Synthesis and structure-activity relationships of novel pyrrolocarbazole lactam analogs as potent and cell-permeable inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).
A series of novel pyrrolocarbazole lactams was identified as potent PARP-1 inhibitors in vitro and in a PC12 cellular NAD(+) depletion assay. The SAR trends of substituents at the 3-position, as well as the effect of blocking the indole or lactam NH-groups of the template by methylation or formylation, are discussed in relation to molecular modeling studies.
Wells
Gregory J
GJ
Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. gwells@cephalon.com
Bihovsky
Ron
R
Hudkins
Robert L
RL
Ator
Mark A
MA
Husten
Jean
J
D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007094:Imides / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D016716:PC12 Cells; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007094:Imides; D007769:Lactams; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011758:Pyrroles; D011065:Poly(ADP-ribose) Polymerases