Enantioselective synthesis and biological evaluation of 5-o-carboranyl pyrimidine nucleosides

Base-modified carborane-containing nucleosides such as 5-o-carboranyl-2'-de oxyuridine (CDU) when combined with neutrons have potential for the treatme nt of certain malignancies. Lack of toxicity in various cells, high accumul ation in cancer cells and intracellular phosphorylation are desirable chara cteristics 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 nu cleosides. 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 a nalogues containing a heteroatom in the sugar moiety were also synthesized. Carboranyl pyrimidine nucleosides were prepared either from the parent bet a-D-nucleoside, beta-L-nucleoside, or by a coupling reaction. The dioxolane derivative 7 was prepared by a coupling reaction between protected 5-o-car boranyluracil (8, CU) and the corresponding protected heterocycle. Specific catalysts were used during the N-glycosylation process to favor the format ion of the beta-isomer. Biological evaluation of these new chiral 5-o-carbo ranyl pyrimidine derivatives indicated that most of these compounds have lo w toxicity in a variety of normal and malignant cells and achieved high cel lular levels in a lymphoblastoid cell line. Increasing the number of hydrox yl groups on the sugar moiety decreased the cellular accumulation and serum binding to different extents. Five compounds were identified for further b iological evaluation as potential agents for BNCT. (C) 1999 Elsevier Scienc e Ltd. All rights reserved.