Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

A "foldamer" is an artificial oligomeric molecule with a regular secondary or tertiary structure consisting of various building blocks. A "stapled peptide" is a peptide with stabilized secondary structures, in particular, helical structures by intramolecular covalent side-chain cross-linking. Helical foldamers and stapled peptides are potential drug candidates that can target protein-protein interactions because they enable multipoint molecular recognition, which is difficult to achieve with low-molecular-weight compounds. This mini-review describes a variety of peptide-based foldamers and stapled peptides with a view to their applications in drug discovery, including our recent progress

Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues

Stimulator of Interferon Genes (STING) is a type of endoplasmic reticulum (ER)-membrane receptor. STING is activated by a ligand binding, which leads to an enhancement of the immune-system response. Therefore, a STING ligand can be used to regulate the immune system in therapeutic strategies. However, the natural (or native) STING ligand, cyclic-di-nucleotide (CDN), is unsuitable for pharmaceutical use because of its susceptibility to degradation by enzymes and its low cell-membrane permeability. In this study, we designed and synthesized CDN derivatives by replacing the sugar-phosphodiester moiety, which is responsible for various problems of natural CDNs, with an amine skeleton. As a result, we identified novel STING ligands that activate or inhibit STING. The cyclic ligand 7, with a cyclic amine structure containing two guanines, was found to have agonistic activity, whereas the linear ligand 12 showed antagonistic activity. In addition, these synthetic ligands were more chemically stable than the natural ligands

Asymmetric oxidation of 1,2-diols using N-bromosuccinimide in the presence of chiral copper catalyst

Asymmetric oxidation of 1,2-diols using N-bromosuccinimide (NBS) in the presence of copper(II) triflate and (R,R)-Ph-BOX has been exploited. This oxidation was applicable to asymmetric desymmetrization of meso-hydrobenzoin and kinetic resolution of dl-hydrobenzoin and racemic-cycloalkane-cis-1,2-diols to afford optically active ﾎｱ-ketoalcohols with good to high enantiomeric excess

Copper complex catalyzed asymmetric monosulfonylation of meso-vic-diols

Asymmetric desymmetrization of meso-vic-diols was performed by tosylation in the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst. The method was successfully applied to asymmetric desymmetrization of cyclic and acyclic meso-vic-diols in high enantioselectivity with up to >99% ee

Regioselective Introduction of Electrophiles into Piperidine Derivatives at the 4-Position

Regioselective introduction of various electrophiles (aldehydes, ketones, and imines) into piperidine skeleton at the 4-position was achieved with a catalytic amount of Pd(OAc)2/PPh3 in the presence of excess Et2Zn. In addition, enantioselective introduction of benzaldehyde into piperidine derivatives was accomplished by using chiral phosphine ligand with moderate enantioselectivity

Ring Contraction of α,β-Unsaturated Cyclic Amines with cis-Dihydroxylation at the α,β-Position

α,β-Unsaturated cyclic amines are oxidized by OsO4 to afford α,β-cis-dihydroxylated compounds which are thermodynamically transformed into ring-opened keto-alcohols. The keto-alcohols are then cyclized to form synthetically useful ring-contracted cyclic amines

Facile synthesis of optically active oxindoles by copper-catalyzed asymmetric monotosylation of prochiral 1,3-diols

A facile synthetic method toward optically active 3,3-disubstituted oxindoles with excellent enantioselectivity was achieved using chiral copper-catalyzed desymmetrization of prochiral 1,3-diols. The monotosylated product was transformed into oxindole derivatives efficiently

Chiral azabicyclo-N-oxyls mediated enantioselective electrooxidation of sec-alcohols

Enantiomerically pure azabicyclo-N-oxyls were prepared from l-hydroxyproline. They mediated enantioselective electrooxidation of racemic sec-alcohols to afford optically active sec-alcohols with moderate to high s value (up to 21)

Low pH-triggering changes in peptide secondary structures

We developed a novel methodology using cyclic α,α-disubstituted α-amino acids (dAAs) with an acetal-side chain to control peptide secondary structures. The introduction of cyclic dAAs into peptides contributed to the stabilization of peptide secondary structures as a helix, while an acidic treatment of peptides resulted in a marked conformational change

Helical structures of homo-chiral isotope-labeled α-aminoisobutyric acid peptides

The chiral deuterium- and 13C-isotope-labeled α-aminoisobutyric acids CD3-Aib and 13CH3-Aib were enantioselectively synthesized from L-Ala aldimine using simplified Maruoka chiral phase-transfer catalysts. Homo-chiral (S)-CD3-Aib homopeptides, up to decamers, were prepared. A (R)-CD3-Aib polymer and (S)-13CH3-Aib polymer were also prepared. Conformational studies on homopeptides using CD spectra and an X-ray crystallographic analysis revealed that the preferred conformations were 310-helical structures comprising equal amounts of right-handed (P) and left-handed (M) helical-screw structures. The α-carbon chiral centers induced by the D- or 13C-isotope substitution of Aib were incapable of controlling the helical-screw directions of their oligopeptides and short polymers