NEW PHENYL NUCLEOSIDES AS ANTI-HIV AGENTS

描述(申请人提供)：由于获得性免疫缺陷综合症(艾滋病)的致命性，一直在加紧努力开发新的治疗方法或改进现有的艾滋病治疗方法。在为治疗人类免疫缺陷病毒(HIV-1)而研究的各种结构类别的抗病毒药物中，核苷类似物是最有效的之一。虽然这些核苷类似物，双脱氧核苷及其碳环类似物，为抑制病毒复制提供了巨大的希望，但也有一些缺点(耐药性、副作用等)。限制它们作为有效的治疗剂的使用。因此，迫切需要开发新的有效且毒性较低的抗病毒药物/先导药物来治疗艾滋病。我们发现新的结构“铅”的方法是探索核苷类似物结构，其中包括一个碳环(或其各种修饰)，其中由于双键(pi电子)的存在而施加的构象限制导致了强大的抗病毒活性。因此，在寻找新的铅作为潜在的抗HIV药物时，我们假设用一个合理取代的、pi双键丰富的苯基碳环取代双脱氧核苷糖环可能模拟核苷N9-嘌呤/NL-嘧啶和C5‘与靶和非靶大分子结合所需的距离/电子分布，这可能至少部分地导致药物的治疗和毒性作用。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嘌呤和苯基嘧啶化合物，b)对腺嘌呤化合物进行腺苷脱氨酶实验，以建立与核苷的类似物，以及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)、人类巨细胞病毒(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。在这个项目中获得的信息不仅对确定这些新的苯基核苷的作用机制和构效关系很有价值，而且还可能导致开发一种选择性和有效的抗艾滋病毒药物。

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.