Stereoselective Synthesis of β‐(5‐Arylthiazolyl) α‐Amino Acids and Use in Neurotensin Analogues. Issue 5 (18th January 2016)

• Record Type: Journal Article
• Authors: Hapău, Denisa; Rémond, Emmanuelle; Fanelli, Roberto; Vivancos, Mélanie; René, Adeline; Côté, Jérôme; Besserer‐Offroy, Élie; Longpré, Jean‐Michel; Martinez, Jean; Zaharia, Valentin; Sarret, Philippe; Cavelier, Florine
• Is Part Of: European journal of organic chemistry. Issue 5(2016)
• Page Start: 1017
• Page End: 1024
• Publication Date: 2016-01-18
• Subjects: Medicinal chemistry -- Receptors -- Neurotensin analogues -- Amino acids -- Peptides -- Alkylation; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201501495
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: 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. Abstract : 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.