Pseudoarginine: synthesis and properties of derivatives of delta-(1-imidazolyl)norvaline.

An analogue of arginine has been synthesized in which an imidazole ring occupies the position of the guanidino group of the natural amino acid. It was expected that peptides containing this amino acid when protonated might bind at enzymic sites specific for arginine, but that the pK of the imidazole ring, near 7, would facilitate entry of such peptides into cells, in contrast to peptides containing arginine. Other analogues of arginine can be visualized with a low side-chain pK, including isomers of the imidazole derivative which is the subject of this paper. These are viewed as 'pseudoarginines'. Our initial observations concern the properties of delta-(1-imidazolyl)norvaline in which a ring nitrogen atom is attached to norvaline, which thus becomes comparable to the guanidino delta-nitrogen. Its synthesis is described along with several derivatives examined as substrates or inhibitors. Potential ligands containing delta-(1-imidazolyl)norvaline (ImNva) did not give evidence of interaction with trypsin or plasma kallikrein, serine proteinases which bind arginine derivatives. However, clostripain, a bacterial cysteine proteinase specific for arginine, was readily inactivated by Cbz-Phe-ImNva-CH2F and the rate of inactivation showed an acid pH-dependence not observed, for example, in the inactivation of clostripain by Bz-Phe-LysCH2F.