title: Identification of Novel Proteasome Inhibitors from an Enaminone Library.
abstract: A library of structurally distinct enaminones was synthesized using sonication or Ru(II) catalysis to couple primary, secondary, and tertiary thioamides with α-halocarbonyls or α-diazocarbonyls. Screening the library for proteasome inhibition using a luciferase-based assay identified seven structurally diverse compounds. Two of these molecules targeted luciferase, while the remaining five exhibited varying potency and specificity for the trypsin-like, chymotrypsin-like, or caspase-like protease activities of the proteasome. Physiological relevance was confirmed by showing these molecules inhibited proteasomal degradation of the full-length protein substrate p21cip1 expressed in tissue culture cells. A cell viability analysis revealed that the proteasome inhibitors differentially affected cell survival. Results indicate a subset of enaminones and precursor molecules identified in this study are good candidates for further development into novel proteasome inhibitors with potential therapeutic value.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, OK, 74104, USA.|College of Osteopathic Medicine, Oklahoma State University, 1111 W. 17th St. Tulsa, OK, 74107, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Elliott
authors.affiliation: Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, OK, 74104, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, OK, 74104, USA.|The University of Toronto Structural Genomics Consortium, 101 College St. MaRS South Tower, Suite 700 Toronto, ON, M5G 1L7, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, OK, 74104, USA.
authors.forename: Naga D
authors.initials: ND
authors.lastname: Koduri
authors.affiliation: Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, OK, 74104, USA.
authors.forename: R Syed
authors.initials: RS
authors.lastname: Hussaini
authors.affiliation: Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, OK, 74104, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheaff
mesh_terms: D000818:Animals; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014357:Trypsin / Q000737:chemistry; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007659:Ketones; D057786:Peptidomimetics; D061988:Proteasome Inhibitors; D054852:Small Molecule Libraries; D014361:Trypsin Inhibitors; D002918:Chymotrypsin; D014357:Trypsin; D046988:Proteasome Endopeptidase Complex
keywords: biological screening; drug design; peptidomimetic; protease and ligands; therapeutic target