Design and Synthesis of 3-Carbamoylbenzoic Acid Derivatives as Inhibitors of Human Apurinic/Apyrimidinic Endonuclease 1 (APE1)

• Published in: ChemMedChem Vol. 7; no. 10; pp. 1825 - 1839
• Main Authors: Aiello, Francesca, Shabaik, Yumna, Esqueda, Adrian, Sanchez, Tino W., Grande, Fedora, Garofalo, Antonio, Neamati, Nouri
• Format: Journal Article
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 01.10.2012; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: anticancer agents; APE1; Benzoic Acid - chemical synthesis; Benzoic Acid - chemistry; Benzoic Acid - toxicity; carbamoylbenzoic acids; Cell Line; Cell Survival - drug effects; Chemistry, Medicinal; Deoxyuridine - analogs & derivatives; Deoxyuridine - toxicity; DNA Repair - drug effects; DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Drug Design; Humans; inhibitors; Life Sciences & Biomedicine; Methylurea Compounds - chemistry; Pharmacology & Pharmacy; Science & Technology; synthesis; synthesis; inhibitors; APE1/REF-1; carbamoylbenzoic acids; DNA-REPAIR ENZYME; RNA; APE1; SUBCELLULAR-LOCALIZATION; BASE EXCISION; OVARIAN-CANCER; anticancer agents; PROGNOSTIC-SIGNIFICANCE; EXPRESSION; BINDING; CELL
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200334

Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is a multifaceted protein with an essential role in the base excision repair (BER) pathway. Its implication in tumor development, progression, and resistance has been confirmed in multiple cancers, making it a viable target for intensive investigation. In this work, we designed and synthesized different classes of small‐molecule inhibitors of the catalytic endonuclease function of APE1 that contain a 3‐carbamoylbenzoic acid scaffold. Further structural modifications were made with the aim of increasing the activity and cytotoxicity of these inhibitors. Several of our compounds were shown to inhibit the catalytic endonuclease function of APE1 with potencies in the low‐micromolar range in vitro, and therefore represent novel classes of APE1 inhibitors worthy of further development. Cancer in disrepair: The base‐excision repair (BER) pathway is the foremost pathway responsible for removal and replacement of damaged DNA bases. Several BER enzymes have altered expression and activation in cancer cells, and among them APE1 has emerged as a particularly attractive target for anticancer drug development, as demonstrated by studies that link its overexpression with resistance to radio‐ and chemotherapy.