Donovan Green

New peptide boronic acid inhibitors of thrombin

Peptides containing α-amino boronic acids bind to the active site of serine protease, forming highly effective inhibitors. The trigonal boron in these compounds contain a vacant 2p orbital that easily reacts with nucleotides such as the Ser hydroxyl or the His imidazole at the catalytic site of the enzyme to give a tetrahedral transition-state boron adduct as shown in Figure 1, similar to that observed with aldehydes which is stabilised in an analogous manner to the transition state of the substrate, by interactions with secondary binding sites (e.g. oxyanion binding pocket)

The synthesis of 1-aminobenzylphosphonic acids from benzylidenediphenylmethylamines, for use as structural units in antithrombotic tripeptides

Abstract Acid hydrolyses of O , O -dimethyl or O , O -diethyl 1-(diphenylmethylamino) benzylphosphonate intermediates 2 , formed from the addition at elevated temperature of dimethyl or diethyl phosphite to benzylidenediphenylmethylamines 1 , generates 1-aminobenzylphosphonic acids 3 in good yield.

The facile synthesis of O,O-dialkyl 1-aminoalkanephosphonates

O,O-Dialkyl 1-hydroxyiminoalkanephosphonates 1, may be conveniently reduced to O,O-dialkyl 1-aminoalkanephosphonates 2, at ambient temperature by application of lithium borohydride/trimethylsilyl chloride

Transition metal complexes of dialkyl α-hydroxyiminophosphonates, a novel class of metal complexes

A new range of dialkyl α-hydroxyiminophosphonates has been prepared and the first examples of metal complexes of this class of compound have been obtained; X-ray crystal structure analysis of the dichlorobis(diethyl E-(α)-hydroxyiminopropanephosphonate)nickel(II) complex shows a distorted octahedral coordination at the nickel atom giving two symmetry related diethyl-(E)-α-hydroxyiminopropanephosphonate ligands and two chlorine donors.

Design of a novel class of bifunctional thrombin inhibitors, synthesised by the first application of peptide boronates in solid phase chemistry

Abstract Borologs containing peptide boronates are new bifunctional biologically active molecules which bind to and inhibit thrombin. These compounds are designed based on the C-terminal sequence of hirudin. The inhibitors consists of four parts, i) an active site inhibitor, D-Phe Pro-Boro(aa)-OPin. ii) an anion binding exosite association moiety, Hirudin, iii) a spacer to link these components and iv) a novel ‘flexor’ non-peptide unit to allow correct orientation. The bivalent nature of the inhibitor [-D-PheProBoroBpgOPin]CO(CH 2 ) 3 COGly 2 Hir enhanced binding up to 10 fold greater than the corresponding native peptide Z-D-PheProBoroBpgOPin or the mixture of non covalently linked units, and resulted in a potent and selective inhibitor of thrombin having a Ki of 0.6nM. For the synthesis of these compounds suitably protected aminoboronate derivatives were shown to be compatible with FMOC solid phase chemistry.

THE PREPARATION AND CHARACTERIZATION OF SOME FLUORINATED α-AMINOARYLMETHANEPHOSPHONIC ACIDS

Abstract α-Aminoarylmethanephosphonic acids have been prepared with a range of fluoro, fluoroalkyl, or fluoroalkoxy substituents in the benzene ring (4-F, 3-F, 2-F, 3,4-F2, F5, 4-CF3, 3-CF3, 4-CF3O, and 3-CF3O). These compounds have relatively low aqueous solubility and their NMR spectra (1H, 13C, 31P and 19F) were therefore recorded in D2O in the presence of an excess of alkali. Under these conditions, the ring substituents appear to have little effect on δH (15–18 ppm), or on the 1H and 13C parameters for the benzylic group (α-CH), which are mainly in the ranges observed for other types of α-aminoarylmethanephosphonic acids under alkaline conditions (δH, 3.8–4.0 ppm, 2 J PH 15.3–16.5 Hz; δc 57–58 ppm, 1 J PC 128–132 Hz). For those examples with fluorine in the ortho position (i.e., the 2-fluoro and pentafluoro derivatives) a slightly higher field chemical shift was observed for the benzylic carbon atom (δc 50–51 ppm). In the fast-atom bombardment mass spectra, pseudo-molecular ions, MH+, and ions result...

Facile routes to 1-halo-1-alkyl boronic esters as precursors for novel thrombin inhibitors

Abstract Methods of synthesis are described of α-haloboronic esters by hydroboration of 1-halo-1-alkenes with catecholborane and by reaction of pinanediol dichloromethylboronate with organometallic reagents. The resulting α-haloboronic esters are synthetically useful, especially for the synthesis of peptides containing α-aminoboronic acids. The inhibitory activities of these peptides have been studied with thrombin.

The facile synthesis of O,O-Dialkyl α-halobenzylphosphonates from O,O-Dialkyl α-hydroxybenzylphosphonates

Abstract O,O-Dialkyl α-hydroxybenzylphosphonates (1) can be easily converted in their corresponding α-bromo (2) or α-iodo (3) phosphonates, in quantitative yield, using N ,N′-carbonyldiimidazole (CDI) in the presence of allyl bromide or methyl iodide.

Rhodium(I)-catalysed hydroboration of 1-halo-1-alkenes

Abstract The hydroboration of 1-halo-1-alkenes by catecholborane is accelerated by a catalytic amount of Wilkinsons catalyst {RhCl(PPh 3 ) 3 } to give α-halo boronic esters in good yields.

Substrate Related O,O-Dialkyldipeptidylaminophosphonates, A New Type of Thrombin Inhibitor

Abstract The facile reduction of O,O-dialkyl 1-hydroxyiminoalkanephosphonate precursors, using LiBH4/Me3SiCl in THF at ambient temperature, conveniently affords O,O-dialkyl 1-aminoalkanephosphonates in good yield and high state of purity. O,O-Dialkyl 1-aminobenzylphosphonates may be prepared in high yield and purity from catalytic hydrogenolysis of their 1-benzylaminobenzylphosphonate precursors. These biologically active aminophosphonates, when coupled to substrate derived dipeptides, produced a range of novel phosphonotripeptides based upon the ‘fibrinogen-like’ sequence H-D-Phe-Pro-Arg; where the phosphorus structural units replace the ‘Pl’Arg. These tripeptides showed a marked inhibitory specificity towards the trypsin-like serine protease thrombin, a ubiquitous enzyme that plays a crucial role in the cardiovascular system. The compounds possess an initial Ki in-vitro in the micromolar range against thrombin. Further enzyme kinetic analysis of the compound Z-D-Dpa-Pro-PglP(OiPr)2 (IC50 11.7 micromolar...