Betidamino acids: versatile and constrained scaffolds for drug discovery.
Betidamino acids (a contraction of "beta" position and "amide") are N'-monoacylated (optionally, N'-monoacylated and N-mono- or N,N'-dialkylated) aminoglycine derivatives in which each N'acyl/alkyl group may mimic naturally occurring amino acid side chains or introduce novel functionalities. Betidamino acids are most conveniently generated on solid supports used for the synthesis of peptides by selective acylation of one of the two amino functions of orthogonally protected aminoglycine(s) to generate the side chain either prior to or after the elongation of the main chain. We have used unresolved Nalpha-tert-butyloxycarbonyl-N'alpha-fluorenylmethoxycarbonyl++ + aminoglycine, and Nalpha-(Nalpha-methyl)-tert-butyloxycarbonyl-N'alpha-fluo renylmethoxycarbonyl aminoglycine as the templates for the introduction of betidamino acids in Acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(A c)-Leu-Ilys-Pro-DAla-NH2, where 2Nal is 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pal is 3-pyridylalanine, Aph is 4-aminophenylalanine, and Ilys is Nepsilon-isopropyllysine], a potent gonadotropin-releasing hormone antagonist, in order to test biocompatibility of these derivatives. Diasteremneric peptides could be separated in most cases by reverse-phase HPLC. Biological results indicated small differences in relative potencies (<5-fold) between the D and L nonalkylated betidamino acid-containing Acyline derivatives. Importantly, most betide diastereomers were equipotent with Acyline. In an attempt to correlate structure and observed potency, Ramachandran-type plots were calculated for a series of betidamino acids and their methylated homologs. According to these calculations, betidamino acids have access to a more limited and distinct number of conformational states (including those associated with alpha-helices, beta-sheets, or turn structures), with deeper minima than those observed for natural amino acids.
Rivier
J E
JE
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Jiang
G
G
Koerber
S C
SC
Porter
J
J
Simon
L
L
Craig
A G
AG
Hoeger
C A
CA
D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D003959:Diamines / Q000737:chemistry*; D015195:Drug Design; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D007987:Gonadotropin-Releasing Hormone / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010060:Ovulation / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats
D003959:Diamines; D010455:Peptides; D007987:Gonadotropin-Releasing Hormone; D005998:Glycine