115186-22-6

Upstream product

• 186581-53-3 diazomethane 
• 3338-39-4 N-benzyloxycarbonyl-L-phenylalanyl-L-alanine 
• 71732-53-1 (Z,3S)-1-diazonio-3-[[(2S)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]but-1-en-2-olate carbamic acid 

Downstream Products

• 133524-87-5 C₂₉H₃₀N₂O₆ 

Relevant academic research and scientific papers

Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases

Dipeptidyl (acyloxy)methyl ketones (AOMKs) have been identified as mechanism-based inhibitors of certain cysteine proteases. These compounds are also inhibitors of the integral membrane proteins Rce1p and Ste24p, which are proteases that independently mediate a cleavage step associated with the maturation of certain isoprenylated proteins. The enzymatic mechanism of Rce1p is ill-defined, whereas Ste24p is a zinc metalloprotease. Rce1p is required for the proper processing of the oncoprotein Ras and is viewed as a potential target for cancer therapy. In this study, we synthesized a small library of dipeptidyl AOMKs to investigate the structural elements that contribute to the inhibitor properties of this class of molecules toward Rce1p and Ste24p. The compounds were evaluated using a fluorescence-based in vitro proteolysis assay. The most potent dipeptidyl AOMKs contained an arginine residue and the identity of the benzoate group strongly influenced potency. A 'warhead' free AOMK inhibited Rce1p and Ste24p. The data suggest that the dipeptidyl AOMKs are not mechanism-based inhibitors of Rce1p and Ste24p and corroborate the hypothesis that Rce1p is not a cysteine protease.

Peptidyl epoxides: Novel selective inactivators of cysteine proteases

Peptidyl epoxides were designed as selective pseudo-mechanism-based inactivators of cysteine proteases. Both threo- and erythro-peptidyl epoxides were synthesized and tested as potential inactivators of serine proteases (chymotrypsin, subtilisin, and elastase) and of cysteine proteases (papain, cathepsin B, and clostripain). Four tripeptidyl epoxides (Cbz-Gly-Leu-Phe-epoxide, Cbz-Ala-Ala-Phe-epoxide, Cbz-Gly-Leu-Ala-epoxide, and Cbz-Ala-Ala-Ala-epoxide), bearing amino acid sequences similar to those of good substrates or known inhibitors of the serine proteases, were tested in this study. Neither the threo- nor the erythro-peptidyl epoxides exhibited any inhibitory activity toward the serine proteases, even at high concentration and long incubation time. Nor did the threo-peptidyl epoxides inhibit the cysteine proteases. On the other hand, the erythro-peptidyl epoxides were time- and concentration-dependent inactivators of the cysteine proteases. Furthermore, stereoselectivity toward the natural L-amino acid at the P1 position was also exhibited upon inhibition of papain. In order to demonstrate selectivity within the cysteine protease family, two other erythro-peptidyl epoxides (Cbz-Phe-Ala-epoxide and Cbz-Phe-O-Bn-Thr-epoxide) were synthesized and tested as inhibitors of the three cysteine proteases. These new peptidyl epoxides exhibited selective inactivation of cysteine proteases, with second-order rate constants (k(i)/K(i)) ranging over 4 orders of magnitude (0.04-330 M-1 s-1). Thus, this new family of highly selective cysteine protease inhibitors offers mechanistic implications and may have useful applications.