Synthesis and in vivo antitumor activity of 2-amino-9H-purine-6-sulfenamide, -sulfinamide, and -sulfonamide and related purine ribonucleosides

Abstract

A number of 6-sulfenamide, 6-sulfinamide, and 6-sulfonamide derivatives of 2-aminopurine and certain related purine ribonucleosides have been synthesized and evaluated for antileukemic activity in mice. Amination of 6-mercaptopurine ribonucleoside (7a) and 6-thioguanosine (7b) with chloramine solution gave 9-beta-D-ribofuranosylpurine-6-sulfenamide (8a) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide (sulfenosine, 8b), respectively. Selective oxidation of 8a and 8b with 3-chloroperoxybenzoic acid (MCPBA) gave (R,S)-9-beta-D-ribofuranosylpurine-6-sulfinamide (9a) and (R,S)-2-amino-9-beta-D-ribofuranosylpurine-6-sulfinamide (sulfinosine, 9b), respectively. However, oxidation of 8a and 8b with excess of MCPBA gave 9-beta-D-ribofuranosylpurine-6-sulfonamide (10a) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfonamide (sulfonosine, 10b), respectively. Similarly, amination of 5'-deoxy-6-thioguanosine (7c) afforded the 6-sulfenamide derivative (8c), which on controlled oxidation gave (R,S)-2-amino-9-(5-deoxy-beta-D-ribofuranosyl)purine-6-sulfinamide (9c) and the corresponding 6-sulfonamide derivative (10c). Treatment of 6-thioguanine (12) with aqueous chloramine solution gave 2-amino-9H-purine-6-sulfenamide (13). Oxidation of 13 with 1 molar equiv of MCPBA afforded (R,S)-2-amino-9H-purine-6-sulfinamide (14), whereas the use of 4 molar equiv of MCPBA furnished 2-amino-9H-purine-6-sulfonamide (15). The resolution of R and S diastereomers of sulfinosine (9b) was accomplished by HPLC techniques. The structures of (R)-9b and 10b were assigned by single-crystal X-ray diffraction studies. (R)-9b exists in the crystal structure in four crystallographically independent conformations. Of the 18 compounds evaluated, 13 exhibited very significant anti-L1210 activity in mice. Sulfenosine (8b) at 22 mg/kg per day X 1 showed a T/C of 170, whereas sulfinosine (9b) at 173 mg/kg per day X 1 showed a T/C of 167 against L1210 leukemia. The 5'-deoxy analogue of sulfinosine (9c) at 104 mg/kg per day also showed a T/C of 172. A single treatment with 8b, 9b, and 9c reduced body burdens of viable L1210 cells by more than 99.8%.

Synergistic effects of the purine analog sulfinosine and curcumin on the multidrug resistant human non-small cell lung carcinoma cell line (NCI-H460/R)

“…Sulfinosine [(R,S)-2-amino-9-β-D-ribofuranosylpurine-6-sulfinamide] was synthesized from 6-thioguanosine according to the published procedure. 7 Curcumin was purchased from SigmaAldrich Chemie GmbH, Germany. SF was stored at -20°C and was freshly diluted in water and filter-sterilized before every treatment.…”

“…7 Sulfinosine exhibits considerable anti-cancer activity in different human cancer cell lines. [8][9][10] It also has multiple metabolic pathways that minimize the possibility of development of cellular resistance.…”

Structure of sulfonosine

“…* Related literature. The title compound has shown antitumor activity (Revankar et al, 1990). The structure of 6-thioguanine (Bugg & Thewalt, 1970) and 6-thioguanosine (Thewalt & Bugg, 1972) have been reported.…”

Sulfinosine enhances doxorubicin efficacy through synergism and by reversing multidrug resistance in the human non-small cell lung carcinoma cell line (NCI-H460/R)

“…Sulfinosine (SF) is one of many synthetic nucleoside analogs with a wide spectrum of antitumor activities. Beside of antitumor effects, SF even at therapeutically effective concentrations are unlikely to induce resistance and are generally less toxic to normal cells [14][15][16]. Also, depending on the target cells and experimental conditions, nucleoside analogs in general have either cytoprotective or toxic effects [17].…”

“…Also, depending on the target cells and experimental conditions, nucleoside analogs in general have either cytoprotective or toxic effects [17]. The anticancer activities of SF were previously described in six solid tumors and four strains of experimental leukemia [15,16] as well as in human lung carcinoma cell lines [18] and neuroblastoma cell line [19]. When SF was applied in combination with 8-Cl-cAMP, considerable synergistic interaction was observed in the neuroblastoma cell line [19].…”