Hybrid alpha/beta3-peptides with proteinogenic side chains. Monosubstituted analogues of the chemotactic tripeptide For-Met-Leu-Phe-OMe.
The alpha/beta3-mixed tripeptides R-CO-beta3-HMet-Leu-Phe-OMe (1a,b), R-CO-Met-beta3-HLeu-Phe-OMe (2a,b) and R-CO-Met-Leu-beta3-HPhe-OMe (3a,b) (a, R = tert-butyloxy-; b, R = H-), analogues of the potent chemoattractant For-Met-Leu-Phe-OMe, have been synthesized by classical solution methods and fully characterized. The activities of the new analogues as chemoattractants, superoxide anion producers and lysozyme releasers have been determined on human neutrophils. Whereas all of the three N-formyl derivatives are significantly less active than the parent tripeptide as chemoattractants, compound 1b has been found to be highly active as a superoxide anion producer and 3b as a lysozyme releaser. The results show that the replacement of the native Leu residue at the central position is, in each of the examined cases, the least favourable modification. The three N-Boc derivatives are, as expected, devoid of activity as agonists, but they are all good inhibitors of chemotaxis. Information on the solution conformation has been obtained by examining the involvement of the NH groups in intramolecular H-bonds using 1H NMR. The conformation of the N-Boc analogue 1a has also been determined in the crystal state by x-ray diffraction analysis. The molecule is extended at the beta3-HMet residue (phi1 = -87 degrees; theta1 = 172 degrees; psi1 = 126 degrees) and no intramolecular H-bond is present.
Giordano
Cesare
C
Istituto di Chimica Biomolecolare, CNR, and Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, 00185 Roma, Italy.
Lucente
Gino
G
Mollica
Adriano
A
Nalli
Marianna
M
Pagani Zecchini
Giampiero
G
Paglialunga Paradisi
Mario
M
Gavuzzo
Enrico
E
Mazza
Fernando
F
Spisani
Susanna
S
D000595:Amino Acid Sequence; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003460:Crystallization; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009113:Muramidase / Q000032:analysis; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D009504:Neutrophils / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000032:analysis; D014961:X-Ray Diffraction
D009842:Oligopeptides; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester; D009113:Muramidase