Colaborative Research on Anti-HIV Triterpenoids

抗HIV三萜类化合物的合作研究

基本信息

批准号：
09044339
负责人：
KASHIWADA Yoshiki
金额：
$ 1.09万
依托单位：
Niigata College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044339/
关键词：
Anti-HIV Triterpenoids Betulinic acid Oleanolic acid Ursolic acid ベツリン酸

项目摘要

A series of lupane-type triterpenoic acid derivatives were synthesized and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells, based on the fact that betulinic acid (1) and dihydrobetulinic acid (9) were identified as anti-HIV agents. Among the derivatives, 3-O-(3 ', 3 '-dimethylsuccinyl)-betulinic acid (3) and 3-O-(3 ', 3 '-dimethyl-succinyl)-dihydrobetulinic acid (11) both demonstrated extremely potent inhibitory activity with EC_<50> values of< 0.00035 muM.They exhibited remarkable in vitro therapeutic index (TI.) values of >20,000 and >14,000, respectively. 3-O-(3', 3'-Dimethylglutaryl)-betulinic acid and -dihydrobetulinic acid(12), 3-O-diglycolyl-betulinic acid and -dihydrobetulinic acid and 3-O-glutaryl- betulinic acid were also potent inhibitors of HIV replication with ED_<50> values ranging from 0.01 to 0.0023 muM and T.I.values from 1,017 to 2,344. In addition, compounds 1 1 and 12 are also active against HLV replica-tion in a monocy … More te cell line and n peripheral blood mononuclear cells (PBMCs). Our in vitro assay indicated that these compounds are not inhibitors on HIV- 1 reverse transcriptase, whereas they inhibited syncytia formation completely in a concentration range of 20 - 40 mug/mL.However, 3-O-(2', 2'-dimethylsuccinyl)-betulinic acid (2) was also found to be an inhibitor of HIV-induced membrane fusion with IC_<100> value of 20mutg/mL, though it displayed significantly lower anti-HIV activity than foregoing compounds with ED_<50> value of 2.7 muM and T.l. values of 5.9. This observation indicated that another mechanism(s) of action other than inhibition of syncytia formation could be involved in the anti-HIV activity shown by these compounds. Compound 3 was not active in the MAGI assay, suggesting that it inhibit HIV replication at a late stage of the viral life cycle, such as after viral protein synthesis.On the other hand, oleanolic acid was identified as an anti-HIV principle from several plants, including Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phorodendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), and Terniroemia gymnanthera (aerial part). It inhibited HIV- 1 replication in acutely infected H9 cells with an EC_<50> value of 3.7 muM, and inhibited H9 cell growth with an IC_<50> value of 47.8 muM [therapeutic index (T.I.) 12.8]. Pomolic acid, isolated from R.woodsii and H.capitata, was also identified as an anti-HIV agent (EC_<50> 3.0 muM, T.I.16.6). Although ursolic acid did show anti-HIV activity (EC_<50> 4.4 muM), it was slightly toxic (IC_<50> 14.3 muM, T.I.3.3). Based on these results, we examined anti-HLV the activity of oleanolic acid- or pomolic acid-related triterpenes isolated from several plants. In addition, we previously demonstrated that derivatives of betulinic acid, isolated from the leaves of S.claviflum as an anti-HIV principle, exhibited extreme potent anti-HIV activity. Accordingly, we prepared derivatives of oleanolic acid, and evaluated their anti-HIV activity. Among the oleanolic acid derivatives, 3-O-(3', 3'-dimethylsuccinyl)-oleanolic acid demonstrated most potent anti-HIV activity, with an EC_<50> value of 0.00086 muM and a T.I.value of 22,400.Though ursolic acid is slightly toxic against H9 cells, it shows similar level of anti-HIV acitivity to that of oleanolic acid. In addition, the structure of ursolic acid is closely correlated with oleanolic acid and betulinic acid, hence it is regarded as a potential lead for anti-HIV agent. Therefore, similar modification of ursolic acid, and evaluated their anti-HIV activities. 3-O-diglycoryl-uroslic acid demonstarated relatively potent anti-HIV activity with an EC_<50> value of 0.31 muM and a T.I.value of 155.5. Hoever, anti-HJV activities for other derivatives, including 3,3-dimethysuccinyl derivative, were not potent as corresponding betulinic acid and oleanolic acid derivatives. Less

基于β-苯甲酸（1）和二氢苯甲酸（9）的事实，将一系列针对HIV-1 y感染的H9细胞的不自越活性合成了一系列lupane型酸衍生物，3-o（3'，3'-二甲基二酸） - 尿酸（3）和3-o-（3' - 二甲基 - 糖基）-Dihydrobetulinic 11）均表现出具有EC_ <50>值的极有效的抑制性活性<0.00035妈妈的酸和 - 二氢蛋白酸（12），3-o-二甲基 - 甲基 - 甲基酸酯和二氢蛋白酶酸和3-o-戊磺胺酸盐酸盐和二羟基苯甲酸甲酸的高核酸的高度复制，范围为0.01至0.0023 MUM，T.I.VALUEs从1,017到2,344。不是HIV-1逆转录酶的抑制剂，而它们完全抑制合成症的形成在20-40 ml的浓度范围为20-40 ml.howver，3- O-（2'，2'，2'-二甲基糖蛋白基） - 蛋白酸（2）成为hiv-niv的抑制剂，其eD_ <50>值为2.7妈妈和T.L的抑制剂。 HESE化合物3所示的良好性在MAGI测定中没有活性。 3.7妈妈的值，抑制H9细胞的生长，IC_ <50>值为47.8 MUM [治疗指数（T.I.）12.8]。 3.0妈妈，T.I.16.6）。作为抗HIV原理的链球菌的叶子相应地表现出极端有效的抗HIV活性，我们制备了橄榄酸的衍生物，并评估了其抗HIV活性。 EC_ <50>值为0.00086 MUM，T.I.值为22,400。尽管Ursolic Accids对H9细胞对橄榄酸的毒性略有毒性，与橄榄酸的含量密切相关，并与橄榄酸和腰酸抗酸密切相关，并评估了其抗HIV活性. -HIV ACTIVITY WITH AN EC_ <50> Value of 0.31 Mum and a T.I.Value of 155.5. CCINYL Derivative, Were Not Potent as CorRespanding Betualinic ACID and Olenolic Acidid Derivatives. Less