Arthropod-Based Libraries for High Throughput Screening

在过去的四十年里，我们一直在研究防御和通信的化学， 陆生昆虫和其他节肢动物，一组生物，包括超过一半的所有描述的物种 地球上虽然我们已经表征的许多化合物具有简单的结构（例如直链的， 链烯烃、羧酸、醛、酚、苯醌等），也有很多例子， 具有生物活性的生物碱、类异戊二烯（包括类固醇）和具有新结构的聚酮化合物， 在研究过程中发现的。我们计划选择一些最有趣的化合物 作为准备试点规模图书馆的主导结构， 高通量筛选中的生物学特性。建议的图书馆包括一组相关的 同类天然产物（如Myrmicaria生物碱或强心光泽蟾毒精）或一组 衍生自合成可获得的天然产物的结构的合成化合物（例如， 螺环Polyzonium生物碱）。从药物发现的角度来看，这个项目是 我们多年来在陆地天然产物化学领域的研究。 有几个原因可以解释为什么这项研究应该与公共卫生直接相关。首先是 事实上，每一个拟议的文库都将基于一种天然存在的分子， 与生物目标相互作用。此外，先导化合物和拟议的衍生物一般 表示尚未通过高通量筛选检查的分子结构。的 在这些库中发现与神经药理学等领域相关的活动的可能性， 传染病和寄生虫病，或癌症的发病率远远高于对其他疾病的研究所预期的。 化学空间的领域，这些领域不是基于生物起源的小分子。

Over the past four decades, we have been studying the chemistry of defense and communication among terrestrial insects and other arthropods, a group of organisms that includes over half of all described species on earth. While many of the compounds we have characterized have simple structures (such as straight chain alkenes, carboxylic acids, aldehydes, phenols, benzoquinones ...), there are also many examples of biologically active alkaloids, isoprenoids (including steroids), and polyketides with novel structures which we have discovered in the course of this research. We plan to select some of the most interesting compounds as lead strutures for the preparation of pilot-scale libraries providing sufficient material to explore their biological properties in high-throuput screening. The proposed libraries consist of either a group of related congeneric natural products (such as the Myrmicaria alkaloids or the cardiotonic lucibufagins) or of a group of synthetic compounds derived from the structure of a synthetically accessible natural product (such as the spirocyclic Polyzonium alkaloids). This project is the culmination, from the viewpoint of drug discovery, of our many years of research in the field of terrestrial natural products chemistry. There are several reasons why this research should be of direct relevance to public health. First of all, there is the fact that each of the proposed libraries will be based on a naturally-occurring molecule of proven ability to interact with biological targets. In addition, the lead compounds and proposed derivatives generally represent molecular structures that have not yet been examined via high throughput screening. The likelihood of discovering activities within these libraries of relevance to areas such as neuropharmacology, infectious and parasitic diseases, or cancer is much greater than would be expected from a study of other areas of chemical space which are not based on small molecules of biological origin.