to synthesize the two beta-enantiomers of several 5-o-carboranyl-containing nucleosides. These derivatives may possess favorable properties such as high lipophilicity, high transportability, the ability to be phosphorylated, and resistance to catabolism. Beta-isomers of 2',3'-dihydroxynucleosides and analogues containing a heteroatom in the sugar moiety were also synthesized. Carboranyl pyrimidine nucleosides were prepared either from the parent beta-D-nucleoside, beta-L-nucleoside, or by a coupling reaction. The dioxolane derivative 7 was prepared by a coupling reaction between protected 5-o-carboranyluracil (8, CU) and the corresponding protected heterocycle. Specific catalysts were used during the N-glycosylation process to favor the formation of the beta-isomer. Biological evaluation of these new chiral 5-o-carboranyl pyrimidine derivatives indicated that most of these compounds have low toxicity in a variety of normal and malignant cells and achieved high cellular levels in a lymphoblastoid cell line. Increasing the number of hydroxyl groups on the sugar moiety decreased the cellular accumulation and serum binding to different extents. Five compounds were identified for further biological evaluation as potential agents for BNCT.
碱基修饰的含碳硼烷核苷，如5 - o - 碳硼烷基 - 2'-脱氧尿苷（CDU），与中子结合时具有治疗某些恶性肿瘤的潜力。在硼中子俘获疗法（BNCT）治疗脑肿瘤和其他恶性肿瘤中使用的修饰核苷，理想的特性是在各种细胞中无毒性、在癌细胞中高积累以及细胞内磷酸化。这项工作的目的是合成几种含5 - o - 碳硼烷基核苷的两种β - 对映体。这些衍生物可能具有诸如高亲脂性、高转运性、磷酸化能力和抗分解代谢等有利特性。还合成了2'，3'-二羟基核苷的β - 异构体以及在糖部分含有杂原子的类似物。碳硼烷基嘧啶核苷可由母体β - D - 核苷、β - L - 核苷制备，或通过偶联反应制备。二氧戊环衍生物7是通过受保护的5 - o - 碳硼烷基尿嘧啶（8，CU）与相应的受保护杂环之间的偶联反应制备的。在N - 糖基化过程中使用特定催化剂以促进β - 异构体的形成。对这些新的手性5 - o - 碳硼烷基嘧啶衍生物的生物学评价表明，这些化合物中的大多数在各种正常细胞和恶性细胞中具有低毒性，并在淋巴母细胞系中达到高细胞水平。糖部分上羟基数量的增加在不同程度上降低了细胞积累和血清结合。鉴定出五种化合物用于进一步的生物学评价，作为BNCT的潜在药物。
