Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1023-6. doi: 10.1016/j.bmcl.2009.12.042. Epub 2009 Dec 14.


Through conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, a series of PARP inhibitors was designed for appropriate orientation for binding to the PARP surface. This series of compounds with a 3-oxoisoindoline-4-carboxamide core structure, displayed modest to good activity against PARP-1 in both intrinsic and cellular assays. SAR studies at the lactam nitrogen of the pharmacophore have suggested that a secondary or tertiary amine is important for cellular potency. An X-ray structure of compound 1e bound to the protein confirmed the formation of a seven-membered intramolecular hydrogen bond. Though revealed previously in peptides, this type of seven-membered intramolecular hydrogen bond is rarely observed in small molecules. Largely due to the formation of the intramolecular hydrogen bond, the 3-oxoisoindoline-4-carboxamide core structure appears to be planar in the X-ray structure. An additional hydrogen bond interaction of the piperidine nitrogen to Gly-888 also contributes to the binding affinity of 1e to PARP-1.

Publication types

  • Comparative Study

MeSH terms

  • Amides / chemistry*
  • Amides / metabolism
  • Amides / therapeutic use
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use
  • Crystallography, X-Ray
  • Drug Discovery / methods*
  • Isoindoles / chemistry*
  • Isoindoles / metabolism
  • Isoindoles / therapeutic use
  • Neoplasms / drug therapy
  • Neoplasms / enzymology*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Structure-Activity Relationship


  • Amides
  • Antineoplastic Agents
  • Isoindoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases

Associated data

  • PDB/3L3L