Date of Award
2025
Document Type
Thesis
Degree Name
MS in Pharmaceutical Science
Department
Pharmaceutical Sciences
First Advisor
Tanaji Talele
Second Advisor
Vijaya Korlipara
Third Advisor
Sandra Reznik
Abstract
Poly (ADP-ribose) polymerase (PARP) is a superfamily of proteins comprising 17 members, with PARP1 and PARP2 most notable for their implications in different types of cancer. PARP inhibitors represent an intriguing class of anticancer agents that have garnered increasing interest over the past decade due to their demonstrated clinical efficacy. AZD-9574 is one of these promising PARP1 selective inhibitors with good blood-brain barrier permeability that is currently in clinical trials for the treatment of solid malignancies and previous research attributed its selectivity and efficacy to the presence of a piperazine ring linker in its structure. However, a structure-activity relationship conducted with a set of truncated piperazine ring surrogates showed that this was not the case, which meant that there were other factors contributing to the activity of this compound. Encouraged by the inhibitory activity shown by pyridyl-2-carboxamide adenine-binding (AB) motif derivative 3 (PARP1/2 % inhibition = 90/17 at 100 nM) and the past work on benzimidazoles as AB motifs from our lab, a study was carried out to improve upon the inhibition shown by 3, while simultaneously prioritizing a selectivity for PARP1 over PARP2. To achieve this objective, 3 was optimized by: (i) varying the piperazine linker surrogates and (ii) extending the structure into the adenine-binding pocket (ABP) using different heteroaromatic moieties including 5-(un)substituted benzimidazole ring. This work led to two promising compounds 10 (PARP1/2 IC50 = 19 nM / >100 nM) and 11 (PARP1/2 IC50 = 12 nM / >100 nM). Predicted binding models of the target compounds using the co-crystal structure of PARP1 provided further insights into the observed structure-activity relationships data.
Recommended Citation
Adiele, Ugochi Ann, "SYNTHESIS AND SAR OF PARP INHIBITORY QUINOXALIN-2(1H)-ONE DERIVATIVES CARRYING POTENCY- AND SELECTIVITY-DRIVING ADENINE-BINDING MOTIFS" (2025). Theses and Dissertations. 855.
https://scholar.stjohns.edu/theses_dissertations/855