Peptide Coupling Challenges to Aza-Pipecolyl Smac Mimetic

Chingle, Ramesh; Lubell, William D.

doi:10.17952/24aps.2015.172

Cited by 1 publication

(3 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relationship between active azabicycloalkanone and azapeptide AVPI mimics may be due to a similar preferred turn geometry . From azopeptides, AVPI analogues possessing constrained aza-valine residues (e.g., 102 – 106 ; Figure ) were made using pericyclic chemistry and methods for effective coupling on relatively bulky electron-deficient semicarbazides . In MCF-7 breast cancer cells, aza-cyclohexanylglycine 106 induced cell death more efficiently than the parent tetrapeptide, likely by a caspase-9-mediated apoptotic pathway …”

Section: Biomedical Applicationsmentioning

confidence: 99%

“…23 Oxidation of azaglycine residues to their azo counterparts has permitted pericyclic chemistry, 24 that was applied to study the second mitochondria-derived activator of caspase (Smac) protein Ala-Val-Pro-Ile (AVPI) sequence with aza analogues that induced apoptosis in breast cancer cells. 25,26 Cyclic azapeptide analogues of GHRP-6 and cilengitide have also provided potent CD36 modulators 27 and antagonists of integrin receptors, 28 respectively. This Account summarizes recent advances in azapeptide chemisty since debut of submonomer synthesis 8 years ago, focusing on amplified aza residue sidechain diversity, and highlights the use of aza analogues to study biologically relevant peptides (e.g., GHRP-6, Smac AVPI, and cilengitide).…”

Section: Introductionmentioning

confidence: 99%

“…Enabling azapeptide library construction, submonomer synthesis has been particularly useful for studying growth hormone-releasing peptide-6 (His- d -Trp-Ala-Trp- d -Phe-Lys-NH 2 , GHRP-6) to develop modulators of the cluster of differentiation-36 scavenger receptor (CD36). , Furthermore, aza-glycine N-arylation and functionalization with reactive ω-chloroalkyl and propargyl side chains by submonomer synthesis have expanded the diversity of aza residues through robust chemistry, including nucleophilic displacements, copper-catalyzed Mannich additions, with A 3 reactions, and [1,3]-dipolar cycloadditions . Oxidation of aza-glycine residues to their azo counterparts has permitted pericyclic chemistry, that was applied to study the second mitochondria-derived activator of caspase (Smac) protein Ala-Val-Pro-Ile (AVPI) sequence with aza analogues that induced apoptosis in breast cancer cells. , Cyclic azapeptide analogues of GHRP-6 and cilengitide have also provided potent CD36 modulators and antagonists of integrin receptors, respectively. This Account summarizes recent advances in azapeptide chemisty since debut of submonomer synthesis 8 years ago, focusing on amplified aza residue side-chain diversity, and highlights the use of aza analogues to study biologically relevant peptides (e.g., GHRP-6, Smac AVPI, and cilengitide).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Azapeptide Synthesis Methods for Expanding Side-Chain Diversity for Biomedical Applications

2017

Self Cite

View full text Add to dashboard Cite

Mimicry of bioactive conformations is critical for peptide-based medicinal chemistry because such peptidomimetics may augment stability, enhance affinity, and increase specificity. Azapeptides are peptidomimetics in which the α-carbon(s) of one or more amino acid residues are substituted by nitrogen. The resulting semicarbazide analogues have been shown to reinforce β-turn conformation through the combination of lone pair-lone pair repulsion of the adjacent hydrazine nitrogen and urea planarity. Substitution of a semicarbazide for an amino amide residue in a peptide may retain biological activity and add benefits such as improved metabolic stability. The applications of azapeptides include receptor ligands, enzyme inhibitors, prodrugs, probes, and imaging agents. Moreover, azapeptides have proven therapeutic utility. For example, the aza-glycinamide analogue of the luteinizing hormone-releasing hormone analogue Zoladex is a potent long-acting agonist currently used in the clinic for the treatment of prostate and breast cancer. However, the use of azapeptides was hampered by tedious solution-phase synthetic routes for selective hydrazine functionalization. A remarkable stride to overcome this bottleneck was made in 2009 through the introduction of the submonomer procedure for azapeptide synthesis, which enabled addition of diverse side chains onto a common semicarbazone intermediate, providing a means to construct azapeptide libraries by solution- and solid-phase chemistry. In brief, aza residues are introduced into the peptide chain using the submonomer strategy by semicarbazone incorporation, deprotonation, N-alkylation, and orthogonal deprotection. Amino acylation of the resulting semicarbazide and elongation gives the desired azapeptide. Since the initial report, a number of chemical transformations have taken advantage of the orthogonal chemistry of semicarbazone residues (e.g., Michael additions and N-arylations). In addition, libraries have been synthesized from libraries by diversification of aza-propargylglycine (e.g., A coupling reactions, [1,3]-dipolar cycloadditions, and 5-exo-dig cyclizations) and aza-chloroalkylglycine residues. In addition, oxidation of aza-glycine residues has afforded azopeptides that react in pericyclic reactions (e.g., Diels-Alder and Alder-ene chemistry). The bulk of these transformations of aza-glycine residues have been developed by the Lubell laboratory, which has applied such chemistry in the synthesis of ligands with promising biological activity for treating diseases such as cancer and age-related macular degeneration. Azapeptide analogues of growth hormone-releasing peptide-6 (His-d-Trp-Ala-Trp-d-Phe-Lys-NH, GHRP-6) have for example been pursued as ligands of the cluster of differentiation 36 receptor (CD36) and show promising activity for the development of treatments for angiogenesis-related diseases, such as age-related macular degeneration, as well as for atherosclerosis. Azapeptides have also been employed to make a series of conformationally constrained second mito...

show abstract

Section: Biomedical Applicationsmentioning

confidence: 99%