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Amphipathic peptides composed of cationic amino acids and hydrophobic amino acids have cell-penetrating ability and are often used as a delivery tool for membrane-impermeable compounds. Small interfering RNA (siRNAs) are one of the delivery targets for such cell-penetrating peptides (CPPs). Cationic CPPs can associate with anionic siRNAs by electrostatic interactions resulting in the formation of nano-sized complexes, which can deliver siRNAs intracellularly. CPPs containing unnatural amino acids offer promising tools to siRNA delivery. However, the detailed structure–activity relationship in siRNA delivery has been rarely studied. In the current study, we designed peptides containing dipropylglycine (Dpg) and explored the cellular uptake and cytotoxicity of peptide/siRNA complexes. The amphipathic structure of the peptides played a key role in complexation with siRNAs and intracellular siRNA delivery. In the amphipathic peptides, cellular uptake of siRNA increased with increasing peptide length, but cytotoxicity was reduced. A peptide containing four Dpg exhibited an effective gene-silencing effect with small amounts of peptides without cytotoxicity in medium containing serum. These findings will be helpful for the design of novel CPPs for siRNA delivery., Chemical & pharmaceutical bulletin, 71(3), pp. 250-256; 2023

We developed a first-in-class proteolysis targeting chimera (PROTAC) for selective degradation of histone deacetylase 8 (HDAC8). The PROTAC induced degradation of HDAC8 without affecting the levels of other HDACs in cellular assays, and inhibited the growth of T-cell leukemia Jurkat cells more potently than a conventional HDAC8 inhibitor.

This paper reports an efficient method for the epoxidation of a variety of functionalized olefins using diaryltellurium dicarboxylates as hypervalent tellurium compounds. This method is able to efficiently convert olefins into epoxides using catalytic amounts of tellurium and urea hydrogen peroxide. Furthermore, we propose that this reaction proceeds

Proteolysis targeting chimeras (PROTACs) have emerged as a powerful technology for the degradation of disease-related proteins by the hijacking of the endogenous ubiquitin-proteasome system. A multitude of bifunctional PROTACs have been developed using small-molecule ligands; one ligand binds to the target protein of interest and one ligand binds to an E3 ligase. The characteristics of those PROTACs vary, including their reversible or irreversible covalent binding to the target protein, their binding to orthosteric and allosteric sites, their agonist or antagonist activity, and their use of multiple ligands. In addition, oligopeptides and nucleotides have recently been used as alternative targeting ligands. The properties of PROTACs, such as selectivity, delivery and sensitivity to drug resistance, can be improved through the use of a variety of targeting ligand modalities. This minireview introduces the mechanisms and behavior of small-molecule based PROTACs as well as targeted proteolysis techniques using peptides and nucleic acids as targeting ligands.

A chiral cyclic α,α-disubstituted α-amino acid, (S)-(-)-cucurbitine, which has a pyrrolidine ring with a chiral center at the α-position, was synthesized, and its homopeptides were prepared. (S)-(-)-Cucurbitine homopeptides with a Boc-protecting group formed helical structures with slight control of the helical screw sense to the left-handed form. The state of the pyrrolidine ring in (S)-(-)-cucurbitine was important for the control of the helical structures and helical screw sense of its homopeptides.

Prolonging the duration of protein expression from mRNA is a major challenge in the development of mRNA nanomedicines. mRNA complexed with helix foldamer oligopeptides consisting of arginine and α-aminoisobutyric acids showed higher intracellular stability than that complexed with oligoarginines, thereby maintaining efficient protein translation for three days.

Various racemic α-trifluoromethyl α,α-disubstituted α-amino acids were synthesized by the reaction of methyl 3,3,3-trifluoropyruvate imines with Grignard reagents. The optical resolution of racemates using (R)-1,1’-bi-2-naphthol {(R)-BINOL} esters gave optically active α-trifluoromethylated α,α-disubstituted α-amino acids, such as α-trifluoromethylalanine (αCF3Ala), α-trifluoromethylleucine (αCF3Leu), and α-trifluoromethylphenylalanine (αCF3Phe). The optically active (R)- or (S)-αCF3Ala was incorporated into the L-Leu-based pentapeptides, and their preferred conformation in solution and in the crystal state was studied by Fourier transform infrared (FT-IR) absorption, nuclear Overhauser effect spectroscopy (NOESY) NMR, and circular dichroism (CD) spectra, as well as X-ray crystallographic analysis. Both L?Leu-based peptides with (R)- or (S)-αCF3Ala formed right-handed 310-helical structures. Both peptide-backbones at the N-terminal residues 1-3 were very similar, but the φ and ψ torsion angles of residues 4 and 5 between peptides with (R)- or (S)- αCF3Ala were different., ChemistrySelect, 5(35), pp.10882-10886; 2020

