Synthesis and In Vivo antitumor and antiviral activities of 2′‐deoxyribofuranosyl and arabinofuranosyl nucleosides of certain purine‐6‐sulfenamides, sulfinamides and sulfonamides

Abstract

2′‐Deoxyribofuranosyl and arabinofuranosyl nucleosides of certain purine‐6‐sulfenamides, sulfinamides and sulfonamides have been prepared by sequential amination and controlled oxidation of the corresponding 6‐thiopurine nucleosides, and evaluated for antiviral and antitumor activities in mice. Amination of 2′‐deoxy‐6‐thioinosine (4a) and 9‐β‐D‐arabinofuranosyl‐6‐thiopurine (4c) with chloramine solution gave the corresponding 6‐sulfenamides 5a and 5c, respectively, which on selective oxidation with 3‐chloroperoxybenzoic acid (MCPBA) gave diastereomeric 9‐(2‐deoxy‐β‐D‐erythro‐pentofuranosyl)purine‐6‐sulfinamide (6a) and 9‐β‐D‐arabinofuranosylpurine‐6‐sulfinamide (6c), respectively. However, oxidation of 5a and 5c with excess of MCPBA gave the corresponding 6‐sulfonamide derivatives 7a and 7c, respectively. Similar amination of 2′‐deoxy‐6‐thioguanosine (4b), ara‐6‐thioguanine (4d) and α‐2′‐deoxy‐6‐thioguanosine (8) gave the respective 6‐sulfenamide derivatives 5b, 5d and 9. Controlled oxidation of 5b, 5d and 9 gave (R,S)‐2‐amino‐9‐(2‐deoxy‐β‐D‐erythro‐pentofuranosyl)purine‐6‐sulfinamide (6b), (R,S)‐2‐amino‐9‐β‐D‐arabinofuranosylpurine‐6‐sulfinamide (6d) and the α‐anomer of (6b) (10), respectively. The diastereomeric mixture of (R,S)‐10 was partially resolved and the structure of S‐10 was assigned by single‐crystal X‐ray diffraction analysis. Oxidation of 5b, 5d and 9 with excess of MCPBA afforded the respective 6‐sulfonamide derivatives 7b, 7d and 11. Nucleosides 5c and 7c were significantly active against Friend leukemia virus in mice, whereas 6c was somewhat less active. Of the 20 nucleosides evaluated, 12 exhibited biologically significant anti‐L1210 activity in mice. Nucleosides 6b and 7a at 173 mg/kg/day × 1 showed a T/C of 153, whereas 7d at 800 mg/kg/day × 1 showed a T/C of 153 against L1210 leukemia. The α‐nucleoside 9 at 480 mg/kg/day × 1 gave a T/C of 172. A single treatment with 6b, 7a, 7d and 9 reduced the body burdens of viable L1210 cells by more than 99.2%. The antileukemic activity of these novel nucleosides tended to parallel solubility.

7-(2'-Deoxy-α-D-ribofuranosyl)hypoxanthine

“…A detailed knowledge of the conformation of the monomeric nucleoside (1) is compulsory to control and refine the initial parameters used in the design of the anticipated triplex structure. Since only three structures of a-ribofuranosides have been reported so far {a-5-acetyl-2'-deoxyuridine (Hamor, O'Leary & Walker, 1977), (Shefter, Kotick & Bardos, 1967) and (S)-2-amino-9-(2-deoxy-/3-D-ribofuransyl)-4-methyl-l,2,4-triazolin-5-one hydrate (Revankar et al, 1990)}, this contribution also helps in determining general structural aspects of this class of nucleosides.…”