Synthese von cyclischen Pentapeptidanalogen des Thymopoietins. – Cyclisierungen mit Carbodiimid und 4‐(Dimethylamino)pyridin

Abstract

Die Synthesen von zehn cyclischen Pentapeptiden mit Thymopoietin-analogen Sequenzen werden beschrieben. Die linearen Vorstufen der Cyclen wurden nach klassischen Methoden der Peptidchemie synthetisiert. Die Cyclisierungen erfolgten mit der neu entwickelten Carbodiimid/DMAP-Methode, deren Vorteile beziiglich Ausbeute und Reinheit gegeniiber der Azidmethode nach Medzhiradsky aufgezeigt werden. Die starke Aktivierung fuhrt ZU Cterminaler Racemisierung bzw. Inversion, wenn die linearen Vorlaufer keine C-oder Nterminale D-Aminosaure enthalten. Synthesis of Cyclic Pentapeptide Analogues of Thymopoietin. -Cyclization with Carbodiimide and 4-(Dimethy1amino)pyridineThe syntheses of ten cyclic pentapeptides with sequences analogous to thymopoietin are described. The linear precursors of the cyclopeptides were synthesized by classical methods of peptide chemistry. Cyclization was exclusively carried out by the newly developed carbodiimide/DMAP method, with the advantage of higher yield and purity compared with the azide method according to Medzhiradsky. The strong activation leads to racemization and inversion, respectively, if the linear precursors contain no C-or N-terminal D-amino acid.Cyclische Peptide, welche die aktive Sequenz von Peptidhormonen enthalten, sind wegen der eingeschrankten konformativen Beweglichkeit und des erschwerten enzymatischen Abbaus von groDem wissenschaftlichen und pharmazeutischem Interesse'). Von Thymopoietin (I und II), einem die Immunabwehr stimulierenden Thymushormon mit 49 Aminosauren, konnte durch Abbaustudien das Pentapeptid H-Arg-Lys-Asp-Val-Tyr-OH (TP5)2) als aktive Sequenz 32 -36 lokalisiert werden (Abb. 1).

Influence of proline and β-turn mimetics on the cyclization of penta- and hexapeptides

“…Techniques are required which permit the efficient, simultaneous cyclization of a large number of linear peptides without regard to their sequences, especially in the design and synthesis of cyclic peptide libraries [1,2]. D-and N-alkylated amino acids are known to be turn-inducing [7][8][9]. The presence of turninducing units should enhance the cyclization of these peptides by the formation of cyclization-prone conformations.…”

What are the structures of phakellistatin 2 and phakellistatin 4?

“…We therefore chose the cyclization site of phakellistatin 2 between Ile 5 and Ile 6 in the assumption that Pro 4 will induce a [3-turn in the i + 1 position. To avoid C-terminal racemization [28], cyclization was carried out under mild conditions at high dilution in DMF (1.25 x 10 -3 M) using DPPA/ NaHCO3 [21] as the cyclization reagent. Sidechain protected phakellistatin 2 was obtained in 14% yield.…”

Total Synthesis of Alloviroidin

“…This was appealing, since the activated tripeptide, with its C -terminal dihydroxyproline residue, would not be susceptible to epimerization during coupling/cyclization (vide infra). This penultimate step should also be favored by the fact that the two residues ( l -Val and d -Thr) are of opposite configuration, albeit somewhat hindered.…”

“…This was appealing, since the activated tripeptide, with its C-terminal dihydroxyproline residue, would not be susceptible to epimerization during coupling/cyclization (vide infra). This penultimate step should also be favored by the fact that the two residues (L-Val and D-Thr) are of opposite configuration, 22 albeit somewhat hindered. While modern peptide synthesis is dominated by Fmoc chemistry, in conjunction with acid-labile side chain protecting groups, this approach would have been incompatible with the DHLeu residue.…”