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
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.