NEW DRUGS FOR OI--NATURAL PRODUCT MODELS

描述（改编自研究者摘要）：获得性 免疫缺陷综合症（艾滋病）的特点是， 免疫系统，表现为严重的，危及生命的形式 机会性感染（OI）。 艾滋病相关性OI的治疗不足 由于许多因素，其中最重要的是缺乏 真正有效的抗生素 作为其他项目的一部分， 两种天然产物，用于治疗艾滋病相关OI的新型原型抗生素 （优泊尿苷和利碘地宁）被发现在治疗癌症方面表现出有希望的作用。 体外抗艾滋病相关的主要真菌和细菌OI活性 病原体，以及在动物模型中的体内功效， 真菌病 拟议项目旨在确定 结构活性关系（SAR）的这些原型天然之一， 产品，优泊尿苷，已证明对 新型隐球菌、白色念珠菌、曲霉属，以及 胞内分枝杆菌，以及选择性抑制酵母 拓扑异构酶I为了实现这一目标，建议：（1）合成一个 拓扑异构酶I的一系列合理设计的结构类似物 用于抗真菌SAR研究的优泊尿苷;（2）体外活性评价 针对机会致病菌新型隐球菌的化合物， 白色念珠菌和胞内分枝杆菌;（3）评估 酵母和哺乳动物拓扑异构酶I的抑制;（4）评估选择性 特定目标1和2中活性最高的化合物的活性， 评价它们对哺乳动物细胞培养物（Vero和H9）的毒性， 驻留的腹腔巨噬细胞，并通过评估它们的老年毒性;（5） 选择最有前途的候选人进行进一步研究，并评估 这些候选物在适当的播散性肿瘤动物模型中的功效 感染;和（6）选择和优先考虑最有效的化合物 用于进一步衍生化，以改善给药和递送至 感染部位（即，生物利用度和药代动力学）。

DESCRIPTION (Adapted from the Investigator's Abstract): Acquired Immunodeficiency Syndrome (AIDS) is characterized by a breakdown in the immune system that manifests itself in the form of serious, life-threatening oppor-tunistic infections (OI). Therapy of AIDS-related OI is inadequate due to a number of factors, among the most important of which is the absence of any truly effective antibiotics. As part of other projects to discover novel prototype antibiotics for AIDS-related OI, two natural products (eupolauridine and liriodenine) were discovered to exhibit promising in vitro activity against the major AIDS-related fungal and bacterial OI pathogens, as well as in vivo efficacy in animal models of disseminated mycoses. The proposed project is aimed at determining the structure-activity-relationships (SAR) of one of these prototype natural products, eupolauridine, which has demonstrated activity against Cryptococcus neoformans, Candida albicans, Aspergillus species, and Mycobacterium intracellulare, as well as selective inhibition of yeast topoisomerase I. Toward this goal it is proposed to: (1) synthesize a series of rationally designed structural analogs of topoisomerase I eupolauridine for antifungal SAR studies; (2) evaluation in vitro activities of compounds against the opportunistic pathogens Cryptococcus neoformans, Candida albicans, and Mycobacterium intracellulare; (3) evaluate the inhibition of yeast and mammalian topisomerase I; (4) assess the selectivity of activity of the most active compounds from Specific Aims 1 and 2 by eval-uating their toxicities to mammalian cell culture (Vero and H9) to resident peritoneal macrophages and by evaluating them for gerotoxicity; (5) select the most promising candidates(s) for further study and to evaluate the efficacy of such candidates in appropriate animal models of disseminated infection; and (6) select and prioritize the most efficacious compound(s) for further derivatization to improve administration and delivery to the site of infection (i.e., bioavailability and pharmacokinetics).