Synthesis and antiviral activity of certain 4- and 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines.
Synthesis and antiviral activity of certain 4- and 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines.
复制标题
DOI：
10.1021/jm00119a006
复制
发表时间：
1988-11
影响因子：
7.3
通讯作者：
J. Pudlo;N. Saxena;M. Nassiri;S. R. Turk;J. Drach;L. Townsend
中科院分区：
文献类型：
--
作者：
J. Pudlo;N. Saxena;M. Nassiri;S. R. Turk;J. Drach;L. Townsend
对一系列先前制备的结核菌素类似物的体外评估表明，某些 5-卤素取代的类似物在浓度低于在未感染细胞中产生类似细胞毒性的浓度时具有抗人巨细胞病毒 (HCMV) 的活性。相反，结核菌素在所有抗病毒浓度下均具有细胞毒性。尽管 5-取代化合物的抗病毒选择性很小，但这一观察结果促使我们制备了一系列无环类似物。用(2-乙酰氧基乙氧基)甲基溴(2a)处理4-氯吡咯并[2,3-d]嘧啶(2)的钠盐，得到无环核苷4-氯-7-[(2-乙酰氧基乙氧基)甲基]吡咯并[2,3-d]嘧啶(3)。用甲醇、甲胺和二甲胺亲核置换4-氯基团，分别以良好的产率产生相应的4-取代的化合物4、5和6。在二氯甲烷中，分别用N-氯代琥珀酰亚胺、N-溴代琥珀酰亚胺和一氯化碘在化合物3的C-5位上进行亲电取代(氯化、溴化和碘化)。在室温下用甲醇氨从这些中间体(7a-9a)中除去乙酰基，得到4-氯-7-[(2-羟基乙氧基)甲基]吡咯并[2,3-d]嘧啶的5-氯(7b)、5-溴(8b)和5-碘(9b)衍生物。在升高的温度下用甲醇氨处理化合物7b-9b分别产生相应的5-卤代杀菌素类似物10、11和12。制备这些4,5-二取代的7-[(2-羟基乙氧基)甲基]吡咯并[2,3-d]嘧啶的另一种方法涉及在杂环与2a缩合之前进行亲电取代。用N-氯代琥珀酰亚胺和N-溴代琥珀酰亚胺处理2分别得到化合物13a和13b。 13a和13b与2a缩合，随后用甲胺和乙胺处理，分别得到相应的5-卤代-4-取代-吡咯并[2,3-d]嘧啶14a、14b、14c和14d。对目标化合物（4-6、7b-9b、10-12和14a-14d）针对HCMV和单纯疱疹病毒1型（HSV-1）的细胞毒性和活性的评估表明，除5-卤素取代的化合物10、11和12之外的所有化合物均无活性。化合物 10、11 和 12 在非细胞毒性浓度下对两种病毒均具有活性。化合物 11 的活性尤其值得注意，其效力比阿昔洛韦至少强 10 倍。
In vitro evaluation of a series of previously prepared tubercidin analogues revealed that certain 5-halogen-substituted analogues were active against human cytomegalovirus (HCMV) at concentrations lower than those that produced comparable cytotoxicity in uninfected cells. In contrast, tubercidin was cytotoxic at all antiviral concentrations. Even though the antiviral selectivity of the 5-substituted compounds was slight, this observation led us to prepare a series of acyclic analogues. Treatment of the sodium salt of 4-chloropyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (2a) provided the acyclic nucleoside 4-chloro-7-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (3). A nucleophilic displacement of the 4-chloro group with methoxide, methylamine, and dimethylamine yielded the corresponding 4-substituted compounds 4, 5, and 6, respectively, in good yield. Electrophilic substitution (chlorination, bromination, and iodination) was effected at the C-5 position of compound 3 with N-chlorosuccinimide, N-bromosuccinimide, and iodine monochloride, respectively, in methylene chloride. Removal of the acetyl group from these intermediates (7a-9a) with methanolic ammonia at room temperature afforded the 5-chloro (7b), 5-bromo (8b), and 5-iodo (9b) derivatives of 4-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine. Treatment of compounds 7b-9b with methanolic ammonia at an elevated temperature produced the corresponding 5-halotubercidin analogues 10, 11, and 12, respectively. An alternate procedure for the preparation of these 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines involved an electrophilic substitution prior to the condensation of the heterocycle with 2a. Treatment of 2 with N-chlorosuccinimide and N-bromosuccinimide gave compounds 13a and 13b, respectively. The condensation of 13a and 13b with 2a and subsequent treatment with methylamine and ethylamine furnished the corresponding 5-halo-4-substituted-pyrrolo[2,3-d]pyrimidines 14a, 14b, 14c, and 14d, respectively. Evaluation of the target compounds (4-6, 7b-9b, 10-12, and 14a-14d) for cytotoxicity and activity against HCMV and herpes simplex virus type 1 (HSV-1) revealed that all compounds except the 5-halogen-substituted compounds 10, 11, and 12 were inactive. Compounds 10, 11, and 12 were active against both viruses at noncytotoxic concentrations. The activity of compound 11 was particularly noteworthy, being at least 10-fold more potent than acyclovir.