Indiana University-Purdue University Indianapolis (IUPUI) / 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 proteinprotein
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 proteinprotein
interaction in a voltage-gated Ca2+ 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
xv
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.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/6366 |
| Date | January 2014 |
| Creators | Han, Xu |
| Contributors | Meroueh, Samy, Long, Eric C. (Eric Charles), McLeish, Michael J. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Rights | Attribution-NoDerivs 3.0 United States, http://creativecommons.org/licenses/by-nd/3.0/us/ |
Page generated in 0.002 seconds