Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design, synthesis, and X-ray cocrystal structure.
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.
Canan Koch
Stacie S
SS
Pfizer Global Research and Development, La Jolla/Agouron Pharmaceuticals, Inc., 10770 Science Center Drive, San Diego, California 92121, USA. stacie.canan@pfizer.com
Thoresen
Lars H
LH
Tikhe
Jayashree G
JG
Maegley
Karen A
KA
Almassy
Robert J
RJ
Li
Jianke
J
Yu
Xiao-Hong
XH
Zook
Scott E
SE
Kumpf
Robert A
RA
Zhang
Cathy
C
Boritzki
Theodore J
TJ
Mansour
Rena N
RN
Zhang
Kanyin E
KE
Ekker
Anne
A
Calabrese
Chris R
CR
Curtin
Nicola J
NJ
Kyle
Suzanne
S
Thomas
Huw D
HD
Wang
Lan-Zhen
LZ
Calvert
A Hilary
AH
Golding
Bernard T
BT
Griffin
Roger J
RJ
Newell
David R
DR
Webber
Stephen E
SE
Hostomsky
Zdenek
Z
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
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