Tricyclic benzimidazoles as potent poly(ADP-ribose) polymerase-1 inhibitors.
Novel tricyclic benzimidazole carboxamide poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been synthesized. Several compounds were found to be powerful chemopotentiators of temozolomide and topotecan in both A549 and LoVo cell lines. In vitro inhibition of PARP-1 was confirmed by direct measurement of NAD+ depletion and ADP-ribose polymer formation caused by chemically induced DNA damage.
Skalitzky
Donald J
DJ
Pfizer Global R&D, La Jolla/Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
Marakovits
Joseph T
JT
Maegley
Karen A
KA
Ekker
Anne
A
Yu
Xiao-Hong
XH
Hostomsky
Zdenek
Z
Webber
Stephen E
SE
Eastman
Brian W
BW
Almassy
Robert
R
Li
Jianke
J
Curtin
Nicola J
NJ
Newell
David R
DR
Calvert
A Hilary
AH
Griffin
Roger J
RJ
Golding
Bernard T
BT
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D019772:Topotecan / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011355:Prodrugs; D003606:Dacarbazine; D019772:Topotecan; D000077204:Temozolomide