The synthesis of peptidomimetic combinatorial libraries through successive amide alkylations

• Published in: Bioorganic & medicinal chemistry 1996-05, Vol.4 (5), p.709-715
• Main Authors: Dörner, Barbara, Husar, Gregory M., Ostresh, John M., Houghten, Richard A.
• Format: Article
• Language: English
• Subjects: Alkylation; Amides - chemistry; Amino Acids - chemistry; Chromatography, High Pressure Liquid - methods; combinatorial library; Dipeptides - chemical synthesis; Fluorenes - chemistry; peptidomimetic; solid phase synthesis; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(96)00067-3

A soluble peptidomimetic combinatorial library of 57,500 compounds was prepared. This library has a dipeptide scaffold with each amide hydrogen replaced with five different alkyl groups (methyl, ethyl, allyl, benzyl, or naphthylmethyl). Solid-phase methodology in combination with N-alkylation were used to synthesize the library, which incorporated 50 different L-, D-, and unnatural amino acids. Repetitive amide alkylations were carried out on the solid support following each amino acid coupling step. Individual model compounds were synthesized in order to optimize the alkylation conditions, to study potential amino acid side chain modifications, to determine the extent of racemization, and to provide analytical controls during the library synthesis. The peptidomimitic combinational library has four diversity positions (R 1-R 4 and is composed of 57,500 compounds. R 1. l-, d and unnatural amino acids R 2. Five alkyl groups (methyl, ethyl, allyl, benzyl, and naphthylmethyl) R 3. 46 l, d-, and unnatural amino acids R 4. Five alkyl groups (methyl, ethyl, allyl, benzyl, and naphthylmethyl)