SULFINOSINE CONGENERS - SYNTHESIS AND ANTITUMOR-ACTIVITY IN MICE OF CERTAIN N9-ALKYLPURINES AND PURINE RIBONUCLEOSIDES
SULFINOSINE CONGENERS - SYNTHESIS AND ANTITUMOR-ACTIVITY IN MICE OF CERTAIN N9-ALKYLPURINES AND PURINE RIBONUCLEOSIDES
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DOI：
10.1021/jm00027a022
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发表时间：
1994-01-07
影响因子：
7.3
通讯作者：
REVANKAR, GR
中科院分区：
文献类型：
--
作者：
HANNA, NB;BHATTACHARYA, BK;REVANKAR, GR
许多 N9-烷基取代的嘌呤和嘌呤核糖核苷已被合成为亚磺苷的同系物，并评估了它们在小鼠中的抗白血病活性。 NaH介导的6-氯嘌呤(4)和2-氨基-6-氯嘌呤(5)与某些烷基溴的烷基化得到N7-和N9-烷基化衍生物(7a-d和6a-d)，其中N9-异构体是主要产物。用硫脲处理6a-d和7a-d得到相应的6-硫代衍生物(9a-d和8a-d)。用氯胺水溶液胺化9a-e，得到相应的嘌呤-6-亚磺酰胺(10a-e)，用3-氯过苯甲酸(MCPBA)控制氧化，得到相应的(R,S)-9-烷基嘌呤-6-亚磺酰胺(11a-e)。用 MCPBA 类似地氧化 2-氨基-6-(甲基/苄硫基)-9-β-D-呋喃核糖基 (12a 和 12b) 和 2-氨基-9-(2-脱氧-β-D-呋喃红基)-6-(甲硫基)嘌呤 (12c) 得到相应的亚砜 (13a-c)，进一步氧化后得到相应的砜（14a-c）。在评估的 20 种化合物中，有 6 种在 BD2F(1) 小鼠中表现出具有生物学意义的抗 L1210 活性，并且通过单次治疗可将活 L1210 细胞的身体负担减少 90-97% 以上。尽管每天 44 mg 和 40 mg/kg X 1 的化合物 9b 和 9c 的 T/C 分别为 147 和 149，但发现这组化合物的效果不如我们之前描述的一些含硫药物（例如磺基苷和磺基苷）。
A number of N9-alkyl-substituted purines and purine ribonucleosides have been synthesized as congeners of sulfinosine and evaluated for their antileukemic activity in mice. NaH-mediated alkylation of 6-chloropurine (4) and 2-amino-6-chloropurine (5) with certain alkyl bromides gave N7- and N9-alkylated derivatives (7a-d and 6a-d), the N9-isomer being the major product. Treatment of 6a-d and 7a-d with thiourea furnished the corresponding 6-thio derivatives (9a-d and 8a-d). Amination of 9a-e with aqueous chloramine solution afforded the corresponding purine-6-sulfenamides (10a-e), which on controlled oxidation with 3-chloroperoxybenzoic acid (MCPBA) gave the respective (R,S)-9-alkylpurine-6-sulfinamides (11a-e). A similar oxidation of 2-amino-6-(methyl/benzylthio)-9-beta-D-ribofuranosy (12a and 12b) and 2-amino-9-(2-deoxy-beta-D-erythropentofuranosyl)-6-(methylthio)purine (12c) with MCPBA gave the corresponding sulfoxides (13a-c), which on further oxidation furnished the respective sulfones (14a-c). Of the 20 compounds evaluated, six exhibited biologically significant anti-L1210 activity in BD2F(1) mice and reduced body burdens of viable L1210 cells more than 90-97% by single treatment. Although compounds 9b and 9c at 44 mg and 40 mg/kg per day X 1 showed a T/C of 147 and 149, respectively, this group of compounds was found to be less effective than some of the sulfur-containing drugs that we previously described (e.g. sulfenosine and sulfinosine).