1-[(2-羟乙氧基)甲基]-6-(苯硫基)胸腺嘧啶类似物的构效关系：C-6苯环和C-5位取代对抗HIV-1活性的影响

Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity.

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 Sciences, Showa University, Tokyo, Japan.

出版信息

J Med Chem. 1992 Jan 24;35(2):337-45. doi: 10.1021/jm00080a020.

DOI:10.1021/jm00080a020

PMID:1732552

Abstract

The effect of substitution on the pyrimidine moiety of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine (HEPT-S) on anti-HIV-1 activity was investigated by synthesizing a series of 5-methyl-6-(arylthio) and 5-substituted-6-(phenylthio) derivatives. Preparation of the 5-methyl-6-(arylthio) derivatives was carried out based on either LDA lithiation of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]thymine (3) and 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiothymine (4) followed by reaction with diaryl disulfides or an addition-elimination reaction of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]-methyl]-6- (phenylsulfinyl)thymine (31) with aromatic thiols. Preparation of the 5-substituted-6-(phenylthio) derivatives was carried out based on either C-5 lithiation of the 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-6-(phenylthio)uraci l (41) with LTMP or the LDA lithiation of 5-alkyl-1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiouraci l derivatives 45-47. Substitution at the meta position of the C-6-(phenylthio) ring by the methyl group improved the original anti-HIV-1 activity of HEPT, and introduction of two m-methyl groups to the phenylthio ring further potentiated the activity [EC50: 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]thymine (28), 0.26 microM; 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]-2-thiothymin e (30), 0.22 microM]. When the 5-methyl group was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity of HEPT was also improved remarkably [EC50: 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (48), 0.11 microM; 5-isopropyl-1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)-2-thiouracil (50), 0.059 microM; 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (54), 0.12 microM; 5-isopropyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (56), 0.063 microM]. 6-[(3,5-Dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]thymine derivatives 51 and 57 and 6-[(3,5-dimethylphenyl)thio]-5-isopropyl-1-[(2- hydroxyethoxy)methyl]thymine derivatives 52 and 58 inhibited the replication of HIV-1 in the nanomolar concentration range.

摘要

通过合成一系列5-甲基-6-（芳硫基）和5-取代-6-（苯硫基）衍生物，研究了嘧啶部分取代对1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶（HEPT）和1-[(2-羟基乙氧基)甲基]-6-(苯硫基)-2-硫代胸腺嘧啶（HEPT-S）抗HIV-1活性的影响。5-甲基-6-（芳硫基）衍生物的制备基于1-[[2-(叔丁基二甲基硅氧基)乙氧基]甲基]胸腺嘧啶（3）和1-[[2-(叔丁基二甲基硅氧基)乙氧基]甲基]-2-硫代胸腺嘧啶（4）的LDA锂化反应，随后与二芳基二硫化物反应，或者基于1-[[2-(叔丁基二甲基硅氧基)乙氧基]甲基]-6-（苯亚磺酰基）胸腺嘧啶（31）与芳族硫醇的加成-消除反应。5-取代-6-（苯硫基）衍生物的制备基于用LTMP对1-[[2-(叔丁基二甲基硅氧基)乙氧基]甲基]-6-(苯硫基)尿嘧啶（41）进行C-5锂化反应，或者基于5-烷基-1-[[2-(叔丁基二甲基硅氧基)乙氧基]甲基]-2-硫代尿嘧啶衍生物45-47的LDA锂化反应。在C-6-（苯硫基）环的间位用甲基取代提高了HEPT原有的抗HIV-1活性，并且在苯硫基环上引入两个间甲基进一步增强了活性[半数有效浓度（EC50）：6-[(3,5-二甲基苯基)硫基]-1-[(2-羟基乙氧基)甲基]胸腺嘧啶（28），0.26微摩尔；6-[(3,5-二甲基苯基)硫基]-1-[(2-羟基乙氧基)甲基]-2-硫代胸腺嘧啶（30），0.22微摩尔]。当5-甲基被乙基或异丙基取代时，HEPT的抗HIV-1活性也显著提高[EC50：5-乙基-1-[(2-羟基乙氧基)甲基]-6-(苯硫基)-2-硫代尿嘧啶（48），0.11微摩尔；5-异丙基-1-[(2-羟基乙氧基)甲基]-6-(苯硫基)-2-硫代尿嘧啶（50），0.059微摩尔；5-乙基-1-[(2-羟基乙氧基)甲基]-6-(苯硫基)-2-硫代尿嘧啶（54），0.12微摩尔；5-异丙基-1-[(2-羟基乙氧基)甲基]-6-(苯硫基)-2-硫代尿嘧啶（56），0.063微摩尔]。6-[(3,5-二甲基苯基)硫基]-5-乙基-1-[(2-羟基乙氧基)甲基]胸腺嘧啶衍生物51和57以及6-[(3,5-二甲基苯基)硫基]-5-异丙基-1-[(2-羟基乙氧基)甲基]胸腺嘧啶衍生物52和58在纳摩尔浓度范围内抑制HIV-1的复制。