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Diversity‐Oriented Synthesis of Cyclic Azapeptides by A 3 ‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics
Author(s) -
Zhang Jinqiang,
Mulumba Mukandila,
Ong Huy,
Lubell William D.
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201611685
Subject(s) - chemistry , peptidomimetic , cyclic peptide , agonist , receptor , combinatorial chemistry , peptide , cd36 , chemokine , solid phase synthesis , biochemistry
Macrocyclization has enabled the use of peptides in drug discovery creating a need for methods to synthesize diverse peptide macrocycles. Azapeptides have advanced to clinically used drugs, however, few cyclic azapeptides have been studied. A multiple component “A 3 ‐macrocyclization” strategy is described for the preparation of diverse cyclic azapeptides and is demonstrated by the synthesis of 15 growth hormone releasing hormone‐6 (GHRP‐6) analogs. Certain cyclic aza‐GHRP‐6 analogs exhibited unprecedented affinity for the CD36 receptor, and capacity to modulate Toll‐like receptor agonist‐induced overproduction of nitric oxide, and reduce pro‐inflammatory cytokine and chemokine production in macrophages.