title: Design and synthesis of 3-carbamoylbenzoic acid derivatives as inhibitors of human apurinic/apyrimidinic endonuclease 1 (APE1).
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende, CS, Italy. francesca.aiello@unical.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Aiello
authors.forename: Yumna
authors.initials: Y
authors.lastname: Shabaik
authors.forename: Adrian
authors.initials: A
authors.lastname: Esqueda
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Fedora
authors.initials: F
authors.lastname: Grande
authors.forename: Antonio
authors.initials: A
authors.lastname: Garofalo
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D019817:Benzoic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D008782:Methylurea Compounds / Q000737:chemistry*
chemical_list: D008782:Methylurea Compounds; C061519:5-formyl-2'-deoxyuridine; D019817:Benzoic Acid; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C006892:carbamol; D003857:Deoxyuridine