Synthesis, conformation, and biological activity of two fMLP-OMe analogues containing the new 2-[2'-(methylthio)ethyl]methionine residue.
The new C alpha-tetrasubstituted alpha-amino acid residue 2-[2'-(methylthio)ethyl]methionine (Dmt) has been introduced into the reference chemotactic tripeptide HCO-Met-Leu-Phe-OMe (fMLP-OMe) in place of the leucine or methionine, respectively. The biological activity of the new analogues [Dmt2]fMLP-OMe (2) and [Dmt1]fMLP-OMe (3) has been determined; whereas 2 is active toward human neutrophils, stimulating directed migration, superoxide anion generation, and lysozyme release, 3 results practically inactive in all tested assays. A conformational analysis on 2 and 3 has been performed in solution by using ir absorption and 1H-nmr. The conformation of 2 was also examined in the crystal by x-ray diffraction methods. Both 2 and 3 adopt fully extended conformation in correspondence with the Dmt residue. Biological and conformational results are discussed and compared with related previously studied models.
Torrini
I
I
Dipartimento di Studi Farmaceutici, Università La Sapienza, Roma, Italy.
Paglialunga Paradisi
M
M
Pagani Zecchini
G
G
Lucente
G
G
Gavuzzo
E
E
Mazza
F
F
Pochetti
G
G
Traniello
S
S
Spisani
S
S
D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000737:chemistry; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation
C108102:2-(2'-(methylthio)ethyl)methionine; D009842:Oligopeptides; C108101:formyl-methionyl-2-(2'-(methylthio)ethyl)methionyl-phenylalanine methyl ester; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester; D008715:Methionine