title: Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure.
abstract: A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.
authors.affiliation: Pfizer Global Research and Development, La Jolla/Agouron Pharmaceuticals, Inc., 10770 Science Center Drive, San Diego, California 92121, USA. stacie.canan@pfizer.com
authors.forename: Stacie S
authors.initials: SS
authors.lastname: Canan Koch
authors.forename: Lars H
authors.initials: LH
authors.lastname: Thoresen
authors.forename: Jayashree G
authors.initials: JG
authors.lastname: Tikhe
authors.forename: Karen A
authors.initials: KA
authors.lastname: Maegley
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Almassy
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Yu
authors.forename: Scott E
authors.initials: SE
authors.lastname: Zook
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kumpf
authors.forename: Cathy
authors.initials: C
authors.lastname: Zhang
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Boritzki
authors.forename: Rena N
authors.initials: RN
authors.lastname: Mansour
authors.forename: Kanyin E
authors.initials: KE
authors.lastname: Zhang
authors.forename: Anne
authors.initials: A
authors.lastname: Ekker
authors.forename: Chris R
authors.initials: CR
authors.lastname: Calabrese
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kyle
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.forename: Lan-Zhen
authors.initials: LZ
authors.lastname: Wang
authors.forename: A Hilary
authors.initials: AH
authors.lastname: Calvert
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Hostomsky
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D019772:Topotecan / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D003606:Dacarbazine; D019772:Topotecan; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide