Dihydroisoquinolinones: the design and synthesis of a new series of potent inhibitors of poly(ADP-ribose) polymerase.
A series of dihydroisoquinolinones, formally rigid analogs of 3-substituted benzamides, and a series of 2,3-disubstituted benzamides were synthesized and evaluated as inhibitors of poly(ADP-ribose) polymerase. The results indicated that the orientation of the amide with respect to the substituent on the aromatic ring was critical for optimum inhibitory activity. Selected compounds were also evaluated for their ability to modify the radiation response of mammalian cells to ionizing radiation. A number of the 5-substituted dihydroisoquinolinones, which were very potent inhibitors of the enzyme, were able to enhance the lethal effects of ionizing radiation in mammalian cells, as measured by changes in the survival curve parameters Do and/or Dq.
Suto
M J
MJ
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Turner
W R
WR
Arundel-Suto
C M
CM
Werbel
L M
LM
Sebolt-Leopold
J S
JS
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry; D002460:Cell Line / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D015195:Drug Design; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
D001549:Benzamides; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents