Anti-HIV Natural Products from the plants Destributed in the Northern Part of Japan

来自日本北部植物的抗 HIV 天然产物

基本信息

批准号：
11694321
负责人：
KASHIWADA Yoshiki
金额：
$ 1.73万
依托单位：
Niigata College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694321/
关键词：
Anti-HIV betulinic acid betulin ursolic acid triterpenoids

项目摘要

As a part of the structure-activity relationship study of the potent anti-HIV agent 3-Ο-(3', 3'-dimenthyl)-succinyl-betulinic acid(DSB), 3-Alkylamido-3-deoxy-betulinic acids were synthesized and evaluated for anti-HIV activity, 3-αDiglycorylamide-3-deoxy-betulinic acid demonstrated relatively potent anti-HIV activity(EC_<50> 0.24 μM, TI 728). However, replacing the ester group at C-3 in DSB and its analogues with an amido group yielded inactive or much less potent compounds against HIV replication, indicating that the ester group at C-3 in is essential for potent anti-HIV activity.Four isomers of 3,28-di-Ο-(dimethylsuccinyl)-betulin were prepared and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. 3-Ο-(3', 3'-Dimethylsuccinyl)-28-Ο-(2", 2"-dimethylsuccinyl)-betulin was the most potent anti-HIV compound with an EC_<50> value of 0.00087 μM and a TI value of 42,400.3-Ο-Acyl-ursolic acids were prepared and evaluated their anti-HIV activities, based on our previous finding that 3-Ο-acyl-betulinic acid and -oleanolic acid, especially 3-Ο-(3', 3'-dimethyl)-succinyl-betulinic acid, and -oleanolic acid demonstrated potent anti-HIV activities(EC_<50> < 0.00035 and 0.00086 μM, respectively, therapeutic index(TI) > 20,000 and 22,326, respectively), as well as the fact that ursolic acid(6)showed similar level of anti-HIV activity(EC_<50> 4,4μM)to that of oleanolic acid(EC_<50> 3.7 μM), though it was slightly toxic(IC_<50> 14.3 μM, T.I.3.3). 3-Ο-Diglycoryl-ursolic acid demonstrated relatively potent anti-HIV activity with an EC_<50> 0.31 μM, and a TI of 155.5. In contrast, 3-Ο-(3', 3'-dimethylsuccinyl)-ursolic acid, corresponding to the extremely potent anti-HIV betulinic acid and oleanolic acid derivatives displayed only a weak anti-HIV activity(EC_<50> 2.1μM, T.I.23.6).

作为有效抗 HIV 药物 3-O-(3', 3'-二甲基)-琥珀酰-桦木酸 (DSB) 构效关系研究的一部分，3-烷基酰胺-3-脱氧-桦木酸被合成并评估了抗 HIV 活性，3-α二甘酰酰胺-3-脱氧-桦木酸表现出有效的抗 HIV 活性（EC_<50> 0.24 μM, TI 728) 然而，用酰胺基取代 DSB 及其类似物中 C-3 上的酯基，产生了针对 HIV 复制无活性或效力低得多的化合物，表明 C-3 上的酯基对于有效发挥作用至关重要。抗HIV活性。制备了3,28-二-O-(二甲基琥珀酰)-桦木醇的四种异构体，并评估了其针对H9淋巴细胞中HIV-1复制的抗HIV活性。 3-O-(3', 3'-二甲基琥珀酰基)-28-O-(2", 2"-二甲基琥珀酰基)-桦木脑是最有效的抗HIV化合物，其EC_<50>值为0.00087μM，TI根据我们之前的发现，制备了 42,400.3-Ο-酰基熊果酸的值并评估了其抗 HIV 活性3-O-酰基-桦木酸和-齐墩果酸，特别是3-O-(3', 3'-二甲基)-琥珀酰-桦木酸和-齐墩果酸表现出有效的抗HIV活性(EC_<50> < 0.00035和 0.00086 μM，分别，治疗指数 (TI) > 20,000 和 22,326），以及事实上，熊果酸(6)表现出与齐墩果酸(EC_<50> 3.7 μM)相似的抗HIV活性水平(EC_<50> 4,4μM)，尽管它有轻微的毒性(IC_<50> 14.3μM，T.I.3.3)，3-O-二甘酰-熊果酸表现出相对有效的抗HIV活性，EC_50。 0.31 μM，TI 为 155.5 相比之下，3-O-(3', 3'-二甲基琥珀酰)-熊果酸（相当于极强的抗 HIV 活性）桦木酸和齐墩果酸衍生物仅表现出弱的抗 HIV 作用。活性(EC_<50>2.1μM，T.I.23.6)。