1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶（HEPT）的脱氧类似物作为强效和选择性抗HIV-1药物的合成及抗病毒活性

Synthesis and antiviral activity of deoxy analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents.

作者信息

Tanaka H, Takashima H, Ubasawa M, Sekiya K, Nitta I, Baba M, Shigeta S, Walker R T, De Clercq E, Miyasaka T

机构信息

School of Pharmaceutical Science, Showa University, Tokyo, Japan.

出版信息

J Med Chem. 1992 Dec 11;35(25):4713-9. doi: 10.1021/jm00103a009.

DOI:10.1021/jm00103a009

PMID:1469700

Abstract

The effect of substitution in the acyclic structure of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) on anti-HIV-1 activity was investigated by synthesizing a series of deoxy analogs and related compounds. Preparation of 1-[(2-alkyloxyethoxy)methyl]-6- (phenylthio)thymine (2-4) derivatives was carried out based on alkylation of HEPT with primary alkyl halides. Preparation of the 1-[(alkyloxy)methyl]-6-(phenylthio)thymine (26-31) and 1-[(alkyloxy)methyl]-6-(arylthio)-2-thiouracil (32-45) derivatives was carried out on the basis of LDA lithiation of 1-[(alkyloxy)-methyl]thymine (9-14) and 1-[(alkyloxy)methyl]-2-thiouracil (15-25) followed by reaction with diaryl disulfides. The oxidative hydrolysis of the 2-thiouracil derivatives gave 1-[(alkyloxy)methyl]-6-(arylthio)uracil derivatives (46-57). 1-Alkyl-6-(phenylthio)thymine (59-61) derivatives were prepared on the basis of alkylation of 6-(phenylthio)thymine (58). Methylation of the hydroxyl group of HEPT did not affect the anti-HIV-1 activity of HEPT. Substitution of the 1-(2-hydroxyethoxy)methyl group by ethyl, butyl, methoxymethyl, (propyloxy)methyl, and (butyloxy)-methyl groups somewhat improved the original anti-HIV-1 activity of HEPT. Substitution with ethoxymethyl and (benzyloxy)methyl groups further potentiated the activity [EC50: 1-(ethoxy-methyl)-6-(phenylthio)thymine (27), 0.33 microM; 1-[(benzyloxy)methyl]-6-(phenylthio)thymine (31), 0.088 microM]. When the 5-methyl group of 27 and 31 was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity was improved remarkably [EC50: 5-ethyl-1-(ethoxymethyl)-6-(phenylthio)-uracil (46), 0.019 microM; 5-ethyl-1-[(benzyloxy)methyl]-6-(phenylthio)uracil (52), 0.0059 microM; 5-isopropyl-1-(ethoxymethyl)-6-(phenylthio)uracil (55), 0.012 microM; 5-isopropyl-1-[(benzyloxy)methyl]-6-(phenylthio)uracil (56), 0.0027 microM]. Introduction of two m-methyl groups into the phenylthio ring also potentiated the activity.

摘要

通过合成一系列脱氧类似物和相关化合物，研究了1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶(HEPT)的无环结构取代对其抗HIV-1活性的影响。1-[(2-烷氧基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶(2-4)衍生物是基于HEPT与伯烷基卤的烷基化反应制备的。1-[(烷氧基)甲基]-6-(苯硫基)胸腺嘧啶(26-31)和1-[(烷氧基)甲基]-6-(芳硫基)-2-硫尿嘧啶(32-45)衍生物是在1-[(烷氧基)甲基]胸腺嘧啶(9-14)和1-[(烷氧基)甲基]-2-硫尿嘧啶(15-25)经LDA锂化后，再与二芳基二硫化物反应的基础上制备的。2-硫尿嘧啶衍生物的氧化水解得到1-[(烷氧基)甲基]-6-(芳硫基)尿嘧啶衍生物(46-57)。1-烷基-6-(苯硫基)胸腺嘧啶(59-61)衍生物是基于6-(苯硫基)胸腺嘧啶(58)的烷基化反应制备的。HEPT羟基的甲基化不影响HEPT的抗HIV-1活性。用乙基、丁基、甲氧基甲基、(丙氧基)甲基和(丁氧基)甲基取代1-(2-羟基乙氧基)甲基基团，在一定程度上提高了HEPT原有的抗HIV-1活性。用乙氧基甲基和(苄氧基)甲基取代进一步增强了活性[半数有效浓度(EC50)：1-(乙氧基甲基)-6-(苯硫基)胸腺嘧啶(27)，0.33微摩尔；1-[(苄氧基)甲基]-6-(苯硫基)胸腺嘧啶(31)，0.088微摩尔]。当27和31的5-甲基被乙基或异丙基取代时，抗HIV-1活性显著提高[EC50：5-乙基-1-(乙氧基甲基)-6-(苯硫基)尿嘧啶(46)，0.019微摩尔；5-乙基-1-[(苄氧基)甲基]-6-(苯硫基)尿嘧啶(52)，0.0059微摩尔；5-异丙基-1-(乙氧基甲基)-6-(苯硫基)尿嘧啶(55)，0.012微摩尔；5-异丙基-1-[(苄氧基)甲基]-6-(苯硫基)尿嘧啶(56)，0.0027微摩尔]。在苯硫基环中引入两个间甲基也增强了活性。