Synthesis of substituted 5[H]phenanthridin-6-ones as potent poly(ADP-ribose)polymerase-1 (PARP1) inhibitors.
1-, 2-, 3-, 4-, 8-, or 10-Substituted 5(H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC(50) values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5(H)phenanthridin-6-one ring.
Li
J H
JH
Guilford Pharmaceuticals Inc., 6611 Tributary Street, 21224, Baltimore, MD, USA. lij@guilfordpharm.com
Serdyuk
L
L
Ferraris
D V
DV
Xiao
G
G
Tays
K L
KL
Kletzly
P W
PW
Li
W
W
Lautar
S
S
Zhang
J
J
Kalish
V J
VJ
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010617:Phenanthridines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors