Synthesis and calpain inhibitory activity of peptidomimetic compounds with constrained amino acids at the P2 position.

The effect of incorporating alpha,alpha'-diethylglycine and alpha-aminocyclopentane carboxylic acid at the P(2) position of inhibitors on mu-calpain inhibition was studied. Compound 3 with alpha,alpha'-diethylglycine was over 20-fold more potent than 2 with alpha-aminocyclopentane carboxylic acid. Additionally, 3 was over 35-fold selective for mu-calpain compared to cathepsin B, while 2 was 3-fold selective for cathepsin B compared to mu-calpain.

Synthesis, calpain inhibitory activity, and cytotoxicity of P2-substituted proline and thiaproline peptidyl aldehydes and peptidyl alpha-ketoamides.

Calpain is a cytosolic cysteine endopeptidase that has been implicated in a number of disorders including cancer. We have synthesized and studied the mu-calpain inhibitory activity and cytotoxicity of peptidyl aldehydes and peptidyl alpha-ketoamides with N-substituted D-proline or L-thiaproline residues at the P2-postion. The most potent and most selective members of the series were (R)-1-(4-nitrophenylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide (1j) and (R)-1-(4-iodophenylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-yl)pyrrolidine-2-carboxamide (1n).

Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines.

Calpain is a class of Ca(2+)-dependent cysteine proteases and has been suggested to be involved in several important signaling cascades. A series of novel aldehyde calpain inhibitors identified in our laboratory were more potent and specific than commercially available calpain inhibitors, and were used to assess the involvement of calpain in cancer. Our inhibitors demonstrated potent anti-proliferative activity in four cancer cell lines (PC-3, HeLa, Jurkat and Daudi) with IC(50)'s ranging from 2 to >30 microM.

Peptidyl aldehyde inhibitors of calpain incorporating P2-proline mimetics.

Four new peptidyl aldehydes bearing proline mimetics at the P(2)-position were synthesized and studied as inhibitors of calpain I, cathepsin B, and selected serine proteases. The ring size of the P(2)-constraining residue influenced the inhibitory potency and selectivity of the compounds for calpain I compared to the other proteases.