Synthesis and antiviral and cytostatic properties of 3'-deoxy-3'-fluoro- and 2'-azido-3'-fluoro-2',3'-dideoxy-D-ribofuranosides of natural heterocyclic bases

Abstract

A series of 3'-deoxy-3'-fluoro- and 2'-azido-2',3'-dideoxy-3'-fluoro-D-ribofuranosides of natural heterocyclic bases have been synthesized with the use of universal carbohydrate precursors, viz., 1-O-acetyl-2,5-di-O-benzoyl-3-deoxy-3-fluoro-D-ribofuranose and methyl 2-azido-5-O-benzoyl-2,3-dideoxy-3-fluoro-beta-D-ribofuranoside, respectively. The cytostatic and antiviral activity of the compounds was evaluated against a variety of tumor cell lines and DNA/RNA viruses, respectively. As the most active compound, from both a cytostatic and antiviral activity viewpoint, emerged 3'-deoxy-3'-fluoroadenosine. It inhibited the proliferation of some tumor cell lines (i.e. murine leukemia L1210 and human T-lymphocyte MT-4) at a concentration of 0.2-2 micrograms/mL, and proved inhibitory to the replication of positive-stranded RNA viruses (i.e. polio, Coxsackie, Sindbis, Semliki forest), double-stranded RNA viruses (i.e. reo), and some DNA viruses (i.e. vaccinia) at a concentration of 1-4 micrograms/mL, which is well below the cytotoxicity threshold (40 micrograms/mL).

Synthesis and Conformational Analysis of 1′‐ and 3′‐Substituted 2‐Deoxy‐2‐fluoro‐D‐ribofuranosyl Nucleosides

“…Debenzoylation of the nucleoside mixture, followed by chromatographic purification, then afforded the pure nucleosides 5 and 6 in yields of 34 and 8%, respectively. It is noteworthy that no anomerization of 4 was observed, in accord with its low reactivity (see, e.g., [29] [30]). …”

“…Synthesis. The synthesis of methyl 3-azido-5-O-benzoyl-2,3-dideoxy-2-fluoro-b-d-ribofuranoside (4), the precursor of the target compounds 5 -8, was realized in three steps starting from the b-d-xylofuranoside derivative 1 [30], via 2 and 3, in ca. 40% combined yield, using conventional methods (Scheme 1).…”

“…Two different routes were tested for the synthesis of the starting difluoride 10. First, treatment of the xyloside 1 [30] with an excess of DAST in toluene at room temperature proceeded smoothly and furnished, after 20 h, the desired difluoride 10 in 30% yield, based on consumed 1, 43% of which was recovered. The second route consisted in the nucleophilic displacement of the 2-TsO group of the arabinoside 9 [29] [30] upon treatment with CsF in DMSO at 190 -1958, which gave, after chromatography, 32% of 10 (based on consumed starting material), along with the initial arabinoside 9 (25%).…”

Thienyl-Substituted Nucleosides and Their Triphosphates

“…Most of these compounds have shown little or no activity (Van Aershot et sl., 1989;Wigerinck et a/., 1990;Mikhailopulo et a/., 1991). We have previously studied various S-substituted 2'-deoxyuridines and cytosines, which also exhibited rather low or no antiviral activity (Peters et a/., 1992).…”

Conformational analysis of 3′‐fluorinated A(2′‐5′)A(2′‐5′)A fragments

“…The synthesis of the fluorine-substituted (A2'p5'),A trimers and of 9-(3'-fluoro-3'-deoxy-~-~-xylofuranosyl)-adenine (AF) will be published elsewhere; 3'-fluoro-3'-deoxyadenosine (A,) and (A2'p5'),A (AAA) were synthesized as described [19,201. NMR samples were lyophilisecl three times from 99.75% D,O and finally taken up in 500 pl D,O.…”