Marianne Borloo

Pyrrolidides: synthesis and structure-activity relationship as inhibitors of dipeptidyl peptidase IV

Summary Dipeptidyl peptidase IV cleaves specifically the peptide bond at the carboxyl side of a proline at the penultimate N-terminal position of a peptide. It is thought to be important for the regulation of biologically active peptides. Moreover, it has been identified as an activation marker of T-lymphocytes (CD26). Pyrrolidides and thiazolidides are known as reversible inhibitors of DPP IV. Several homologues, unsaturated, open and 3-substituted analogues were synthesized in order to determine the structure-activity relationship of the P-1 site. l -Isoleucine was taken as P-2 amino acid. 1-( l -Isoleucyl)-3( S )-fluoropyrrolidine is about as active as the non-fluorinated compound and behaves as a competitive inhibitor. Other changes decrease or abolish the activity.

Dipeptide-derived diphenyl phosphonate esters: mechanism-based inhibitors of dipeptidyl peptidase IV

A number of dipeptide diphenyl phosphonate esters were studied as inhibitors of dipeptidyl peptidase IV, focusing on the role of the P2 residue in the inactivation process. The active compounds were slow irreversible inhibitors of the catalytic activity of the enzyme. With proline (or alanine) in the P1 position, the rate constants of inactivation correlated with the acylation rate constants reported for homologous dipeptide derived substrates. The kinetic data indicate that the mechanism of inhibition consists of the formation of a fairly weak initial complex, followed by a slow irreversible inactivation step. This indicates that, as in the case of trypsin-like proteinases, dipeptide diphenyl phosphonate esters form a covalent adduct with the catalytic site of DPP IV, even though this enzyme belongs to a completely distinct class of serine peptidases. Enantioselectivity and secondary specificity further support the evidence that diphenyl phosphonate esters are mechanism-based inhibitors. The dipeptide diphenyl phosphonate esters had a half-life of 3-10 h at 37 degrees C in Tris buffer. The inhibitors were degraded in human plasma, depending on the type of amino-terminal amino acid. The compound with proline in the P2 position was the most resistant to degradation in plasma. Due to their stability and the irreversible nature of the inhibition, the diphenyl phosphonate esters promise to be useful tools in the continuing investigation of the physiological function of dipeptidyl peptidase IV.

Phosphonic acid and phosphinic acid tripeptides as inhibitors of glutathionylspermidine synthetase

Abstract A series of phosphonic and phosphinic acid derivatives of glutathione were synthesized as potential inhibitors of glutathionylspermidine synthetase, an essential enzyme in the biosynthesis of trypanothione in trypanosomatids. The compounds showed moderate activity.

A new synthetic method for proline diphenyl phosphonates

Abstract The diphenyl ester of the phosphonic acid analogue of proline and related dipeptides were prepared by a reaction of the corresponding N-substituted 4-aminobutyraldehyde and triphenyl phosphite. Diastereoisomers were separated and their configuration determined by X-ray crystallography.

Synthesis of peptidyl acetals as inhibitors of prolyl endopeptidase

Several acyclic and cyclic dipeptidyl acetals were synthesized. Among these, N-[N-benzyloxycarbonyl-(S)-prolyl]-(S)-prolinal dimethyl acetal 8 was shown to be a potent inhibitor of prolyl endopeptidase.

Synthesis and evaluation of azaproline peptides as potential inhibitors of dipeptidylpeptidase IV and prolyl oligopeptidase

A series of azaproline dipeptides with various N-substituents were synthesized as possible active-site-directed inhibitors of two proline-specific serine proteases, dipeptidyl peptidase IV and prolyl oligopeptidase. Compounds with semicarbazide, carbazate, acylhydrazine and sulphonylhydrazine structures were tested. Some compounds show moderate activity, i.e., in the millimolar range.

A new method for the preparation of 2-pyrrolidinylphosphinic acid and homologues

Abstract 2-Pyrrolidinylphosphinic acid has been synthesized in a one pot reacion in 90% yield from 1-pyrroline trimer and bis(trimethylsilyl) phosphonite. The same procedure has been applied for the preparation of the piperidine and perhydroazepine homologues.