Étude structurale de la liaison thioamide: Synthèse et conformation de dérivés de la thioalanine et de la thioglycine

Abstract

Requ le 15 juin 1 9 8 8~ ANDRE G. MICHEL, CHAKIB AMEZIANE-HASSANI, GASTON BOULAY et GILLES LAJOIE. Can. J. Chem. 67, 1312 (1989). Cette Ctude rapporte la synthkse, la dktermination de structures cristallines et l'analyse conformationnelle par calculs empiriques de la N-tertiobutyloxycarbonyl N'-mCthylthioalanine (Boc-Alas-NHCH3, C9H18N202S) et de la N-tertiobutyloxycarbonyl N'-mCthylthioglycine (Boc-GlyS-NHCH3, C8H16N2O2S), C O~P O S C S a l'intcrieur desquels la liaison amide conventionnelle a CtC remplacCe par un lien thioamide. Boc-Alas-NHCH3 cristallise dans le systkme quadratique, le groupe d'espace Ctant P4,z12. Boc-GlyS-NHCH3 a cristallisC dans le systkme monoclinique, correspondant au groupe d'espace P21 / c . Les deux structures ont CtC rCsolues par mCthodes directes et affintes par la mCthode des moindres carrCs (matrices entikres), jusqu'a des valeurs de Rw de 0,045 et 0,035 pour 827 et 1335 reflexions respectivement pour lesquelles 1'intensitC I Ctait suptrieure a 2,5u(I). Les conformations observ6es pour Boc-Alas-NHCH3 et Boc-GlyS-NHCH, correspondent toutes 1 des minima d'Cnergie conformationnelle calcults pour les rCsidus classiques. La longueur du lien C=S de 1,665(9) A et de 1,650(3) A constitue la modification majeure en compafaison avec les molCcules oxygCnCes; la presence de I'atome de soufre ne semble pas modifier les propriCtCs du lien peptidique. A partir des structures cristallines ainsi dtterminies, les cartes d'knergie conformationnelle pour des dCrivCs de la dithioalanine et la dithioglycine ont Ct C calculCes par une mtthode classique dans le cadre de 1' Ctude structurale des peptides (ECEPP/2) et compartes a celles que l'on obtient pour les rCsidus classiques. On peut conclure que la synthtse d'une part et l'analyse conformationnelle d'autre part permettent d'inclure le lien thiopeptidique dans des structures plus complexes et d'en prCvoir les conformkres prtftrentiels. Mots c l b : conformation molCculaire, structures peptidiques, cristallographie. ANDRE G. MICHEL, CHAKIB AMEZIANE-HASSANI, GASTON BOULAY, and GILLES LAJOIE. Can. J. Chem. 67, 1312 (1989).The present study reports the synthesis, crystal structure determinations, and the conformational analysis of N-tertiobutyloxycarbonyl Ni-methylthioalanine (Boc-Alas-NHCH3, C9H18N202S) and of N-tertiobutyloxycarbonyl N'-methylthioglycine (Boc-GlyS-NHCH3, C8HI6N202S). The particular feature of these compounds is the replacement of the classical oxopeptide linkage by a thioamide bond. Crystals of Boc-Alas-NHCH3 are tetragonal, space group P4,2,2. Those of Boc-GlyS-NHCH, are monoclinic, space group P21/c. Both structures were solved by direct methods and refined by full-matrix least-squares methods to Rw = 0.045 and 0.035 for 827 and 1335 reflections respectively, with intensities greater than 2.5u(I). The conformations of both compounds corres ond to conformational energy minima, calculated for classical amino acids. The C=S bond lengths of 1.665(9) and 1.650(3) 1 constitute the major difference compared to oxopeptides; the crystal struct...

Endothioxopeptides: A conformational overview

“…The ψ[CSNH]Aib homo‐polymer folds in a semi ‐extended helical conformation with the CS pointing away and NH pointing toward the helix axis and both perpendicular to it. The mono‐ and dithionated Ac‐ (or Boc)‐Xxx‐NHMe (XxxGly and l ‐Ala) were investigated also by Lajoie and coworkers . In general, it was found that the energy maps do not vary significantly from those of the related oxo‐derivatives.…”

Conformational analysis of thiopeptides: (ϕ,ψ) maps of thio‐substituted dipeptides

“…The dots on some maps are the (ϕ,ψ) values found in experimental X‐ray crystal data. Dot 1: Boc‐Glyt‐Ala‐Aib‐OMe,71 Dot 2: (Z)‐Glyt‐Glyt‐Gly‐OBzl,73 Dot 3: (Z)‐Glyt‐Gly‐OBzl,74 and Dot 4: Boc‐Glyt‐NHMe 3…”

“…One therapeutic problem that arises when using peptides is the rapid degradation by the peptidases that normally digest dietary proteins. Noncoding amino acids can confer resistance to such enzymatic degradation 2–4. Noncoded amino acids have also been useful for probing the function of protein structural motif,5–7 during the process of de novo design,8–13 to build structures with novel folds or particular secondary structures14, 15 or for creating new combinatorial chemistry libraries 16–21.…”

“…This article focuses on the hypothesis that the conformational space available to the thiopeptide will be altered and restricted by the bulkier sulfur. This putative conformation restriction and the resistance to enzymatic degradation3, 4 of thiopeptides suggests that they are potentially useful building blocks for drug design and protein engineering.…”

“…Several authors3, 26–28 have examined the conformational implications of thio substitution, however, none of the calculations parameterized adequately for the thioamide interactions, and the published results are in conflict 29. Consequently, we have derived of parameters for the thioamide group29 for the molecular mechanics CFF91 force field 30–32.…”