4-Thiofuranoid Glycal: Versatile Glycosyl Donor for the Selective Synthesis of beta-anomer of 4'-thionucleoside and its Biological Activities

The first highly diastereoselective synthesis of beta-anomers of 4 '-thionucleosides has been carried out by means of electrophilic glycosidation utilizing 3,5-O-(di-tert-butylsilylene) (DTBS)-4-thiofuranoid glycal as a glycosyl donor. The resulting glycosides were transformed into ribo-, 2 '-deoxy-, and arabinofuranosyl nucleosides through a chemical transformation of the 2 '-substituent. The additive Pummerer reaction of the glycal S-oxide gave 1,2-di-O-acetyl-3,5-O-DTBS-4-thioribofuranose. The utility of the DTBS-protected 4-thioribofuranose has been demonstrated by the preparation of 4 '-thio analogues of pyrimidine- and purine-4 '-thioribonucleosides based on the Vorbruggen glycosidation. Synthesis of 4 '-thio-counterpart of C-nucleoside antibiotic tiazofurin has also been carried out. alpha-Face selective hydroboration of 1-C-aryl- or 1-C-heteroaryl-glycals obtained by cross-coupling of 1-tributylstannylglycal has furnished the respective beta-anomer of 4 '-thio-C-ribonucleosides, including 4 '-thio analogue of nucleoside antibiotic pseudouridine and 9-deazaadenosine. On the basis of lithiation chemistry, 1-C- and 2-C-carbon-carbon-substituted 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3- diyl) (TIPDS)- 4-thiofuranoid glycal were synthesized. These glycals enabled us to prepare 1 '-C- and 2 '-beta-C-carbon-substituted 2 '-deoxy-4 '-thionucleosides, including thio-counterpart of antitumor nucleoside antibiotic angustmycin C. Furthermore, 1 '-C-methyl-4 '-thiothymidine emerged as a potent inhibitor of angiogenesis. In addition, 1 '-C-methyl-4 '-thiothymidine exhibited more potent inhibitory activity against thymidine kinase-deficient mutant of herpes virus than that of ganciclovir. Among the 4 '-substituted 4 '-thiothymidines, the 4 '-C-cyano- and 4 '-C-ethynyl derivatives inhibited replication of HIV variant resistant to 3TC (HIVM184V) as potently as HIV-1(IIIB). In terms of the value of selectivity index (SI), 4 '-C-cyano-4 '-thiothymidine showed a 3-fold selective index (SI) than that of the corresponding thymidine derivative. Furthermore, 4 '-C-ethynyl-2 '-deoxy-4 '-thioguanosine has a 20-fold better value (>18,200) than that of 2 '-deoxyguanosine counterpart (933). Furthermore, 4 '-azido-4 '-thiothymidine emerged as a selective and potent anti-EBV agent. In terms of antineoplastic activity, 4 '-azido- and 4 '-C-fluoromethyl-2 '-deoxy-4 '-thiocytidine inhibited proliferation of human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines, although the parent compound 2 '-deoxy-4 '-thiocytidine did not exhibit any cytotoxicity up to 100 mu M. These facts concerning the biological activities suggested that replacement of the furanose oxygen with a sulfur atom is a promising approach for the development of less toxic antiviral and antineoplastic nucleoside antimetabolites. 4 '-Thionucleoside also acts as a monomer for oligonucleotides (ONs) therapeutics, exhibiting superior biological properties. Therefore, this review provides a wide range of potential monomers for antisense ON and siRNA.