The Great East Japan Earthquake (GEJE) in March 2011 greatly changed the spatial pattern of energy use in Fukushima Prefecture. The previously nuclear-reliant energy policy has transformed, with energy now generated mainly by fossil fuels and renewable sources. The spatio-temporal variation of fossil fuel use and the major causes of these changes have not previously been fully clarified. This study quantified the annual fossil fuel use in eight user sectors at high spatial resolution using a bottom-up approach. The total fossil fuel use in Fukushima is estimated to have increased by about 91,233TJ from 2010 to 2015, despite decreases in most socioeconomic indicators. The increase was mainly attributed to changes inelectricity generation(104,521TJ). The three sectors with the greatest decrease in energy use were road transportation (-7159TJ), industrial and commercial (-3608TJ), and residential (-2334TJ). Spatial analysis using high-resolution maps identified areas of increased energy use mainly in central, southeastern, and northeastern Fukushima and confirmed some local variations in energy use by sector. It showed that decreasing energy use in the area within 20km of the Fukushima DaiichiNuclear Power Stationresulted in increased use in areas located >20km from the power station. Sensitivity analysis clarified the relations among factors underlying each sector’s changing energy use before and after the GEJE. For instance, consider the electricity generation sector: reduced energy use was caused by decreased energy use intensity (-23,299TJ) and the increased use of biomass (-4848TJ), whereas increases were caused by rising utilization efficiency (102,410TJ) and increased electricity generation capacity (35,988TJ), which led to a large overall increase for this sector (104,521TJ). However, road transportation’s negative energy use change (-7159TJ) arose owing to decreased traffic volumes (-7573TJ) and decreased energy use intensity (-7177TJ), despite some positive energy use changes caused by the increased proportion of large vehicles (3684TJ) and changes in mean travel speed (1381TJ). The approach used in this study will be helpful for policy makers to evaluate spatio-temporal variations and develop policies to reduce energy use in response to unusual local events.

Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO-selective inhibitors.

Arginine (Arg)-rich peptides can penetrate the cell membrane and deliver nucleic acid-based therapeutics into cells. In this study, a helical template designed with a repeating sequence composed of two l-leucines (l-Leu) and a 2-aminoisobutyric acid (Aib) (l-Leu-l-Leu-Aib) was conjugated to nona-arginine on either the C- or N- terminus, designated as Block 1 and Block 2. Each terminal modification induced helical structure formation and improved the physicochemical properties of peptide/plasmid DNA (pDNA) complexes, resulting in efficient intracellular pDNA delivery. The introduction of a helical template may be effective for the endosomal escape of pDNA and pDNA release from complexes in cells. These results emphasized the potency of a helical template for the development of novel cell-penetrating peptides for pDNA delivery.

Only two crystal structures of diorganotellurones have been reported to date, both of which contain cocrystallized solvents and one of which is stabilized by intramolecular Te—N secondary bonding interactions. This work describes the crystal structure of bis(2,6-diisopropylphenyl) tellurone, (C12H17)2TeO2 or C24H34O2Te, the first well-defined diorganotellurone without cocrystallized solvents and without stabilizing intramolecular contacts. The molecule has crystallographic twofold symmetry, with half the molecule as the asymmetric unit. The molecular structure is compared to previously reported tellurones and those computed at the density functional theory DFT/B3PW91 level. The molecules form two-dimensional layers as a result of a weak intermolecular hydrogen-bonding network. The layers are then stacked in an antiparallel manner to form the crystal packing structure. The Hirshfeld surface analysis was employed to visualize and quantify the intermolecular contacts in the molecular crystal structure, and the contribution of O...H and H...H interactions was found to be the dominating factor.

We describe the synthesis of an ionic-liquid (IL)-supported organotelluride catalyst and its application as a recyclable catalyst for the aerobic oxidation of phosphite esters to phosphate esters. This method shows high conversion rates, allows the ready isolation and purification of the resulting products, and exhibits good reusability of the catalyst.

