Revankar G R, Hanna N B, Imamura N, Lewis A F, Larson S B, Finch R A, Avery T L, Robins R K
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
J Med Chem. 1990 Jan;33(1):121-8. doi: 10.1021/jm00163a020.
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%.
已经合成了多种2-氨基嘌呤以及某些相关嘌呤核糖核苷的6-亚磺酰胺、6-亚砜酰胺和6-磺酰胺衍生物，并在小鼠中评估了它们的抗白血病活性。用氯胺溶液对6-巯基嘌呤核糖核苷（7a）和6-硫鸟苷（7b）进行胺化反应，分别得到9-β-D-呋喃核糖基嘌呤-6-亚磺酰胺（8a）和2-氨基-9-β-D-呋喃核糖基嘌呤-6-亚磺酰胺（亚磺腺苷，8b）。用3-氯过氧苯甲酸（间氯过氧苯甲酸，MCPBA）对8a和8b进行选择性氧化，分别得到（R,S）-9-β-D-呋喃核糖基嘌呤-6-亚砜酰胺（9a）和（R,S）-2-氨基-9-β-D-呋喃核糖基嘌呤-6-亚砜酰胺（亚砜腺苷，9b）。然而，用过量的MCPBA对8a和8b进行氧化反应，分别得到9-β-D-呋喃核糖基嘌呤-6-磺酰胺（10a）和2-氨基-9-β-D-呋喃核糖基嘌呤-6-磺酰胺（磺酰胺腺苷，10b）。同样，对5'-脱氧-6-硫鸟苷（7c）进行胺化反应得到6-亚磺酰胺衍生物（8c），对其进行可控氧化得到（R,S）-2-氨基-9-（5-脱氧-β-D-呋喃核糖基）嘌呤-6-亚砜酰胺（9c）和相应的6-磺酰胺衍生物（10c）。用氯胺水溶液处理6-硫鸟嘌呤（12）得到2-氨基-9H-嘌呤-6-亚磺酰胺（13）。用1摩尔当量的MCPBA氧化13得到（R,S）-2-氨基-9H-嘌呤-6-亚砜酰胺（14），而使用4摩尔当量的MCPBA则得到2-氨基-9H-嘌呤-6-磺酰胺（15）。通过高效液相色谱技术实现了亚砜腺苷（9b）的R和S非对映异构体的拆分。通过单晶X射线衍射研究确定了（R）-9b和10b的结构。（R）-9b在晶体结构中以四种晶体学独立构象存在。在所评估的18种化合物中，有13种在小鼠中表现出非常显著的抗L1210活性。亚磺腺苷（8b）以每天22毫克/千克×1给药时，T/C为170，而亚砜腺苷（9b）以每天173毫克/千克×1给药时，对L1210白血病的T/C为167。亚砜腺苷（9c）的5'-脱氧类似物以每天104毫克/千克给药时，T/C也为172。单次用8b、9b和9c处理可使存活的L1210细胞的体内负荷降低超过99.8%。
