Citation

Wakselman M, Mazaleyrat J, Xie J, Montagne J, Vilain A, Reboud-Ravaux M. Eur. J. Med. Chem. 1991; 26(7): 699-707.

Copyright

(Copyright © 1991, Elsevier Publishing)

DOI

10.1016/0223-5234(91)90119-8

PMID

unavailable

Abstract

Cyclopeptides containing a functionalized meta-aminobenzoic acid residue (m-aB[CH2X] with X = OC6H5, OAc, Br, C1) linked to a tetraglycyl-phenylalanyl sequence, have been synthesized in solution. A phenyl ether group has been used during chain elongation and cyclisation, and then cleaved by treatment with HBr/HOAc to give the corresponding bromide, from which the acetate and the chloride have been obtained. The functionalized aminobenzoic acid residues possess a latent quinonimmonium methide electrophilic function, and these cyclopeptides are potential "suicide" substrates of chymotrypsin-like proteases. The cyclopeptides with X = Br or Cl irreversibly inhibit α-chymotrypsin ( kinact KI = 180 M-1min-1 for X = Cl). The compounds with poorer leaving groups X = OAc or OC6H5 are devoid of inactivating effect and only behave as substrates of this enzyme ( kcat KM = 31 800 M-1min-1 and 120 000 M-1min-1, respectively). © 1991.

Language: en

Keywords

article; priority journal; enzyme inhibition; enzyme inhibitor; drug synthesis; proteinase inhibitor; structure activity relation; suicide substrates; serine proteases; chymotrypsin a; cyclopeptide; cyclopeptides; meta-aminobenzoic acid; quinonimmonium methide; α-chymotrypsin