title: Aromatic tetra-amidines: synthesis of halo-derivatives and their antiproteolytic activity.
abstract: Mono-halo derivatives of 1,3-di-(p-amidinophenoxy)-2,2-bis-(p-amidinophenoxymethyl)p ropane (TAPP-H) have been synthesized and their inhibitory effect on the bovine trypsin, bovine thrombin and porcine pancreatic kallikrein catalyzed hydrolysis of p-nitroanilides of amino acids was investigated, at pH 8.1 and 37 degrees, in parallel with that of TAPP-H and benzamidine. The addition of a halogen (Cl, Br or I) at position 2 of each benzamidine moiety of TAPP-H is accompanied by an increase of the inhibitory effect. This is especially evident in the case of porcine pancreatic kallikrein inhibition by TAPP-Cl. The structural basis of the different inhibitory effect of TAPP-H, TAPP-halo derivatives and benzamidine on the catalyzed hydrolysis of the proteinases examined are discussed and the role of Asp-189 in bovine trypsin, Asp-189 and Glu-149 or Asp-192 in bovine thrombin and Asp-189 and Asp-A148 or Glu-150 in porcine pancreatic kallikrein is focused.
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D006219:Halogens / Q000138:chemical synthesis / Q000494:pharmacology; D007610:Kallikreins / Q000037:antagonists & inhibitors; D007700:Kinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis
chemical_list: D000578:Amidines; D006219:Halogens; D011480:Protease Inhibitors; D014361:Trypsin Inhibitors; D007610:Kallikreins; D013917:Thrombin