Synthesis and exploration of boron-containing heterocycles as potential PARP inhibitors
| dc.contributor.author | Berk, Ahmet Burak | |
| dc.contributor.examiningcommittee | Sorensen, John (Chemistry) | |
| dc.contributor.examiningcommittee | Marzban, Lucy (Pharmacy) | |
| dc.contributor.supervisor | Tranmer, Geoffrey | |
| dc.date.accessioned | 2024-12-11T15:31:17Z | |
| dc.date.available | 2024-12-11T15:31:17Z | |
| dc.date.issued | 2024-12-06 | |
| dc.date.submitted | 2024-12-06T17:37:32Z | en_US |
| dc.degree.discipline | Pharmacy | |
| dc.degree.level | Master of Science (M.Sc.) | |
| dc.description.abstract | The 18 members of the poly (ADP-Ribose) Polymerase (PARP) family of enzymes are involved in a variety of biological processes, such as apoptosis and DNA repair. The PARP enzyme consumes NAD+ as a substrate, and competitive inhibitors are used to mimic the natural NAD+ substrate and prevent PARylation. Inhibiting PARP is therapeutically utilized in anticancer treatment. These inhibitors have the potential to function as sensitizers, so they can increase the effectiveness of anticancer therapies, including radiation therapy and chemotherapy medications. Since PARP inhibitors cause synthetic lethality in homologous recombination-dysfunction cells, they are also used as single-agent treatments in individuals with BRCA-deficient breast, ovarian, or prostate cancer. Organoboron compounds can be described as Lewis acids due to their empty p-orbital, which accepts lone pair electrons (Lewis Base) and changes hybridization. This unique feature makes organoboron compounds preferred drug candidates, leading to an increase in the number of functional groups, including boronic acid, in medicinal chemistry. Boron-containing heterocyclic rigid structures improve drug-enzyme interactions based on forming tertiary complexes between boronic acids and responsible amino acids such as serine. For this reason, we created a boron-containing heterocyclic library that includes 21 benzoxazaborinin derivatives, and their yields range from 20% to 99%. Those compounds are characterized by utilizing NMR spectroscopy and HRMS and tested with a PARP-1 screening assay, which is cost-effective and does not require special laboratory equipment. This assay quantifies leftover NAD+ substrate by converting it to a fluorophore group that makes excitation (372 nm) and emission (444 nm). Overall, we were able to synthesize benzoxazaborinin-based PARP inhibitors, with the lowest IC50 value of 31 M for structure 15A. | |
| dc.description.note | February 2025 | |
| dc.description.sponsorship | The student was funded by the Republic of Turkey and its Ministry of National Education. | |
| dc.identifier.uri | http://hdl.handle.net/1993/38704 | |
| dc.language.iso | eng | |
| dc.rights | open access | en_US |
| dc.subject | Organoboron Compounds | |
| dc.subject | PARP Inhibitors | |
| dc.title | Synthesis and exploration of boron-containing heterocycles as potential PARP inhibitors | |
| dc.type | master thesis | en_US |
| local.subject.manitoba | no | |
| project.funder.name | Natural Sciences and Engineering Research Council of Canada |