Proline-glutamate chimeras in isopeptides. Synthesis and biological evaluation of conformationally restricted glutathione analogues.
The two novel diastereoisomeric glutathione analogues 1 and 2 have been designed and synthesized by replacing the native gamma-glutamylic moiety with the conformational rigid skeleton of cis- or trans-4-carboxy-L-proline residue. Both analogues have been obtained by following the solution phase peptide chemistry methodologies and final reduction of the corresponding disulfide forms 13 and 14. The two analogues 1 and 2 have been tested towards gamma-glutamyltranspeptidase (gamma-GT) and human glutathione S-transferase (hGST P1-1). Both analogues 1 and 2 are completely resistant to enzymatic degradation by gamma-GT. The S-transferase utilizes the analogue 2 as a good substrate while is unable to bind the analogue 1.
Paradisi
Mario Paglialunga
MP
Istituto di Chimica Biomolecolare, CNR Sezione di Roma, c/o Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, P.le A. Moro, 00185 Rome, Italy.
Mollica
Adriano
A
Cacciatore
Ivana
I
Di Stefano
Antonio
A
Pinnen
Francesco
F
Caccuri
Anna Maria
AM
Ricci
Giorgio
G
Duprè
Silvestro
S
Spirito
Alessandra
A
Lucente
Gino
G
D004137:Dinitrochlorobenzene / Q000378:metabolism; D005971:Glutamates / Q000737:chemistry*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D005723:gamma-Glutamyltransferase / Q000187:drug effects / Q000378:metabolism
D004137:Dinitrochlorobenzene; D005971:Glutamates; D011392:Proline; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D005978:Glutathione