title: Synthesis and inhibiting properties toward trypsin like proteases of N alpha-(N,N-dimethylcarbamoyl)-alpha-azaornitine and alpha-azalysine esters.
abstract: N alpha-(N,N-dimethylcarbamoyl)-alpha-azaornitine and N alpha-(N,N-dimethylcarbamoyl)-alpha-azalysine phenyl and p-nitrophenyl esters (7-10) were synthesized and tested as inhibitors of trypsin, chymotrypsin and thrombin. The N,N-dimethylcarbamoyl group was chosen to decrease the tendency of acylcarbazates to cyclization into 1,3,4-oxadiazol-2(3H)-ones. Only the p-nitrophenyl alpha-azaornithine derivative 8 was inactivated rapidly by intramolecular acylation of the terminal amino group, rather than by cyclization to oxadiazolone, in aqueous solution at pH 8. The corresponding alpha-azalysine derivative 10 is completely unaffected under the same conditions. Rapid inactivation of thrombin and trypsin only was observed for all alpha-azapeptide esters 7-10 at 0.5 mM inhibitor concentration. No proteolytic activity was restored after 24 h following 2,000 fold dilution of the inhibitor concentration suggesting formation of very stable acylenzymes.
authors.affiliation: C.N.R. Centro Sintesi e Stereochimica di Speciali Sistemi Organici, Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Ferraccioli
authors.forename: P D
authors.initials: PD
authors.lastname: Croce
authors.forename: C
authors.initials: C
authors.lastname: Gallina
authors.forename: V
authors.initials: V
authors.lastname: Consalvi
authors.forename: R
authors.initials: R
authors.lastname: Scandurra
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D002675:Child, Preschool; D002918:Chymotrypsin / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D014357:Trypsin / Q000032:analysis; D014361:Trypsin Inhibitors / Q000138:chemical synthesis*
chemical_list: D001372:Aza Compounds; D014361:Trypsin Inhibitors; C075753:N(alpha)-(N,N-dimethylcarbamoyl)-alpha-azaornithine phenyl ester; C075754:N-(alpha)-(N,N-dimethylcarbamoyl)-alpha-azaornithine 4-nitrophenyl ester; C075755:N(alpha)-(N,N-dimethylcarbamoyl)alpha-azalysine phenyl ester; C075756:N(alpha)(N,N-dimethylcarbamoyl)-alpha-azalysine 4-nitrophenyl ester; D009952:Ornithine; D002918:Chymotrypsin; D014357:Trypsin; D013917:Thrombin; D008239:Lysine