Synthesis and SAR of novel tricyclic quinoxalinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).
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.
Miyashiro
Julie
J
Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064, USA. julie.miyashiro@abbott.com
Woods
Keith W
KW
Park
Chang H
CH
Liu
Xuesong
X
Shi
Yan
Y
Johnson
Eric F
EF
Bouska
Jennifer J
JJ
Olson
Amanda M
AM
Luo
Yan
Y
Fry
Elizabeth H
EH
Giranda
Vincent L
VL
Penning
Thomas D
TD
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004260:DNA Repair; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009536:Niacinamide / Q000737:chemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011810:Quinoxalines; D009536:Niacinamide