Design, synthesis, and evaluation of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as inhibitors of poly(ADP-ribose) polymerase.
The design, synthesis, and biological evaluation of potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are reported. A novel series of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones were designed using a combination of protein structure-based drug design, molecular modeling, and structure-activity relationships (SAR). These novel submicromolar inhibitors possess a tricyclic ring system conformationally restricting the benzamide in the preferred cis orientation. The compounds were designed to optimize space-filling and atomic interactions within the NAD+ binding site of PARP-1. Previously described and newly adapted methods were applied to syntheses of these tricyclic inhibitors. Various modifications were made to the diazepinoindolones at the 6- and 7-positions in order to study this region of the active site and optimize noncovalent interactions. The electron density of derivative 28 bound to chicken PARP-1 revealed that the oxime makes a tight hydrogen bond with the catalytic gamma-carboxylate of glutamic acid (Glu) 988 in accordance with our original designs and models. Most of the compounds have been evaluated for inhibition of human PARP-1. Selected inhibitors were also tested for the ability to potentiate the cytotoxic effect of the DNA-damaging agent Topotecan.
Tikhe
Jayashree G
JG
Pfizer Global R&D--La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA. jayashree.tikhe@pfizer.com
Webber
Stephen E
SE
Hostomsky
Zdenek
Z
Maegley
Karen A
KA
Ekkers
Anne
A
Li
Jianke
J
Yu
Xiao-Hong
XH
Almassy
Robert J
RJ
Kumpf
Robert A
RA
Boritzki
Theodore J
TJ
Zhang
Cathy
C
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
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D001381:Azepines; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059004:Topoisomerase I Inhibitors