Bifunctional scaffolds as templates for synthetic combinatorial libraries

Abstract

A small-molecule synthetic combinatorial library was designed and synthesized that features potential pharmacophores attached to a variety of small cyclic scaffolds. The synthesis of the library involved randomization of three types of building blocks: 20 amino acids, 10 aromatic hydroxy acids and 21 alcohols, totaling a library complexity of 4200 compounds. Mitsunobu polymer-supported etherification was used in the last randomization. The library compounds were attached to beads via an ester-bond linkage enabling both on-bead as well as in-solution screening. When the library was tested against a model target, streptavidin, specific binders were found. The structures of the most active compounds were determined from the fragmentation pattern in MS/MS experiments.

The “One-Bead-One-Compound” Combinatorial Library Method

“…Six examples of libraries were reported: N -(alkoxyacyl) amino acids, N , N ‘-bis(alkoxyacyl) diamino acids, N -acyl amino ethers, N -(alkoxyacyl) amino alcohols, N -alkylamino ethers, and N -(alkoxyaryl) diamines (Figure ). Specific streptavidin ligands were reported from the library of 4200 N -(alkoxyacyl) amino acids 33 Examples of structurally heterogeneous libraries. …”

Multifunctional multivalency: a focused library of polymeric cholera toxin antagonists

“…Polymer-supported synthesis is often used for generation of compound libraries. [29][30][31][32] We propose to employ a polymeric support both to facilitate synthesis and biological assays of novel ligands. Since the basic anchoring ligand was only a monosaccharide a multivalent scaffold was also necessary to permit detection of weak activities.…”

Synthesis, Screening, and Sequencing of Cysteine-Rich One-Bead One-Compound Peptide Libraries

“… 13 , 14 Tandem mass spectrometry (MS/MS)( 15 ) is still the most direct approach to peptide sequence determination and does not share the structural limitations imposed by Edman chemistry. ( 16 ) Therefore it is suprising that there are so few examples of MS/MS sequencing applied to peptides obtained from single beads. 17 , 18 In no case have single-bead MS/MS analyses been applied to oligomers containing cysteine.…”

“…Surprisingly, after two decades of research using OBOC peptide libraries, free cysteines have been included in variable positions and identified by Edman sequencing in only a handful of instances . Continuing advances in the efficiency and economy of mass spectrometry have led to powerful new methods of peptide sequencing based on chemical formation of mass ladders. , Tandem mass spectrometry (MS/MS) is still the most direct approach to peptide sequence determination and does not share the structural limitations imposed by Edman chemistry . Therefore it is suprising that there are so few examples of MS/MS sequencing applied to peptides obtained from single beads. , In no case have single-bead MS/MS analyses been applied to oligomers containing cysteine.…”