title: α,β-Unsaturated carbonyl system of chalcone-based derivatives is responsible for broad inhibition of proteasomal activity and preferential killing of human papilloma virus (HPV) positive cervical cancer cells.
abstract: Proteasome inhibitors have potential for the treatment of cervical cancer. We describe the synthesis and biological characterization of a new series of 1,3-diphenylpropen-1-one (chalcone) based derivatives lacking the boronic acid moieties of the previously reported chalcone-based proteasome inhibitor 3,5-bis(4-boronic acid benzylidene)-1-methylpiperidin-4-one and bearing a variety of amino acid substitutions on the amino group of the 4-piperidone. Our lead compound 2 (RA-1) inhibits proteasomal activity and has improved dose-dependent antiproliferative and proapoptotic properties in cervical cancer cells containing human papillomavirus. Further, it induces synergistic killing of cervical cancer cell lines when tested in combination with an FDA approved proteasome inhibitor. Exploration of the potential mechanism of proteasomal inhibition by our lead compound using in silico docking studies suggests that the carbonyl group of its oxopiperidine moiety is susceptible to nucleophilic attack by the γ-hydroxythreonine side chain within the catalytic sites of the proteasome.
authors.affiliation: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States. mbazzaro@umn.edu
authors.forename: Martina
authors.initials: M
authors.lastname: Bazzaro
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Anchoori
authors.forename: Mohana Krishna R
authors.initials: MK
authors.lastname: Mudiam
authors.forename: Olga
authors.initials: O
authors.lastname: Issaenko
authors.forename: Srinivas
authors.initials: S
authors.lastname: Kumar
authors.forename: Balasubramanyam
authors.initials: B
authors.lastname: Karanam
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Lin
authors.forename: Rachel
authors.initials: R
authors.lastname: Isaksson Vogel
authors.forename: Riccardo
authors.initials: R
authors.lastname: Gavioli
authors.forename: Federica
authors.initials: F
authors.lastname: Destro
authors.forename: Valeria
authors.initials: V
authors.lastname: Ferretti
authors.forename: Richard B S
authors.initials: RB
authors.lastname: Roden
authors.forename: Saeed R
authors.initials: SR
authors.lastname: Khan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008958:Models, Molecular; D027383:Papillomaviridae; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000821:virology
chemical_list: D000970:Antineoplastic Agents; D047188:Chalcones; D061988:Proteasome Inhibitors