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

新型编码“一珠一化合物”组合小分子文库的开发

• 批准号: 0302122
• 负责人: Kit Lam
• 金额: $ 42.4万
• 依托单位: University of California-Davis
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0302122&HistoricalAwards=false
• 关键词: Development; Novel; Encoded; Bead; Compound

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.

该项目涉及开发和验证“一珠一化合物”（OBOC）小分子组合文库的新型编码技术。使用固相分离混合合成方法，可以获得珠文库，使得每个珠仅表达一种化合物，在一个单个珠中具有1013个拷贝的该化合物。然后可以针对感兴趣的生物、化学和物理性质筛选珠库，然后分离阳性珠用于结构测定。在合成和筛选方面，OBOC技术是高效的。然而，小分子OBOC组合文库方法的主要限制是难以阐明单个珠上的小分子化合物的化学结构。一个快速，灵敏，可靠的编码/解码方法是必要的OBOC组合方法的充分利用。在该方案中，将开发拓扑隔离的双功能珠粒，其中测试分子在珠粒的外层中，编码分子在珠粒的内部中。三重或四重可切割编码臂将在珠粒内部构建。这些编码臂中的每一个含有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，从而消除了许多合成步骤和冗长的编码时间。解码是通过一次切割所有编码标签并通过质谱分析释放的分子来完成的。这种新颖的编码方法是高度通用和高效的。超过100个珠子可以在一天内轻松解码。在样品制备和数据分析方面有自动化的余地。从文献中获得的12种不同的模型库化合物将用于优化程序，并通过设计、合成和筛选3种编码的小分子库来验证编码方法。近年来，许多有机化学家将注意力从单分子的合成转向相关化合物的大“库”的制备，允许快速和有效地筛选所需的性质。这些“组合”合成方法具有其自身的挑战，通常与确定产生最有希望的性质的特定分子的结构的能力有关。在有机和高分子化学项目的支持下，Kit S教授。血液学和肿瘤学系的Lam和Carlito B。加州-戴维斯大学化学系的Lebrilla博士正在开发新的方法，用于简单、快速和有效地鉴定组合文库中的分子。