Design, synthesis and evaluation of graftable thrombin inhibitors for the preparation of blood-compatible polymer materials

Abstract

Piperazinyl-amide derivatives of N-a-(3-trifluoromethyl-benzenesulfonyl)-L-arginine(1) were synthesized as graftable thrombin inhibitors. The possible disturbance of biological activity due to a variable spacer-arm fixed on the N-4 piperazinyl position was evaluated in vitro, against human a-thrombin, and in blood coagulation assay. Molecular modelling (in silico analysis) and X-ray diffraction studies of thrombin-inhibitor complexes were also performed. The fixation of bioactive molecules on poly(butylene terephthalate) (PBT) and poly(ethylene terephthalate) (PET) membranes was performed by wet chemistry treatment and evaluated by XPS analysis. Surface grafting of inhibitor 1d improved the membrane hemocompatibility by reducing blood clot formation on the modified surface.

Inhibition of dd-Peptidases by a Specific Trifluoroketone: Crystal Structure of a Complex with the Actinomadura R39 dd-Peptidase

“…The other two fluorine atoms appear to interact in a bifurcated fashion at a distance of 3.0 Å each with the hydroxyl of Ser298. This kind of arrangement has been previously observed, for example in a trifluoroketone adduct with chymotrypsin (55), where two fluorines interact with a water molecule, and in a thrombin complex where a similar interaction with a water molecule has been observed (57). It is interesting that the Lys52 terminal nitrogen has not moved closer than 4.0 Å distance to a fluorine atom.…”

“…This conformation would be expected, of course, on steric and electrostatic grounds and has been observed in serine protease/trifluoroketone complexes (for example, in reference 55). One fluorine atom is directed out of the active site into solvent where it might well interact with water molecules in the manner observed in a variety of crystal structures (55)(56)(57)(58). Such interactions are probably more dipolar in nature than involving classical hydrogen bonding and are probably of ca 1 kcal/mol strength (59,60).…”

Anticoagulant Activity of a Unique Sulfated Pyranosic (1→3)-β-l-Arabinan through Direct Interaction with Thrombin

“…Accordingly, the orientations obtained for the disulfated and non-sulfated arabinan octasaccharides on the surface of both BT and HT enclosed thrombin exosite 2, mostly superimposing heparin arrangement on the surface of thrombin, as observed in previous crystal structures (47). Additionally, because sulfated compounds have also been described to bind exosite 1 (48), docking procedures of the disulfated oligosaccharides were also carried out at such a region. Such complexes were further refined through MD simulations, from which data on the dynamics of thrombin-arabinan complexes were retrieved.…”

{4(S)-(Piperidin-1-ylcarbonyl)-4-[3-(trifluoromethyl)phenylsulfonamido]butyl}guanidinium chloride: a model of a graftable thrombin inhibitor

“…The synthesis of (I) has been described previously (Salvagnini et al, 2005). Colourless crystals suitable for X-ray analysis were obtained by slow evaporation of an ethanol solution of (I).…”

“…Thrombin is a key enzyme in the blood coagulation system and represents a main target in medicinal chemistry (Weitz, 2003). Recently, we became interested in designing thrombin inhibitors for the biocompatibilization of polymer materials (Salvagnini et al, 2005). Our strategy relies upon the covalent grafting of biologically active molecules, via a spacer arm, on the surface of polymer devices.…”