New Cyanopeptide‐Derived Low MolecularWeight Thrombin Inhibitors

Abstract

Thrombosis is the result of defective regulation of the hemostasis system. This cardiovascular disorder may lead to deep vein thrombosis, myocardial infarction, and stroke. The majority of current drug research is focused on finding inhibitors of thrombin - the global player in hemostasis. In our work, we emphasize investigation of the marine environment to yield new lead structures from marine organisms like blue-green algae (cyanobacteria). This article deals with the design, syntheses, and inhibition tests of new low molecular weight thrombin inhibitors utilizing cyanopeptides, the secondary metabolites of cyanobacteria with interesting biological activities, as new lead structures. Starting with aeruginosin 98-B (2) as a lead structure, we have developed and synthesized new, selective acting inhibitors of thrombin (RA-1001 and RA-1002), which are suitable targets for further structure-activity studies.

New Cyanopeptide‐Derived Low Molecular Weight Inhibitors of trypsin‐like Serine Proteases

“…In previous reports, we described the syntheses of the thrombin inhibitors RA-1001 and RA-1002 as well as their precursors (RA-1003 and RA-1004) utilizing aeruginosin 98-B -a secondary metabolite from cyanobacterium Microcystis aeruginosa -as the starting lead structure ( Figure 1) [8][9]. Compounds RA-1001, RA-1002, and RA-1003 are equipotent thrombin inhibitors (Table 1).…”

“…Compound RA-1009 was obtained in very low yield by condensation of the synthetic precursor of RA-1002, Bz-L-Leu-L-Pro-OH (27) [8], with N-(2-pyrimidinyl)-1,4-diaminobutane (8) -a cyclic guaninidine derivative, which was synthesised according to the synthesis of N-(2-pyrimidinyl)-1,3-diaminopropane [19].…”

“…There is a lack of any close interactions of structural elements of aeruginosin 98-B and its synthetic analogues with trypsin's catalytic triad (His57, Asp102, Ser195) -especially concerning residue Ser195. This fact is remarkable, because Ser195 usually attacks the carbonyl group in position P1 of the substrate as a nucleophil ("acylation mechanism", for details see [8] and [10]). Therefore, cyanopeptides of the aeruginosin family as well as their synthetic analogues inhibit trypsin in a non-classical manner.…”

“…Compounds RA-1001, RA-1002, and RA-1003 are equipotent thrombin inhibitors (Table 1). Moreover, RA-1002, RA-1003, and RA-1004 seem to be selective inhibitors of thrombin [8].…”

“…The synthesis of RA-1005 starts with the synthesis of 3-(4-hydroxyphenyl)propionyl-L-isoleucine (2) which was described previously [8] (Scheme 1). Compound 2 reacts in a high-yielded reaction with glycine ethyl ester hydrochloride under DCC-catalysis and basic conditions (DIPEA: diisopropylethylamine; DCC: N,NЈ-dicyclohexylcarbodiimide).…”