A Novel Synthesis of 2‘-Modified 2‘-Deoxy-4‘-thiocytidines from d-Glucose¹

Abstract

Novel 2'-deoxycytidine antimetabolites, specifically several 2'-modified 2'-deoxy-4'-thiocytidines, were synthesized as potential new antineoplastic agents. Methyl 3-O-benzylxylofuranoside was converted to a 1,4-anhydro-4-thioarabitol 24. Protection of the primary alcohol of 24 gave a common intermediate (15) which was useful for the synthesis of various 2'-modified 2'-deoxy-4'-thionucleosides. Oxidation of the secondary hydroxyl group of 15, followed by the Wittig reaction or treatment with (diethylamido)sulfur trifluoride (DAST) produced 2-deoxy-2-methylene (26) and 2-deoxy-2,2-difluoro (34) derivatives, respectively. Unique Pummerer-type glycosylation between the corresponding sulfoxides and trimethylsilylated N(4)-acetylcytosine produced 2'-deoxy-2'-methylene- (10) and 2'-deoxy-2',2'-difluoro-4'-thiocytidines (11). On the other hand, treatment of 15 with DAST introduced a fluorine atom with retention of the 2'-stereochemistry, yielding 40. In contrast, the Mitsunobu reaction of 3-O-benzoyl derivative 53 which was obtained from 15 in five steps, using diphenylphosphoryl azide gave azide derivative 54 with inverted stereochemistry. These derivatives were converted to the corresponding 1-O-acetyl derivatives via the usual Pummerer rearrangement, which were in turn used to synthesize 4'-thiocytidines 12 and 58. Among the 2'-modified 4'-thiocytidines obtained, 2'-methylene (10) and 2'-fluoro (12) derivatives were found to have potent antineoplastic properties in vitro.

Inhibitory Effects of 9-(4-Thio-.BETA.-D-ribo-pentofuranosyl)guanine on Tumor Growth and Angiogenesis

“…6) The nucleosides containing a sulfur atom at the 4Ј-position, where oxygen is in the case of natural nucleosides, were reported to have antitumor or antiviral activity. [16][17][18][19] However, they were shown or suggested to inhibit DNA synthesis by inhibiting DNA polymerases. 20,21) 4Ј-Thioguanosine is not suggested to act as a mere DNA or RNA synthesis inhibitor because it did not inhibit [ 3 H]thymidine or [ 3 H]uridine incorporation into the macromolecular fraction of HUVEC unlike araC (data not shown).…”

Synthesis of 4′-Thionucleosides as Antitumor and Antiviral Agents

“…Deprotection of 15 and the separation of anomers by octadecyl silica (ODS) column chromatography furnished 4′-thioDMDC (3) along with its α-anomer. 27,28) We also synthesized 4′-thiogemcitabine (16) from 11 by using a similar synthetic scheme 27,28) (Chart 4).…”

“…30) The synthesis of 2′-flluoro-arabino-4′-thionucleosides 21 from 19 was achieved by the Vorbrüggen reaction and the subsequent deprotection as in the case of 4′-thioarabinonucleosides 28,31) (Chart 5).…”

“…27,28) On the other hand, 4′-thiogemcitabine (16) showed only moderate activity against the same cell lines. 27,28) It is worth noting that 21 was 15-30 times more active against KB cells than cytarabine or DMDC (Table 1).…”

“…27,28) On the other hand, 4′-thiogemcitabine (16) showed only moderate activity against the same cell lines. 27,28) It is worth noting that 21 was 15-30 times more active against KB cells than cytarabine or DMDC (Table 1). Further evaluation of the antitumor activity of 21 revealed it had broad antineoplastic activity against various tumor cell lines including pancreas and colon cancers, and was also active in an in vivo assay using nude mice implanted with human tumor cells.…”