Histidine racemization in the synthesis of an analog of the lutenizing hormone releasing factor

Abstract

To investigate histidine racemization in the synthesis of a LHRH analog, (D‐Trp)6‐LHRH2–10 was built up by stepwise elongation of the sequence 3–10 using the solid phase technique on a 1% cross‐linked chloromethyl polystyrene. For the whole synthesis the tert.‐butyloxycarbonyl (BOC) group was used for temporary N‐terminal protection. To protect the π‐nitrogen in histidine the benzyloxymethyl (BOM) group was utilized. The condensation position in the (D‐Trp)6‐LHRH analog was chosen so as to be able to investigate the racemization of histidine. We coupled BOC‐His(BOM) with the (D‐Trp)6‐LHRH3–10 fragment using three different activating agents, mixed anhydride, carbonyldiimidazole (1 equiv.)/1‐hydroxybenzotriazole (2 equiv.) and dicyclohexylcarbodiimide/1‐hydroxybenzotriazole. The racemization was investigated by enzymatic digestion and by HPLC. For HPLC, (D‐His(BOM)2‐(D‐Trp)6‐LHRH2–10 was also synthesized. It could be proved that practically no racemization occurs during the actual peptide synthesis. The small amount (1%) of D‐histidine found is due to racemization in the synthesis of BOC‐His(BOM).

Σχεδιασμός Και Ανάπτυξη Νέων Συνθετικών Αναλόγων Της Ωκυτοκίνης Με Ανταγωνιστική Δράση

“…[191,192]. Συνδέεται με το π-άτομο αζώτου και έτσι ελαχιστοποεί τον κίνδυνο ρακεμίωσης κατά τη διάρκεια σχηματισμού του πεπτιδικού δεσμού [191][192][193]. 20 Η χρήση της Bom ομάδας είναι συμβατή με κάθε αντιδραστήριο σύζευξης, ενώ η απομάκρυνσή της πραγματοποιείται εύκολα με τη χρήση HF ή ακόμα και με καταλυτική υδρογόνωση.…”