Constrained phenylalanine analogues. Preferred conformation of the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) residue.
Three Tic-containing (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) model peptides were synthesized to assess the tendency of this constrained Phe analogue to fold into a beta-bend and a helical structure, and to adopt a preferred side-chain disposition. The results of the solution conformational analysis, performed by using Fourier transform infrared absorption and 1H nuclear magnetic resonance, indicate that in chloroform the -Aib-D-Tic-Aib-, -(Aib)2-D-Tic-(Aib)2-, and -L-Pro-D-Tic- sequences fold into intramolecularly H-bonded forms to a great extent. An X-ray diffraction analysis on p-BrBz-(Aib)2-DL-Tic-(Aib)2-OMe monohydrate and p-BrBz-L-Pro-D-Tic-NHMe allows us to conclude that, while the pentapeptide methylester forms an incipient (distorted) 3(10)-helix, the dipeptide methylamide adopts a type-II beta-bend conformation. In both cases, the D-Tic side-chain conformation is D, gauche(-). The implications for the use of the Tic residue in designing conformationally restricted analogues of bioactive peptides are briefly discussed.
Valle
G
G
Department of Organic Chemistry, University of Padova, Italy.
Kazmierski
W M
WM
Crisma
M
M
Bonora
G M
GM
Toniolo
C
C
Hruby
V J
VJ
D005583:Fourier Analysis; D007546:Isoquinolines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis*; D010649:Phenylalanine / Q000031:analogs & derivatives*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011522:Protons; D012996:Solutions; D013055:Spectrophotometry, Infrared; D044005:Tetrahydroisoquinolines; D014961:X-Ray Diffraction
D007546:Isoquinolines; D010455:Peptides; D011522:Protons; D012996:Solutions; D044005:Tetrahydroisoquinolines; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D010649:Phenylalanine