European Journal of Organic Chemistry p. 1017 - 1024 (2016)
Update date:2022-08-02
Topics:
Hap?u, Denisa
Rémond, Emmanuelle
Fanelli, Roberto
Vivancos, Mélanie
René, Adeline
C?té, Jér?me
Besserer-Offroy, élie
Longpré, Jean-Michel
Martinez, Jean
Zaharia, Valentin
Sarret, Philippe
Cavelier, Florine
A series of new unnatural amino acids bearing a β-arylthiazole side chain was synthesized by exploiting a diastereoselective alkylation starting from glycine tert-butyl ester Schiff base with hydroxypinanone as the chiral inducer. This strategy afforded β-arylthiazole alanines in good chemical yields and with 98 % ee. Due to their aromatic properties, these newly generated amino acids were used to prepare neurotensin (NT)[8-13] analogues by serving as replacements for the native Tyr11 residue. Incorporation of the (L)-(+)-(β-phenylthiazol-4-yl)alanine residue at NT[8-13] position 11 improved plasma stability and selectivity towards NTS1, while also preserving native receptor binding affinity and biological activity. New β-arylthiazole alanines were synthesized in good chemical yields and with 98 % ee using a diastereoselective alkylation; these alanine derivatives were then used as Tyr11 replacements in the construction of neurotensin (NT)[8-13] analogues. The new NT analogues showed improved plasma stability and selectivity towards NTS1 thus preserving the hypotensive properties of the native peptide.
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