A Biomimetic Approach to Generating Molecular Diversity

描述(申请人提供)：化学遗传学领域使用小分子来扰乱和研究生物系统。为了获得适合化学遗传分析的多样化和复杂的化合物选择，必须开发创新的合成方法。这项建议描述了一种概念上的新方法，用于快速合成骨架和立体化学多样性的小分子探针，其灵感来自于生物大分子中看到的结构多样性。为此，反应性单体将被组装成低聚物，并经历化学转化，使其“折叠”成共价键合的刚性结构。根据所用单体的特性和它们在低聚物链中的位置，化学转化可以产生骨架和立体化学上不同的分子实体。提出的小分子骨架被设计成类似于已知的天然产品，希望最大限度地与生物靶标相容。这些化合物可以针对多种疾病状态进行筛选；初步筛选工作将集中在与癌症相关的过程上。

DESCRIPTION (provided by applicant): The field of chemical genetics uses small molecules to perturb and study biological systems. In order to obtain a diverse and complex selection of compounds appropriate for chemical genetic analyses, innovative synthetic approaches must be developed. This proposal describes a conceptually novel method for the rapid synthesis of skeletally and stereo chemically diverse small molecule probes, drawing its inspiration from the structural diversity seen in biological macromolecules. To this end, reactive monomers will be assembled into oligomers and subjected to chemical transformations that cause them to "fold" into covalently bonded, rigid structures. Depending upon the identity of the monomers employed and their position within the oligomeric chain, chemical transformation can give rise to skeletally and stereo chemically distinct molecular entities. Proposed small molecule skeletons have been engineered to resemble known natural products with the hope of maximizing compatibility with biological targets. These compounds can be screened against a number of disease states; initial screening efforts will focus on processes relevant to cancer.