NEW DRUGS FOR OI--NATURAL PRODUCT MODELS

描述(改编自《调查员摘要》)：已获得 免疫缺陷综合症(AIDS)的特征是 免疫系统表现为严重的、危及生命的 细菌感染(OI)。艾滋病相关OI的治疗不充分 由于许多因素，其中最重要的是缺席 任何真正有效的抗生素。作为要发现的其他项目的一部分 艾滋病相关OI的新型原型抗生素--两种天然产品 (优波利定和利洛丹宁)被发现在 体外抗艾滋病相关主要真菌和细菌油的活性 播散性肺炎动物模型中的病原体以及体内疗效 真菌病。拟议的项目旨在确定 这些天然原型之一的结构-活性-关系(SAR) 产品，优波利定，已显示出抗肿瘤活性 新生隐球菌、白色念珠菌、曲霉菌和 胞内分枝杆菌和酵母菌的选择性抑制 拓扑异构酶I.为实现这一目标，建议：(1)合成一种 一系列合理设计的拓扑异构酶I结构类似物 尤波利定用于抗真菌合成孔径雷达研究；(2)体外活性评价 对抗条件致病菌新生隐球菌的化合物， 白念珠菌和胞内分枝杆菌；(3)评价 酵母菌和哺乳动物拓扑异构酶I的抑制；(4)评价选择性 来自特定目标1和2的最活跃化合物的活性 评价它们对哺乳动物细胞培养(Vero和H9)的毒性 常驻腹膜巨噬细胞及其毒性评价；(5) 遴选最有前途的候选人(S)深造并进行评估 这些候选者在适当的播散性动物模型中的疗效 感染；以及(6)选择并优先选择最有效的化合物(S) 用于进一步的衍生化，以改善管理和交付到 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).