CYCLIC-PEPTIDES AS SELECTIVE SUBSTRATES AND SUICIDE SUBSTRATE PRECURSORS OF TRYPSIN-LIKE PROTEINASES

Citation
N. Boggetto et al., CYCLIC-PEPTIDES AS SELECTIVE SUBSTRATES AND SUICIDE SUBSTRATE PRECURSORS OF TRYPSIN-LIKE PROTEINASES, Bulletin de la Societe chimique de France, 131(2), 1994, pp. 152-166
Citations number
42
Categorie Soggetti
Chemistry Inorganic & Nuclear",Biology,Chemistry
ISSN journal
00378968
Volume
131
Issue
2
Year of publication
1994
Pages
152 - 166
Database
ISI
SICI code
0037-8968(1994)131:2<152:CASSAS>2.0.ZU;2-Y
Abstract
Cyclopeptides of general formula c[P1-aB(CH2X)-Gly4], in which P1 is a rginine or lysine and aB(CH2X) an ortho- or meta-aminobenzoic acid res idue substituted in the para position to the nitrogen atom by a methyl (X = H), a phenoxymethyl (X = OC6H5) or an acetoxymethyl (X = OCOCH3) group, have been evaluated as substrates and/or inhibitors of serine proteinases. These compounds are selective substrates of trypsin-like enzymes (urokinase, plasmin, thrombin). The presence of lysine or argi nine at the P1 position induces a selective cleavage of the P1-P1' ani lide bond. The efficiency of the enzymic hydrolysis is generally highe r for cyclopeptides containing a meta rather than an ortho-aminobenzoi c acid residue. The arginine derivatives are more easily cleaved by ur okinase (u-PA) than their lysine analogues. No hydrolysis is observed in the presence of t-PA. The compounds with X = OC6H5 or OCOCH3 are th e most reactive substrates. In spite of the presence of the phenolate or acetate latent nucleofugal substituent, which could induce the form ation of an electrophilic quinoniminium methide moiety, they fail to i nactivate the studied proteases. However, substitution of X by better latent leaving groups makes these compounds immediate precursors of su icide substrates, in particular of urokinase, an enzyme involved in th e process of metastasis.