title: Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors.
abstract: A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis. The six most active inhibitors of cathepsin L (IC50<85 nM) in this series incorporate a meta-bromo substituent in one aryl ring along with a variety of functional groups in the second aryl ring. These six analogs are selective for their inhibition of cathepsin L versus cathepsin B (IC50>10,000 nM). The most active analog in the series, 3-bromophenyl-2'-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell invasion of the DU-145 human prostate cancer cell line.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Kishore Kumar
authors.forename: Gustavo E
authors.initials: GE
authors.lastname: Chavarria
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Charlton-Sevcik
authors.forename: Wara M
authors.initials: WM
authors.lastname: Arispe
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Macdonough
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
authors.forename: Shen-En
authors.initials: SE
authors.lastname: Chen
authors.forename: Bronwyn G
authors.initials: BG
authors.lastname: Siim
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
mesh_terms: D020134:Catalytic Domain; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D056668:Cathepsin L / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C549648:3-bromophenyl-2;-fluorophenyl thiosemicarbazone; D015853:Cysteine Proteinase Inhibitors; D013882:Thiosemicarbazones; D002401:Cathepsin B; D056668:Cathepsin L