Ferroni R, Menegatti E, Orlandini P, Guarneri M, Taddeo U, Bolognesi M, Ascenzi P, Bertollini A, Amiconi G
Farmaco Sci. 1986 Jun;41(6):464-70.
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.
研究了1,3-二-（对脒基苯氧基）-2,2-双-（对脒基苯氧甲基）丙烷（TAPP-H）、TAPP-卤代衍生物（含氯、溴或碘）和苯甲脒在pH 8.1和37℃条件下对安克洛酶、牛凝血因子Xa以及人纤溶酶催化的氨基酸酯和氨基酸酰苯胺水解反应的抑制作用，并将其与这些化合物对牛凝血酶和猪胰激肽释放酶催化反应的抑制作用进行了比较。TAPP-H和TAPP-卤代衍生物对在血液凝固和血栓溶解中不同程度起作用的蛋白酶的抑制作用，比苯甲脒高至少10倍，苯甲脒结合在丝氨酸内肽酶的一级特异性亚位点（S1），通常被用作分子抑制剂模型。考虑到第二个苯甲脒或卤代苯甲脒部分与酶表面的额外有效结合，对芳香族四脒的高抑制作用进行了解释。此外，本文报道的数据使我们能够阐明TAPP-H对Wistar大鼠Walker癌产生的“癌凝血因子”诱导的血液凝固以及纤维蛋白原向纤维蛋白转化的体外抑制机制，并确定一些作为芳香族四脒作用靶点的丝氨酸蛋白酶。
