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 "A -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.

Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators

“…14 Moreover, 18 F-substitution may offer opportunities for PET-imaging, 15 and for enhancing metabolic stability.16 Unnatural, unsaturated/α-branched amino acids are also of interest as building blocks for modified non-ribosomal peptide synthesis17 and programmed unnatural amino acid mutagenesis at the ribosome.18 Quaternary AAs also find application in driving the formation of useful secondary structure when strategically incorporated into α- 19 and β-peptides 20 as well as hybrid α/β-peptides, 21 or in promoting interesting helical motifs such as the 3 10 -helix 22 and the 2.05-helix. 23 Elements of side chain unsaturation can serve as useful conformational constraints 24 and contribute to overall peptide stability via stapling technology. 25 …”

A Review on Azapeptides: The Promising Peptidomimetics

“…The aza-pipecolyl peptidomimetics were reported to display antibacterial and antidiabetic activities, based on their conformational significance, the synthesis of new modular sulphur containing dipeptide mimetics (diazabicycloalkanes) and azapolycyclic compounds was performed [39]. Few cyclic aza-GHRP-6 analogs exhibited unprecedented affinity for the CD36 receptor and also reduced the pro-inflammatory cytokines [40]. Importance of azapeptides as cysteine and serine protease inhibitors: A number of human diseases are associated with aberrant activity of mammalian, viral, bacterial or parasitic proteases.…”

Aza‐propargylglycine installation by aza‐amino acylation: Synthesis and Ala‐scan of an azacyclopeptide CD36 modulator

“…Recently, azaPra residues have been employed in the so‐called A 3 ‐macrocyclizations to synthesize side chain‐to‐side chain constrained azapeptides (e.g., 1 ), some of which have demonstrated unprecedented binding affinity and modulatory effects on the cluster of differentiation‐36 receptor (CD36). For example, azacyclopeptide 1a exhibited high CD36 binding affinity (IC 50 of 0.08 μm) and suppressed downstream release of pro‐inflammatory cytokines, chemokines, and nitric oxide in macrophages exposed to a Toll‐like receptor agonist . Azacyclopeptide 1a and related analogs are thus promising targets because of potential to mitigate macrophage‐driven inflammation.…”

“…The azaPra residue has been installed by a process featuring activation of benzophenone hydrazone ( 6 ) as methylidene carbazate 8 which on reaction with peptide resin 7 gave semicarbazone 9 (Scheme ) . Alkylation of aza‐glycine 9 with propargyl bromide gave protected azaPra 10 , which upon treatment with 1.5 M hydroxylamine hydrochloride in pyridine gave semicarbazide 11 .…”

“…To synthesize azapeptides, semicarbazone alkylation offers advantages because various alkyl halides can be used to install different side chains on the aza‐residue . Toward the specific synthesis of azacyclopeptide 1a , alkylation necessitated, however, an additional step on resin. Moreover, nucleophilic conditions were required to liberate the semicarbazide .…”