Bifunctional scaffolds as templates for synthetic combinatorial libraries.
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.
Krchnák
V
V
Selectide Corporation, Hoechst Marion Roussel, Tucson, AZ 85737, USA.
Weichsel
A S
AS
Issakova
O
O
Lam
K S
KS
Lebl
M
M
D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry; D001426:Bacterial Proteins; D001665:Binding Sites; D002625:Chemistry, Organic / Q000379:methods; D019020:Directed Molecular Evolution / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006880:Hydroxy Acids / Q000138:chemical synthesis / Q000737:chemistry; D013058:Mass Spectrometry; D015394:Molecular Structure; D019809:Streptavidin
D000438:Alcohols; D000596:Amino Acids; D001426:Bacterial Proteins; D006880:Hydroxy Acids; D019809:Streptavidin