title: Potentiation of cytotoxic drug activity in human tumour cell lines, by amine-substituted 2-arylbenzimidazole-4-carboxamide PARP-1 inhibitors.
abstract: The synthesis and biological evaluation of a new series of amine-substituted 2-arylbenzimidazole-4-carboxamide inhibitors of the DNA-repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is reported. The introduction of an amine substituent at the 2-aryl position is not detrimental to activity, with most inhibitors exhibiting K(i) values for PARP-1 inhibition in the low nanomolar range. Two compounds in this series were found to potentiate the cytotoxicity of the DNA-methylating agent temozolomide by 4-5-fold in a human colorectal cancer cell line.
authors.affiliation: Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle Upon Tyne NE1 7RU, UK.
authors.forename: Alex W
authors.initials: AW
authors.lastname: White
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Brian W
authors.initials: BW
authors.lastname: Eastman
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Hostomsky
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kyle
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
authors.forename: Karen A
authors.initials: KA
authors.lastname: Maegley
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Skalitzky
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Yu
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship; D000077204:Temozolomide
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; D000077204:Temozolomide