title: Synthesis and Evaluation of a Library of Trifunctional Scaffold-Derived Compounds as Modulators of the Insulin Receptor.
abstract: We designed a combinatorial library of trifunctional scaffold-derived compounds, which were derivatized with 30 different in-house-made azides. The compounds were proposed to mimic insulin receptor (IR)-binding epitopes in the insulin molecule and bind to and activate this receptor. This work has enabled us to test our synthetic and biological methodology and to prove its robustness and reliability for the solid-phase synthesis and testing of combinatorial libraries of the trifunctional scaffold-derived compounds. Our effort resulted in the discovery of two compounds, which were able to weakly induce the autophosphorylation of IR and weakly bind to this receptor at a 0.1 mM concentration. Despite these modest biological results, which well document the well-known difficulty in modulating protein-protein interactions, this study represents a unique example of targeting the IR with a set of nonpeptide compounds that were specifically designed and synthesized for this purpose. We believe that this work can open new perspectives for the development of next-generation insulin mimetics based on the scaffold structure.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fabre
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Pícha
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Vaněk
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Selicharová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Chrudinová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Collinsová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Žáková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Miloš
authors.initials: M
authors.lastname: Buděšínský
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences , Flemingovo n. 2, 16610 Praha 6, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Jiráček
mesh_terms: D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D020650:Combinatorial Chemistry Techniques; D003300:Copper / Q000032:analysis; D007328:Insulin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011485:Protein Binding; D011972:Receptor, Insulin / Q000737:chemistry* / Q000378:metabolism*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D060327:Solid-Phase Synthesis Techniques
chemical_list: D001386:Azides; D007328:Insulin; D054852:Small Molecule Libraries; D003300:Copper; D011972:Receptor, Insulin
keywords: insulin mimetics; insulin receptor; library; protein-protein interactions; scaffold; trifunctional