某些与亚磺腺苷、亚磺肌苷和磺基肌苷结构相关的7-脱氮嘌呤（吡咯并[2,3-d]嘧啶）和3-脱氮嘌呤（咪唑并[4,5-c]吡啶）核苷在小鼠体内的合成及抗肿瘤评价

Synthesis and antitumor evaluation in mice of certain 7-deazapurine (pyrrolo[2,3-d]pyrimidine) and 3-deazapurine (imidazo[4,5-c]pyridine) nucleosides structurally related to sulfenosine, sulfinosine, and sulfonosine.

作者信息

Ramasamy K, Imamura N, Hanna N B, Finch R A, Avery T L, Robins R K, Revankar G R

机构信息

ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.

出版信息

J Med Chem. 1990 Apr;33(4):1220-5. doi: 10.1021/jm00166a021.

DOI:10.1021/jm00166a021

PMID:2319564

Abstract

7-Deaza (pyrrolo[2,3-d]pyrimidine) and 3-deaza (imidazo[4,5-c]pyridine) congeners of sulfenosine (5a and 9), sulfinosine (6a and 10), and sulfonosine (7a) have been prepared and evaluated for their antileukemic activity in mice. Amination of 2-amino-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-4(3H)-th ion e (4a) and its 2'-deoxy analogue (4c) with a chloramine solution gave the corresponding 4-sulfenamides (5a and 5c, respectively), which on selective oxidation with m-chloroperoxybenzoic acid (MCPBA) gave the respective diastereomeric 2-amino-7-beta-D-ribofuranosyl-pyrrolo[2,3-d]pyrimidine-4-sulfinamide (7-deazasulfinosine, 6a) and its 2'-deoxy derivative (6c). A similar amination of 7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4(3H)- thione (4b) gave the corresponding 4-sulfenamide derivative (5b). Oxidation of 5b with 1 molar equiv of MCPBA furnished (R,S)-7-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine- 4- sulfinamide (6b), whereas use of excess of MCPBA afforded the corresponding sulfonamide derivative (7b). Treatment of 3-deaza-6-thioguanosine (8) with a chloramine solution gave 3-deazasulfenosine (6-amino-1-beta-D- ribofuranosylimidazo[4,5-c]pyridine-4-sulfenamide, 9). Controlled oxidation of 9 with MCPBA afforded 3-deazasulfinosine (10). As gauged by increases in the mean postinoculation life spans of L1210 inoculated mice, none of these nucleosides exhibited biologically significant activity (T/C greater than or equal to 125). Even so, antileukemic activity appeared to be influenced, albeit not uniformly, by structural modifications in the base and carbohydrate moieties of sulfenosine and sulfinosine. Thus, while several of the compounds were lacking in cytotoxic activity, eight others (4c, 5a, 5c, 6a, 6b, 7b, 9, and 10) were estimated to have reduced body burdens of viable L1210 cells by 16-77%.

摘要

已制备了亚磺腺苷（5a和9）、亚磺肌苷（6a和10）和磺胍苷（7a）的7-脱氮（吡咯并[2,3-d]嘧啶）和3-脱氮（咪唑并[4,5-c]吡啶）类似物，并在小鼠中评估了它们的抗白血病活性。用氯胺溶液对2-氨基-7-β-D-呋喃核糖基吡咯并[2,3-d]嘧啶-4(3H)-硫酮（4a）及其2'-脱氧类似物（4c）进行胺化反应，得到相应的4-亚磺酰胺（分别为5a和5c），用间氯过氧苯甲酸（MCPBA）进行选择性氧化，得到各自的非对映体2-氨基-7-β-D-呋喃核糖基-吡咯并[2,3-d]嘧啶-4-亚磺酰胺（7-脱氮亚磺肌苷，6a）及其2'-脱氧衍生物（6c）。对7-(2-脱氧-β-D-赤式-戊呋喃糖基)吡咯并[2,3-d]嘧啶-4(3H)-硫酮（4b）进行类似的胺化反应，得到相应的4-亚磺酰胺衍生物（5b）。用1摩尔当量的MCPBA氧化5b得到(R,S)-7-(2-脱氧-β-D-赤式-戊呋喃糖基)吡咯并[2,3-d]嘧啶-4-亚磺酰胺（6b），而使用过量的MCPBA则得到相应的磺酰胺衍生物（7b）。用氯胺溶液处理3-脱氮-6-硫鸟苷（8）得到3-脱氮亚磺腺苷（6-氨基-1-β-D-呋喃核糖基咪唑并[4,5-c]吡啶-4-亚磺酰胺，9）。用MCPBA对9进行可控氧化得到3-脱氮亚磺肌苷（10）。以接种L1210小鼠的平均接种后寿命延长来衡量，这些核苷均未表现出生物学上显著的活性（T/C大于或等于125）。即便如此，抗白血病活性似乎受到亚磺腺苷和亚磺肌苷的碱基和碳水化合物部分结构修饰的影响，尽管这种影响并不一致。因此，虽然其中几种化合物缺乏细胞毒性活性，但另外八种（4c、5a、5c、6a、6b、7b、9和10）估计可使存活的L1210细胞的体内负荷降低16 - 77%。