Development of Novel Encoded "One-Bead One-Compound" Combinatorial Small Molecule Libraries

该项目涉及开发和验证一种新的编码技术，用于“一珠一化合物”(OBOC)小分子组合文库。使用固相分离-混合合成方法，可以获得珠体库，使得每个珠体仅表达一种化合物，在单个珠体中具有该化合物的1013个拷贝。然后可以对珠库进行筛选，以获得感兴趣的生物、化学和物理性质，然后分离阳性珠子以进行结构确定。在合成和筛选方面，OBOC技术是高效的。然而，小分子OBOC组合文库方法的一个主要局限性是难以在单个珠子上阐明小分子化合物的化学结构。为了充分利用OBOC组合方法，需要一种快速、灵敏和可靠的编码/解码方法。在这项提议中，将开发出拓扑分离的双功能微珠，其测试分子位于微珠的外层，编码分子位于微珠的内部。在珠子的内部将构造三个或四个可劈开的编码臂。这些编码臂中的每一个都包含与待合成的测试化合物的支架上的官能团相同或相关的官能团。在这种编码方法中，每个构建块将同时与测试臂和编码臂反应，从而省去了许多合成步骤和漫长的编码时间。解码是通过一次切割所有编码标签并通过质谱学分析释放的分子来完成的。这种新的编码方法具有很高的通用性和效率。一天内就能轻松破译100多颗珠子。在样品准备和数据分析方面还有自动化的余地。从文献中获得的12种不同的模型库化合物将被用来优化程序，编码方法将通过设计、合成和筛选三个编码的小分子库来验证。近年来，许多有机化学家将他们的注意力从单分子的合成转移到相关化合物的大“库”的制备上，从而快速有效地筛选出所需的性质。这些“组合”合成方法有其自身的挑战，通常与确定特定分子结构的能力有关，从而产生最有希望的特性。在有机化学和大分子化学项目的支持下，加州大学戴维斯分校血液学和肿瘤学系的Kit S.Lam教授和化学系的Carlito B.Lebrilla教授正在开发简单、快速和高效地识别组合文库中的分子的新方法。

This project involves the development and validation of a novel encoding technique for "one-bead one-compound" (OBOC) small molecule combinatorial libraries. Using a solid phase split-mix synthesis method, bead libraries can be obtained such that each bead expresses only one compound, with 1013 copies of that compound in one single bead. The bead-library can then be screened for biological, chemical and physical properties of interest, and positive beads are then isolated for structure determination. In terms of synthesis and screening, the OBOC technique is highly efficient. However, a major limitation in the small molecule OBOC combinatorial library method is the difficulty in elucidating the chemical structure of a small molecule compound on one single bead. A rapid, sensitive, and reliable encoding/decoding methodology is necessary for full exploitation of the OBOC combinatorial method. In this proposal, topologically segregated bi-functional beads with testing molecules in the outer layer of the bead and coding molecules in the interior of the beads will be developed. Triple or quadruple cleavable coding arms will be constructed in the interior of the bead. Each of these coding arms contains a functional group that is identical or related to the functional groups on the scaffold of the testing compound to be synthesized. In this encoding method, each building block will react with the testing arm and the encoding arms simultaneously, thus eliminating many synthetic steps and lengthy encoding times. Decoding is accomplished by cleaving all the coding tags at once and analyzing the released molecules by mass spectroscopy. This novel encoding method is highly versatile and efficient. Over 100 beads can easily be decoded in one day. There is room for automation in terms of sample preparation and data analysis. Twelve different model library compounds obtained from the literature will be used to optimize the procedure, and the encoding method will be validated by designing, synthesizing, and screening three encoded small molecule libraries.In recent years, many organic chemists have turned their attention from the synthesis of single molecules to the preparation of large "libraries" of related compounds, permitting fast and efficient screening for desirable properties. These "combinatorial" synthesis approaches come with their own challenges, often relating to the ability to determine the structure of the specific molecule giving rise to the most promising properties. With the support of the Organic and Macromolecular Chemistry Program, Professors Kit S. Lam, of the Department of Hematology and Oncology, and Carlito B. Lebrilla, of the Department of Chemistry at the University of California - Davis, are developing new methods for the simple, rapid, and efficient identification of molecules in combinatorial libraries.