Design and synthesis of small-molecule protein-protein interaction antagonists
Abstract
Protein-protein interactions play a crucial role in a wide range of biological processes. Research on the design and synthesis of small molecules to modulate these protein-protein interactions can lead to new targets and drugs to modulate their function. In Chapter one, we discuss the design and synthesis of small molecules to probe a protein-protein interaction in a voltage-gated Ca 2+ channel. Virtual screening identified a compound (BTT-3) that contained a 3,4-dihydro-3,4'-pyrazole core. This compound had modest biological activity when tested in a fluorescence polarization (FP) assay. The synthetic route to BTT-3 consisted of six steps. In addition, analogs of BTT-3 were made for a structure-activity study to establish the importance of a carboxylate moiety. We also synthesized a biotinylated benzophenone photo-affinity probe and linked it to BTT-3 to identify additional protein targets of the compound. In Chapter two, small-molecule antagonists targeting uPA-uPAR protein-protein interaction are presented. A total of 500 commercially-available compounds were previously identified by virtual screening and tested by a FP assay. Three classes of compounds were found with biological activity. The first class of compounds contains pyrrolidone core structures represented by IPR-1110, the second class has a novel pyrrolo[3,4-c]pyrazole ring system, represented by IPR-1283 and the last series had compounds with a 1,2-disubstituted 1,2-dihydropyrrolo[3,4- b]indol-3(4H)-one core structure, represented by IPR-540. Each of these three compounds were synthesized and assessed by FP and ELISA assays. A binding mode of IPR-1110 with uPA was subsequently proposed. Based on this binding mode, another 61 IPR-1110 derivatives were synthesized by us to illustrate the SAR activity. Analogs of the other two series were also synthesized.
Degree
M.S.
Advisors
Meroueh, Purdue University.
Subject Area
Molecular chemistry
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