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Investigations on different coupling reagents for the synthesis of a cyclopeptide analog of neuropeptide Y
Author(s) -
Hoffmann Eike,
BeckSickinger Annette G.,
Jung Günther
Publication year - 1991
Publication title -
liebigs annalen der chemie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 0170-2041
DOI - 10.1002/jlac.1991199101106
Subject(s) - chemistry , reagent , triethylamine , amide , peptide synthesis , peptide , combinatorial chemistry , propanoic acid , yield (engineering) , amine gas treating , chromatography , organic chemistry , materials science , metallurgy , biochemistry
The short‐cut analog of neuropeptide Y (NPY), NPY 1 YESK‐Ahx‐ 25 RHYINKITRQRY‐NH 2 , was synthesized on the amide anchor 5‐(4‐aminomethyl‐3,5‐dimethoxyphenoxy)valeric acid (ADPV) attached to polystyrene/1% divinylbenzene by using the 9‐fluorenylmethoxycarbonyl/ tert ‐butyl (Fmoc/tBu) strategy. Side‐chain‐to‐side‐chain cyclization of residues Glu 2 to Lys 30 of this linear heptadecapeptide amide was carried out by using different activating reagents under high‐dilution conditions of the free peptide. The use of diphenylphosphoryl azide (DPPA) with the addition of triethylamine gave the highest yield of cyclic peptide. Replacing the tertiary amine by dipotassium hydrogen phosphate as an insoluble inorganic base did not improve the cyclization. Complete cyclization was achieved within four hours by using 2‐(1 H ‐benzotriazol‐1‐yl) ‐1,1,3,3‐tetramethyluronium tetrafluoroborate (TBTU) in combination with 1‐hydroxybenzotriazol (HOBt) as activating agent, but the separation from excess TBTU resulted in lower yields. Reactions were monitored by HPLC and kinetic investigations were made. The identity and purity of the final productwere proven by various analytical methods including atmospheric pressure ionization mass spectrometry (API‐MS). The receptor binding constant of the cyclic analog was found to be comparable to that of NPY.