α,α-Disubstituted α-amino acids (dAAs), in which the α-hydrogen of the α-amino acid is replaced with an alkyl substituent, stabilize peptide secondary structures and have been utilized as a tool for building blocks of peptide foldamers. Peptides composed of acyclic dAAs with two bulky substituents equal to or larger than ethyl groups are more likely to form an extended planar conformation, whereas peptides with cyclic dAAs are more likely to adopt a helical structure. Based on these conformational properties of dAA-containing peptides, we developed a novel methodology using cyclic dAAs with an acetal side chain for conformational changes in peptides from a helical to a random structure with acidic treatment. Furthermore, peptide foldamers containing dAAs are useful for the design of functional peptides. In addition to the stabilization properties of peptide secondary structures, peptides foldamers exhibit resistance to degradation by proteases and thus are expected to be useful for development into bioactive peptides. In this presentation, I introduce cell-penetrating peptide foldamers as an application for dAAs in functional peptides. Peptide foldamers with appropriate functional groups at target positions show excellent, continuous cell membrane permeability and the ability to deliver biomacromolecules, such as plasmid DNA, into cells efficiently.

We have designed and synthesized a set of cell-penetrating foldamers (CPFs), Blocks 1-8, composed of the common amino acids Leu, Arg, and Gly, as well as the helicogenic amino acid 2-aminoisobutyric acid. The findings showed that Block 3 could deliver siRNA into cells without significant cytotoxicity. We also demonstrated that Block 3 could be applied to selectively kill the oncogene-driven cancer cells.

A chiral cyclic α,α-disubstituted α-amino acid, (

SVS-1 is a cationic amphiphilic peptide (CAP) that exhibits a preferential cytotoxicity towards cancer cells over normal cells. In this study, we developed radiogallium-labeled SVS-1 (67Ga-NOTA-KV6), as well as two SVS-1 derivatives, with the repeating KV residues replaced by RV or HV (67Ga-NOTA-RV6 and 67Ga-NOTA-HV6). All three peptides showed high accumulation in epidermoid carcinoma KB cells (53–143% uptake/mg protein). Though 67Ga-NOTA-RV6 showed the highest uptake among the three CAPs, its uptake in 3T3-L1 fibroblasts was just as high, indicating a low selectivity. In contrast, the uptake of 67Ga-NOTA-KV6 and 67Ga-NOTA-HV6 into 3T3-L1 cells was significantly lower than that in KB cells. An endocytosis inhibition study suggested that the three 67Ga-NOTA-CAPs follow distinct pathways for internalization. In the biodistribution study, the tumor uptakes were found to be 4.46%, 4.76%, and 3.18% injected dose/g of tissue (% ID/g) for 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6, respectively, 30 min after administration. Though the radioactivity of these peptides in tumor tissue decreased gradually, 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6 reached high tumor/blood ratios (7.7, 8.0, and 3.8, respectively) and tumor/muscle ratios (5.0, 3.3, and 4.0, respectively) 120 min after administration. 67Ga-NOTA-HV6 showed a lower tumor uptake than the two other tracers, but it exhibited very low levels of uptake into peripheral organs. Overall, the replacement of lysine in SVS-1 with other basic amino acids significantly influenced its binding and internalization into cancer cells, as well as its in vivo pharmacokinetic profile. The high accessibility of these peptides to tumors and their ability to target the surface membranes of cancer cells make radiolabeled CAPs excellent candidates for use in tumor theranostics., Cancers, 13(10), art. no. 2388; 2021

In the delivery of cell-impermeable molecules, cell-penetrating peptides (CPPs) have been attracting increasing attention as intracellular delivery tools. In the present study, we designed four types of cyclic α,α-disubstituted α-amino acids (dAAs) with basic functional groups on their five-membered rings and different chiralities at the α-position and introduced them into arginine (Arg)-rich peptides. The evaluation of cell-penetrating abilities indicated that these peptides exhibited better cell permeabilities than an Arg nonapeptide. Furthermore, peptides containing dAAs delivered plasmid DNA (pDNA) better than a commercially available transfection reagent with a longer incubation time. These results demonstrate that the introduction of cyclic dAAs with basic functional groups into Arg-rich peptides is an effective strategy for the design of CPPs as a pDNA delivery tool.

