Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer
| Autor: | Gui-Dong Zhu, Xuesong Liu, Yan Shi, Thomas D. Penning, Viraj B. Gandhi, Chang Park, Vered Klinghofer, Vincent L. Giranda, Yan Luo, Eric F. Johnson |
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| Rok vydání: | 2010 |
| Předmět: |
Tertiary amine
medicine.drug_class Stereochemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Carboxamide Isoindoles Poly(ADP-ribose) Polymerase Inhibitors Crystallography X-Ray Biochemistry Structure-Activity Relationship chemistry.chemical_compound Neoplasms Drug Discovery medicine Oxindole Molecular Biology Chemistry Hydrogen bond Organic Chemistry Amides Intramolecular force PARP inhibitor Lactam Molecular Medicine Poly(ADP-ribose) Polymerases Pharmacophore |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 20:1023-1026 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2009.12.042 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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