Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors.
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.
Kishore Kumar
G D
GD
Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, USA.
Chavarria
Gustavo E
GE
Charlton-Sevcik
Amanda K
AK
Arispe
Wara M
WM
Macdonough
Matthew T
MT
Strecker
Tracy E
TE
Chen
Shen-En
SE
Siim
Bronwyn G
BG
Chaplin
David J
DJ
Trawick
Mary Lynn
ML
Pinney
Kevin G
KG
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*
C549648:3-bromophenyl-2;-fluorophenyl thiosemicarbazone; D015853:Cysteine Proteinase Inhibitors; D013882:Thiosemicarbazones; D002401:Cathepsin B; D056668:Cathepsin L