Arginine (Arg)-rich cell-penetrating peptides (CPPs) are promising tools for plasmid DNA (pDNA) delivery. α-Aminoisobutyric acid (Aib) is known to stabilize peptide helical secondary structures and has been used as a building block for foldamers. In the current study, we prepared Aib CPP foldamers, (Arg–Arg–Aib)n (n = 1–6) and examined their pDNA transfection abilities. Transfection efficiencies of peptide/pDNA complexes are dependent on peptide chain length, with longer peptides (n ≥ 4) exhibiting better transfection abilities than an Arg nonapeptide. Furthermore, Aib CPP foldamers achieve prolonged transfection abilities compared with commercially available transfection reagents, which is probably because of the high resistance of the peptides to enzymatic degradation, thereby protecting the encapsulated pDNA for a long period. The obtained results demonstrated promising features of Aib CPP foldamers as pDNA delivery carriers.

Lysine demethylase 5 C (KDM5C) controls epigenetic gene expression and is attracting great interest in the field of chemical epigenetics. KDM5C has emerged as a therapeutic target for anti-prostate cancer agents, and recently we identified triazole 1 as an inhibitor of KDM5C. Compound 1 exhibited highly potent KDM5C-inhibitory activity in in vitro enzyme assays, but did not show strong anticancer effects. Therefore, a different approach is needed for the development of anticancer agents targeting KDM5C. Here, we attempted to identify KDM5C degraders by focusing on a protein-knockdown strategy. Compound 3 b, which was designed based on compound 1, degraded KDM5C and inhibited the growth of prostate cancer PC-3 cells more strongly than compound 1. These findings suggest that KDM5C degraders are more effective as anticancer agents than compounds that only inhibit the catalytic activity of KDM5C.

Organotellurium compounds are known to be useful oxidation reagents. For developing a recoverable and reusable reagent, this paper describes the use of an ionic liquid (IL) support for the organotellurium reagent and its application as a recyclable catalyst for thiol oxidation. We have successfully prepared a novel diphenyl telluride derivative 5 bearing an imidazolium hexafluorophosphate group in its structure. It is found that the IL-supported diphenyl telluride 5 efficiently catalyzed the aerobic oxidation of various thiols in [bmim]PF6 solution under photosensitized conditions to provide the corresponding disulfides in excellent yields. The product can be isolated by simple ether extraction. The IL-supported catalyst 5 remaining in the ionic liquid phase can be reused for five successive runs while retaining high catalytic activity (97% yield even in the fifth run).

A chiral three-membered ring Cα,α-disubstituted α-amino acid (R,R)-Ac3cdMOM, in which the α-carbon is not a chiral center, but two side chain β-carbons are chiral centers, was synthesized from dimethyl l-(+)-tartrate, and its homopeptides were prepared. X-ray crystallographic analysis of (R,R)-Ac3cdMOM pentapeptide showed bent left-handed (M) 310-helical structures with an unusual intramolecular hydrogen bond of the N–H···O (ethereal) type. The left-handedness of the bent helices was exclusively controlled by the side-chain β-carbon chiral centers.

We designed and synthesized a series of cell-penetrating peptides containing cationic proline derivatives (ProGu) that exhibited responsive changes in their secondary structures to the cellular environment. Effects of the peptide length and steric arrangement of the side chain in cationic proline derivatives [Pro4SGu and Pro4RGu] on their secondary structures and cell membrane permeability were investigated. Moreover, peptides 3 and 8 exhibited efficient intracellular delivery of plasmid DNA.

l?Leu-based heteropeptides having (R)- or (S)-chiral five-membered carbocyclic ring amino acids (Ac5c3EG) with an ethylene acetal moiety were prepared. A conformational analysis using FT-IR absorption, 1H NMR, and circular dichroism (CD) spectra revealed that l?Leu-based hexapeptides and nonapeptides having (R)- or (S)-Ac5c3EG formed right-handed (P) helical structures in solution. An X-ray crystallographic analysis of nonapeptides 5 a and 5 b showed similar right-handed (P) α-helical structures, without an intramolecular hydrogen bond of the peptide N?H????O? (acetal) type., ChemistrySelect, 2(26), pp.8108-8114; 2017

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., Organic and Biomolecular Chemistry, 15(30), pp.6302-6305; 2017

Cell-penetrating peptides are receiving increasing attention as drug delivery tools, and the search for peptides with high cell-penetrating ability and negligible cytotoxicity has become a critical research topic. Herein, cyclic α,α-disubstituted α-amino acids were introduced into arginine-rich peptides and an additional staple was provided in the side chain. The peptides designed in the present study showed more enhanced and prolonged cell-penetrating abilities than an arginine nonapeptide due to high resistance to protease and conformationally stable helical structures.