Chemical Tools to Monitor and Inhibit poly(ADP -Ribosyl)ation

While several promising inhibitors of PARP have been developed, no crystal structure of the complementary enzyme poly(ADP-ribose)glycohydrolase (PARG) is available, and therefore it has been difficult to intelligently design compounds to inhibit this enzyme. To date, the known inhibitors of PARG can be predominantly grouped into the three categories of DNA intercalators, tannins, and ADP-ribose analogues. While these compounds have proven valuable in the in vitro analysis of PARG, due to toxicity (intercalators), cell permeability issues (ADP-HPD), and nonspecific activity (tannins), few if any of these compounds have been useful for evaluating the effects of PARG inhibition in cell culture and in vivo. Thus, efforts to synthesize and assess cell ADP-HPD based PARG inhibitors will be discussed in the second half of this document. Furthermore, as compounds based on rhodanine scaffolds have been identified as inhibitors of enzymes utilizing pyrophosphate-containing substrates, we have screened a collection of rhodanine-containing small molecules for their ability to inhibit PARG. Through this screen several novel PARG inhibitors were identified, and subsequent derivative synthesis has elucidated structural features important for PARG inhibition. Several of the compounds are cell permeable and induce the build-up of poly(ADP-ribose) in the cell. Details of the TLC based screen, synthesis, and evaluation of hit compounds in cell culture will be discussed.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Boye, Amanda

Contributors dc:contributor

• Hergenrother, Paul J.

• Chemistry, Organic

Language dc:language

eng

Identifier

(MiAaPQ)AAI3337726

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/84304