a series of novel non-peptidic furin inhibitors with values of inhibitory constants (Ki) in the range of 0.74-1.54 μM was obtained by interactions of aminoguanidine hydrocarbonate with three diaryldicarbaldehydes. correspondingly p-hydroquinone, piperazine and adipic acid were used as linkers between their benzene moieties. docking studies of these new inhibitors into recently published 3d-structure of human furin (PDB code 4OMC) showed that they were able to interact with subsites S1 and S4 of the enzyme. The overall arrangement of bisamidinohydrazones into furin active site was similar to the position of the ligand cocrystallized with a protease. Observations obtained with molecular modeling allowed further guidance into chemical modifications of the synthesized inhibitors which improve their inhibitory activity.

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The review is devoted to the analysis of the relationship between a chemical structure and properties of low-molecular weight inhibitors of furin, the most studied proprotein convertase, which is involved in the development of some pathologies, such as oncologic diseases, viral and bacterial infections, etc. The latest data concerning the influence of peptides, pseudo-peptides, aromatic and heterocyclic compounds, some natural ones such as flavonoids, coumarins, and others on enzyme inactivation are considered. The power of furin inhibition is shown to rise with the increasing number of positively charged groups in the structure of these compounds. Peptidomimetics (Ki = 5-8 pM) are shown to be the most effective furin inhibitors. The synthesized substances, however, have not been used in practical application yet. Nowadays it is very important to find more selective inhibitors, improve their stability, bioavailability and safety for the human organism.

Abstract. Analogues of both the nonapeptides, bradykinin and bradykinin potentiating nonapeptide BPP 9α , were synthesized using HYCRAM™-technique. The bradykinin analogues were assembled by the Boc-, Ddz-and Fmoc-strategy starting with Boc-Arg(Aloc) 2 -OCr-OH, Ddz-Arg(Mtr)-OCr-OH and Fmoc-Arg(Mtr)-OCr-OH. While Boc-and Ddz-strategy provide peptides in good yield and purity, the Fmoc-strategy leads to a loss of peptide from resin. For simultaneous cleavage from HYCRAM™-resin and removal of Aloc-side chain protection optimized conditions for catalytic cleavage with Pd° were developed. As shown by the synthesis of BPP 9α analogues the HYCRAM™-linker and the chlorotrityl resin Solid phase syntheses of peptides with sensitive amino acids or sensitive pseudopeptide bonds require special linkers, which are stable under the conditions of coupling and deprotection and very smoothly to cleave without strong acidic or basic conditions. With the development of the hydroxycrotonoyl amino methyl linker (HYCRAM TM ) by Kunz et al. [1,2,3] and Birr [4, 5] a linker was found which fulfills these requirements in a good manner. The assembled peptides can be removed from the resin by treatment with Pd[P(C 6 H 5 ) 3 ] 4 as catalyst under nearly neutral conditions. Catalysts, scavallow the assembly of peptides with the C-terminal sequence Pro-Pro by preventing dioxopiperazine formation. Since the BPP 9α sequence contains the tripeptide Trp-X-Arg an intramolecular migration of the N G -protecting group to the indole ring under conditions used for its removal had to be avoided. By the use of HYCRAM™-linker in combination with Aloc protection for the guanidino group and Ddz for N α no modification of Trp occurred. HYCRAM™-technology in combination with Boc-, Ddz-or Aloc/All-protecting groups facilitates the synthesis of peptides with such very labile amino acids like cis-4-hydroxyproline. 1 ) Other abbreviations include: o-Aba; m-Aba, ortho, meta amino benzoic acid; Aloc, allyl oxycarbonyl; BK, bradykinin; Boc, tert-butyloxycarbonyl; BPP 9α , bradykinin potentiating peptide 9α (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro); BOP, benzotriazole-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate; Bu 3 SnH, tributyltin hydride; Bu

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