title: Diversity-Oriented Synthesis of Cyclic Azapeptides by A3-Macrocyclization Provides High-Affinity CD36-Modulating Peptidomimetics.
abstract: 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 "A3-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.
authors.affiliation: Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, Canada.|Present address: School of Pharmaceutical Science, Chongqing University, Chongqing, 401331, China.
authors.forename: Jinqiang
authors.identifier: 0000-0002-4541-240X
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Mukandila
authors.initials: M
authors.lastname: Mulumba
authors.affiliation: Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, Canada.
authors.forename: Huy
authors.initials: H
authors.lastname: Ong
authors.affiliation: Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, Canada.
authors.forename: William D
authors.identifier: 0000-0002-3080-2712
authors.initials: WD
authors.lastname: Lubell
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis*; D018955:CD36 Antigens / Q000737:chemistry*; D003500:Cyclization; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D057786:Peptidomimetics / Q000737:chemistry*
chemical_list: D001372:Aza Compounds; D018955:CD36 Antigens; D010456:Peptides, Cyclic; D057786:Peptidomimetics
keywords: A3-macrocyclization; CD36 modulation; GHRP-6 analogs; cyclic azapeptide; solid-phase synthesis