698982-90-0Relevant academic research and scientific papers
Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors
Kishore Kumar,Chavarria, Gustavo E.,Charlton-Sevcik, Amanda K.,Arispe, Wara M.,MacDonough, Matthew T.,Strecker, Tracy E.,Chen, Shen-En,Siim, Bronwyn G.,Chaplin, David J.,Trawick, Mary Lynn,Pinney, Kevin G.
supporting information; experimental part, p. 1415 - 1419 (2010/07/06)
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 50 > 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.
Rational Design and Synthesis of Novel Dimeric Diketoacid-Containing Inhibitors of HIV-1 Integrase: Implication for Binding to Two Metal Ions on the Active Site of Integrase
Long, Ya-Qiu,Jiang, Xiao-Hua,Dayam, Raveendra,Sanchez, Tino,Shoemaker, Robert,Sei, Shizuko,Neamati, Nouri
, p. 2561 - 2573 (2007/10/03)
Discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors played a major role in validating this enzyme as an important target for the development of therapeutics against HIV infection. In fact, S-1360, the first clinically used IN inhibitor containing a triazole ring as a bioisostere of a carboxylic acid moiety belongs to this class of compounds. To understand the role of divalent metal-chelating in the inhibition of IN (J. Med. Chem. 2002, 45, 5661-5670), we designed and synthesized a series of novel dimeric diketo-containing compounds with the notion that such dimeric compounds may simultaneously bind to two divalent metal ions on the active site of IN. We rationalized that the two diketo subunits separated by uniquely designed linkers can potentially chelate two metal ions that are either provided from one IN active site or two active sites juxtaposed together in a higher order tetramer. Herein, we show that all the new compounds are highly potent against purified IN with varied selectivity for strand transfer, and that some of the analogues exert potent inhibition of the cytopathic effect of HIV-1 in infected CEM cells. This study represents the first attempt to rationally target two divalent metal ions on the active site of IN and may have potential implications for the design of second generation diketoacid-containing class of inhibitors.
