Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents
Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents
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DOI：
10.1021/jm950922q
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发表时间：
1996-03-01
影响因子：
7.3
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Kashiwada, Y;Hashimoto, F;Lee, KH
目前正在进行各种努力，以开发治疗药物，以阻止人类免疫缺陷病毒（HIV）的复制。尽管几种核苷类HIV-1逆转录酶（RT）抑制剂AZT、ddI、ddC和D4T已被FDA批准并用于临床，但已有不良副作用和耐药病毒的报道。2,3因此，迫切需要具有有效抗hiv活性并具有新型作用模式的化合物加入现有的抗hiv治疗中。目前，新的抗hiv药物的开发重点是发现具有新结构或新的作用机制的各种化合物。发现新的植物源性天然产物作为抗hiv药物的潜在新先导化合物以及这些新先导化合物的修饰是我们实验室的持续目标。对初始先导结构进行适当的结构修饰可以提供活性大大增强的类似物。作为一个成功的例子，我们从Lomatim suksdorfii中分离并鉴定了suksdorfin作为抗hiv的原理。4随后对suksdorfin进行修饰，得到了3′，4′-二o -(-)-樟脑酰基-(+)-顺式helhellactone (DCK)，显示出对H9淋巴细胞HIV复制极有效的抑制活性，EC50值为0.0004 μM，治疗指数（TI）值为136 719。5,6以前，我们从丁香中分离到白桦酸和铂酸作为抗hiv的主要成分。7白桦酸(1)和铂酸（11）对H9淋巴细胞的HIV-1复制具有抑制作用，EC50分别为1.4 μM和6.5 μM， TI分别为9.3和14。白桦酸加氢生成二氢白桦酸(6)，其抗hiv活性略强，EC50值为0.9，TI值为14。在这些发现的基础上，对这些先导化合物白桦酸和二氢白桦酸进行了修饰，并发现了六种有效的抗艾滋病毒药物。本文介绍了这些白桦酸和脱氢白桦酸衍生物的制备及其抗hiv活性的评价。
Various efforts are currently underway to develop therapeutic agents to arrest the replication of the human immunodeficiency virus (HIV). Although several nucleoside HIV-1 reverse transcriptase (RT) inhibitors, AZT, ddI, ddC, and D4T, are approved by the FDA and used clinically, adverse side effects and the development of drug resistant virus have been reported. 2, 3 Therefore, compounds possessing potent anti-HIV activity with novel modes of action are urgently needed to add to the existing anti-HIV therapies. Currently, the development of new anti-HIV agents is focused on discovering diverse compounds with either novel structures or a new mechanism (s) of action. Discovery of novel plant-derived natural products as potential new lead compounds for anti-HIV agents as well as the modification of these new lead compounds are continuing goals of our laboratory. Suitable structural modification of the initial lead structures may provide analogs with greatly enhanced activity. As a successful example, we isolated and identified suksdorfin as an anti-HIV principle from Lomatim suksdorfii. 4 Subsequent modification of suksdorfin has yielded 3′, 4′-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK), which demonstrated extremely potent inhibitory activity against HIV replication in H9 lymphocyte cells with an EC50 value of 0.0004 μM and a therapeutic index (TI) value of 136 719. 5, 6Previously, we isolated betulinic acid and platanic acid as anti-HIV principles from Syzigium claviflorum. 7 Betulinic acid (1) and platanic acid (11) exhibited inhibitory activity against HIV-1 replication in H9 lymphocyte cells with EC50 values of 1.4 and 6.5 μM, respectively, and TI values of 9.3 and 14, respectively. Hydrogenation of betulinic acid yielded dihydrobetulinic acid (6), which showed slightly more potent anti-HIV activity with an EC50 value of 0.9 and a TI value of 14. On the basis of these findings, modification of these lead compounds, betulinic acid and dihydrobetulinic acid, has been carried out and has led to the discovery of six potent anti-HIV agents. This paper describes the preparation of these betulinic acid and dehydrobetulinic acid derivatives and evaluation of their anti-HIV activities.