SAMPANGINES--NOVEL ANTIBIOTICS FOR AIDS-RELATED OI

这个项目的总体目标是从小说课开始准备 一种或多种抗真菌生物碱，称为三丁香碱(SAM) 治疗某些艾滋病相关疾病的潜在有用药物 机会感染(OI)。目前，OI的治疗通常是 由于各种原因而不足，包括缺乏有效的 抗菌治疗。作为发现原型的计划的一部分 来自高等植物的抗真菌抗生素，一种新的生物碱， 3-甲氧基三苯乙胺(3-MeO-SAM)是从西非分离得到的 灌木，蜡梅属植物。初步研究已完成至 日期为进一步、更广泛的发展提供了重要动力 这类新型抗真菌药物的研究进展 抗生素。因此，我们在这里提出了一系列的化学和 生物学研究将提供必要的信息 完成研制最有效药物的总目标(S) 在这个班上。这一主要目标将通过以下方式实现 以下是具体目标： (1)综合出一系列设计合理的SAM结构 用于合成孔径雷达研究的类似物。 (2)评价(1)中类似物的体外抗真菌作用 (隐球菌属、假丝酵母属)、抗分枝杆菌属(分支杆菌属 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发挥作用。 (4)评估SAM活性的选择性。 预计这些具体目标的成功实现 将提供临床设计所需的信息 这一系列中有用的药物。此外，如果发现SAM采取了行动 通过一种新的抗真菌机制，这可以提供信息 有必要设计一种搜索来自Natural的其他此类代理 消息来源。

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.