The inhibitory effect of 1,3-di-(p-amidinophenoxy)-2,2-bis-(p-amidinophenoxymethyl)propane (
TAPP-H),
TAPP-halo derivatives (with Cl, Br or I) and
benzamidine on the
Ancrod, bovine
Factor Xa, and human
plasmin catalyzed hydrolysis of
esters and
anilides of
amino acids was investigated, at pH 8.1 and 37 degrees, and compared with that shown from these compounds on bovine
thrombin and porcine
pancreatic kallikrein catalysis. The inhibitory effect of
TAPP-H and
TAPP-halo derivatives on the
proteinases considered, involved, to different extents, in blood coagulation and clot lysis, is higher by at least 10-fold, than that of
benzamidine, which binds at the primary specificity subsite (S1) of
serine endopeptidases and is commonly taken as a molecular inhibitor model. The high inhibitory effect of aromatic tetra-
amidines has been interpreted taking into account an additional productive binding for a second
benzamidine or halo-
benzamidine moiety to the
enzyme surface. Moreover, the data reported here allowed us to clarify the inhibition mechanism (in vitro) of
TAPP-H on blood coagulation, induced by the "
cancer coagulation factor" produced by the Walker
carcinoma in Wistar rats and on the
fibrinogen-to-
fibrin conversion, and to identify some
serine proteinases which act as targets for aromatic tetra-
amidines.