NEW PHENYL NUCLEOSIDES AS ANTI-HIV AGENTS

描述（由申请人提供）：由于获得性免疫缺陷综合征（艾滋病）的致命性质，人们正在努力开发新的治疗方法或改进现有的治疗艾滋病的方法。在研究用于治疗人类免疫缺陷病毒（HIV-1）（一种导致艾滋病的病毒）的各种结构类抗病毒药物中，核苷类似物是最有效的。虽然这些核苷类似物，二脱氧核苷及其碳环类似物，在抑制病毒复制方面有很大的希望，但一些缺点（耐药性、副作用等）限制了它们作为有效治疗药物的使用。因此，迫切需要开发新的强效和毒性较低的抗病毒药物/先导物来治疗艾滋病。我们发现新结构“铅”的方法是探索核苷类似物结构，其中包括碳环（或其各种修饰），其中双键（pi电子）的存在施加的构象限制导致了强大的抗病毒活性。因此,在寻找一个新的铅作为潜在的抗艾滋病代理商,我们假设dideoxynucleoside糖环的替代理性取代,π双键丰富、苯基碳环可能模拟所需的距离/电子分布,核苷,N9-puine / Nl-pyrimidine和C5的之间的绑定目标和不属预定目标的大分子,这可能结果,至少在某种程度上,在药物的治疗以及不良行为。为了验证这一假设，我们建议进行以下研究：a)设计和合成一系列新的苯基嘌呤和苯基嘧啶化合物；b)用腺嘌呤化合物进行腺苷脱氨酶实验，以建立与核苷的相似性；c)评估体外抗HIV-1的活性。核苷类似物对疱疹病毒感染也有效，如单纯疱疹病毒（HSV）、水痘带状疱疹病毒（VZV）、人巨细胞病毒（HCMV）和eb病毒（EBV），因此我们也将测试这些苯基化合物对这些病毒的作用。本项目所获得的信息不仅对确定这些新苯基核苷的作用机制和构效关系具有重要意义，而且可能有助于开发一种选择性强效的抗hiv药物。

DESCRIPTION (provided by applicant): Due to the fatal nature of acquired immunodeficiency syndrome (AIDS), an intensive effort has been underway to develop new therapies or to improve existing therapies for the treatment of AIDS. Among the various structural classes of the antiviral agents investigated for the tretment of human imunodeficiency virus (HIV-1), a virus resposnsible for AIDS disease, nucleoside analogues are among the most effective. Although these nucleoside analogues, dideoxynucleosides and their carbocyclic analogs, offer great promise for the inhibition of viral replication, several shortcomings (resistance, side effects etc.) limit their use as effective therapeutic agents. Therefore, there is a critical need for the development of new potent and less toxic antiviral drugs/leads for the treatment of AIDS. Our approach to uncover new structural "lead" is to explore the nucleoside analogue structures which include a carbocycle (or various modifications thereof) wherein the conformational restrains imposed by the presence of a double bond (pi electrons) has resulted in potent antiviral activity. Therefore, in the search for a new lead as potential anti-HIV agents we hypothesize that the replacement of a dideoxynucleoside sugar ring with a rationally substituted, pi double bond rich, phenyl carbocyclic ring might mimic the required distance/electronic distribution, as in nucleosides, between the N9-puine/Nl-pyrimidine and the C5' for the binding to both target and nontarget macromolecules and this may result, at least in part, in the therapeutic as well as toxic actions of the drug. To test this hypothesis, we propose to conduct the following studies: a) design and synthesize a series of new phenylpurine and phenylpyrimidine compounds, b) conduct adenosine deaminase experiments with adenine compounds to establish the analogy with the nucleosides, and c) evaluate in-vitro activity against HIV-1. Nucleoside analogues are also effective against herpesvirus infections such as herpes simples virus (HSV), varicella zoster virus (VZV), human cytomegalovirus (HCMV), and Epstein-Barr virus (EBV), therefore we will also test these phenyl compounds against these viruses. The information gained in this project will be valuable not only in determining the mechanism of action and structure-activity relationship of these new phenyl nucleosides, but may also result in the development of a selective and potent anti-HIV agent.