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

University Of California-Davis, Davis CA

Investigators

Abstract

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.