Synthesis and SAR of novel tricyclic quinoxalinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Julie Miyashiro; Keith W Woods; Chang H Park; Xuesong Liu; Yan Shi; Eric F Johnson; Jennifer J Bouska; Amanda M Olson; Yan Luo; Elizabeth H Fry; Vincent L Giranda; Thomas D Penning

doi:10.1016/j.bmcl.2009.06.016

Synthesis and SAR of novel tricyclic quinoxalinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4050-4. doi: 10.1016/j.bmcl.2009.06.016. Epub 2009 Jun 13.

Authors

Julie Miyashiro¹, Keith W Woods, Chang H Park, Xuesong Liu, Yan Shi, Eric F Johnson, Jennifer J Bouska, Amanda M Olson, Yan Luo, Elizabeth H Fry, Vincent L Giranda, Thomas D Penning

Affiliation

¹ Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064, USA. [email protected]

PMID: 19553114
DOI: 10.1016/j.bmcl.2009.06.016

Abstract

Based on screening hit 1, a series of tricyclic quinoxalinones have been designed and evaluated for inhibition of PARP-1. Substitutions at the 7- and 8-positions of the quinoxalinone ring led to a number of compounds with good enzymatic and cellular potency. The tricyclic quinoxalinone class is sensitive to modifications of both the amine substituent and the tricyclic core. The synthesis and structure-activity relationship studies are presented.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Apoptosis
Cell Nucleus / metabolism
Chemistry, Pharmaceutical / methods*
DNA Repair
Drug Design
Drug Screening Assays, Antitumor
Humans
Kinetics
Models, Molecular
Molecular Conformation
Niacinamide / chemistry
Poly(ADP-ribose) Polymerase Inhibitors*
Quinoxalines / chemical synthesis*
Quinoxalines / chemistry*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Quinoxalines
Niacinamide