Synthesis and antiviral activity of some 7-[(2-hydroxyethoxy)methyl]pyrazolo[3,4-d]pyrimidine analogues of sangivamycin and toyocamycin.
Synthesis and antiviral activity of some 7-[(2-hydroxyethoxy)methyl]pyrazolo[3,4-d]pyrimidine analogues of sangivamycin and toyocamycin.
复制标题
桑吉瓦霉素和丰加霉素的一些 7-[(2-羟基乙氧基)甲基]吡唑并[3,4-d]嘧啶类似物的合成和抗病毒活性。
DOI：
10.1021/jm00169a027
复制
发表时间：
1990
影响因子：
7.3
通讯作者：
Townsend,LB
中科院分区：
文献类型：
--
作者：
Saxena,NK;Coleman,LA;Drach,JC;Townsend,LB
将4-氨基-3-氰吡唑[3,4 -d]嘧啶(1)的钠盐与（2-乙酰氧基乙氧基）甲基溴(2)缩合，得到相应的保护无环核苷，4-氨基-3-氰-1-[（2-乙酰氧基乙氧基）甲基]-吡唑[3,4 -d]嘧啶(3)。甲氧基钠在甲醇中处理3，得到了产率较高的4-氨基- 1 -[（2-羟基乙氧基）甲基]吡唑啉[3,4 -d]嘧啶-3-甲咪酯(4)。用硫化氢钠处理亚咪酯(4)得到硫代氨基甲酸乙酯衍生物5。水基将4转化为4-氨基-[（2-羟基乙氧基）甲基]吡唑[3,4 -d]嘧啶-3-羧酰胺(6)，收率较高。用氯化汞处理5，得到toyocamycin类似物7。对化合物1,3 -7的评价表明，只有杂环(1)和硫代羧酰胺无环核苷(5)具有活性。化合物5对人巨细胞病毒和1型单纯疱疹病毒具有较强的抑制作用。无环核苷是一类重要的化合物，具有强效和选择性抗病毒活性。在无环核苷中，acyclovir2和ganciclovir3 45'6 （DHPG）已成为寻找更好药物的关键化合物。这些化合物对1型和2型疱疹病毒（HSV-1、HSV-2）的特异性是细胞和病毒激酶之间的不同底物特异性以及DNA聚合酶水平上的生化选择性的结果。这两种化合物对人类巨细胞病毒（HCMV）也有活性，并已在临床上使用。然而，每种化合物在临床治疗HCMV方面都面临着不同的问题。无环鸟苷虽然没有毒性，但只是一种弱的病毒抑制剂，而更昔洛韦是一种更有效的抑制剂，但并非没有毒性。作为抗病毒药物研究的一部分，我们一直在探索吡咯[2,3 -d]嘧啶核苷作为HCMV的潜在选择性抑制剂。9 10" 13
The sodium salt of 4-amino-3-cyanopyrazolo [3, 4-d] pyrimidine (1) was condensed with (2-acetoxyethoxy) methyl bromide (2) to provide the corresponding protected acyclic nucleoside, 4-amino-3-cyano-1-[(2-acetoxyethoxy) methyl]-pyrazolo [3, 4-d] pyrimidine (3). Treatment of 3 with sodium methoxide in methanol provided a good yield of methyl 4-amino-l-[(2-hydroxyethoxy) methyl] pyrazolo [3, 4-d] pyrimidine-3-formimidate (4). Treatment of the imidate (4) with sodium hydrogen sulfide gave the thiocarboxamide derivative 5. Aqueous base transformed 4 into 4-aminol-[(2-hydroxyethoxy) methyl] pyrazolo [3, 4-d] pyrimidine-3-carboxamide (6) in good yield. Treatment of 5 with mercuric chloride furnished the toyocamycin analogue 7. Evaluation of compounds 1, 3-7 revealed that onlythe heterocycle (1) andthe thiocarboxamide acyclic nucleoside (5) were active. Compound 5 was the more potent with activity against human cytomegalovirus and herpes simplex virus type 1.Acyclonucleosides are an important class of compounds having potent and selective antiviral activity. 1 Among the acyclic nucleosides, acyclovir2 and ganciclovir3 45'6 (DHPG) have been key compounds in the search for better drugs. The specificity of these compounds against herpessimplex virus types 1 and 2 (HSV-1, HSV-2) is a consequence of differential substrate specificity between cellular and viral kinases and of biochemical selectivity at the level of DNA polymerases. 6 Both of these compounds also are active against human cytomegalovirus (HCMV) and have been used clinically. 7, 8 Eachcompound, however, suffers from a different problemregarding clinical utility against HCMV. Acyclovir, althoughnot toxic, is only a weak inhibitor of the virus7 whereas ganciclovir is a more potent inhibitor but is not as free from toxicity. 8 As a part of our research on antiviral drugs, we have been exploring pyrrolo [2, 3-d] pyrimidine nucleosides as potential selective inhibitors of HCMV. 9 10" 13