SAMPANGINES--NOVEL ANTIBIOTICS FOR AIDS-RELATED OI

这个项目的总体目标是准备，从小说类 抗真菌生物碱称为sampangines（SAM），一个或多个 治疗某些艾滋病相关疾病的潜在有用药物 机会性感染（OI）。 目前，OI的治疗通常是 由于各种原因，包括缺乏有效的 抗菌治疗 作为发现原型计划的一部分 来自高等植物的抗真菌抗生素，一种新的生物碱， 3-3-MeO-SAM是从非洲西部分离的一种生物碱 灌木，隐花柳。 完成的初步研究， 日期提供了重大的推动力，进一步，更广泛的 这类新型抗真菌药物研究进展 抗生素 因此，我们在此提出了一系列化学和 生物学研究将提供必要的信息， 实现开发最有效药物的总体目标 在这堂课上。 这一主要目标将通过以下方式实现： 具体目标如下： (1)综合一系列合理设计的SAM结构 用于SAR研究的类似物。 (2)评价（1）的类似物的体外抗真菌活性 （隐球菌，念珠菌），抗分枝杆菌（分枝杆菌 细胞内）和抗病毒（单纯疱疹病毒1型） 活动 (3)确定SAM是否通过一种新的机制起作用。 (4)评估自评机制活动的选择性。 预计这些具体目标的成功实现 将为临床设计提供必要信息 这一系列的药物。 此外，如果发现SAM起作用， 通过一种新的抗真菌机制， 有必要设计一个搜索其他这样的代理人从自然 源

The overall goal of this project is to prepare, from the novel class of antifungal alkaloids known as sampangines (SAMs), one or more potentially useful drugs for the treatment of certain AIDS-related opportunistic infections (OI). Currently, treatment of OI is often inadequate for a variety of reasons, including the lack of effective antimicrobial therapy. As part of a program to discover prototype antifungal antibiotics from higher plants, a novel alkaloid, 3-methoxysampangine (3-MeO-SAM), was isolated from the West African shrub, Cleistopholis patens. Preliminary studies accomplished to date have provided significant impetus for further, more extensive investigation and development of this novel class of antifungal antibiotics. Thus, we propose herein a series of chemical and biological studies that will provide the information necessary to accomplish the overall goal of developing the most effective drug(s) in this class. This major objective will be accomplished through the following specific aims: (1) Synthesize a series of rationally designed SAM structural analogs for SAR studies. (2) Evaluate the analogs from (1) for in vitro antifungal (Cryptococcus, Candida), antimycobacterial (Mycobacterium intracellulare) and antiviral (Herpes simplex virus type-1) activity. (3) Establish whether the SAMs act by a novel mechanism. (4) Assess the selectivity of the activity of the SAMs. It is anticipated that successful achievement of these specific aims will provide information necessary for the design of a clinically useful drug in this series. Further, if the SAMs are found to act by a novel antifungal mechanism, this could provide the information necessary to design a search for other such agents from natural sources.