Disulfide‐Unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA

Development of intracellular delivery methods for antisense DNA and siRNA is important. Previously reported methods using liposomes or receptor‐ligands take several hours or more to deliver oligonucleotides to the cytoplasm due to their retention in endosomes. Oligonucleotides modified with low molecular weight disulfide units at a terminus reach the cytoplasm 10 minutes after administration to cultured cells. This rapid cytoplasmic internalization of disulfide‐modified oligonucleotides suggests the existence of an uptake pathway other than endocytosis. Mechanistic analysis revealed that the modified oligonucleotides are efficiently internalized into the cytoplasm through disulfide exchange reactions with the thiol groups on the cellular surface. This approach solves several critical problems with the currently available methods for enhancing cellular uptake of oligonucleotides and may be an effective approach in the medicinal application of antisense DNA and siRNA.     

N‐Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β‐Unsaturated Amides

Concerted nucleophilic aromatic substitution (CS_NAr) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CS_NAr reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N‐heterocyclic carbene (NHC)‐catalyzed intramolecular cyclization of acrylamides that contain a 2‐fluorophenyl group on the nitrogen through a CS_NAr reaction. By using this catalytic method, it is possible to synthesize an array of quinolin‐2‐one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (C_ipso‐C_β)→ σ*(C_ipso‐F) interaction critically contributes to the stabilization of the transition state for the cyclization.     

Molecular dynamics study of solubilization of cyclohexane,benzene, and phenol into mixed micelles composed of sodium dodecyl sulfate and octaethylene glycol monododecyl ether

Molecular dynamics calculations of a mixed micelle composed of sodium dodecyl sulfate (SDS) and octaethylene glycol monododecyl ether (C₁₂E₈) were performed for six compositions (SDS/C₁₂E₈ = 100/0, 80/20, 60/40, 40/60, 20/80, and 0/100) to investigate the composition dependence of the mixed micelle structure and solubilization of cyclohexane, benzene, and phenol molecules by the micelle. The radial density distribution of the hydrophilic polyoxyethylene (POE) group of C₁₂E₈ as a function of distance from the micelle center is very sharp for micelles with high SDS content because the POE group captures a Na⁺ ion in solution and wraps around it to form a compact crown-ether-like complex. The hydrophobic dodecyl groups of SDS and C₁₂E₈ were separately distributed in the mixed micelle core. ΔG(r) evaluated for each solute showed that despite the structural changes of the micelle the binding strength of the solute molecules to the micelle did not change significantly. © 2019 Wiley Periodicals, Inc.     

Crystal structures of calcium IV and V under high pressure

High-pressure phases IV and V of calcium discovered in 2005 have the highest superconducting transition temperature of 25 K among all the elements; however, their crystal structures have not been determined. From the x-ray powder diffraction data, both Ca IV and V have been found to form unique and complex structures with a coordination number of 7. They were confirmed to be identical to the theoretical models that were recently predicted [Ishikawa, Phys. Rev. B 77 020101(R) (2008)].     

Chiral cyclic [n]spirobifluorenylenes: carbon nanorings consisting of helically arranged quaterphenyl rods illustrating partial units of woven patterns

Chiral cyclic [n]spirobifluorenylenes consisting of helically arranged quaterphenyl rods, illustrating partial units of woven patterns, were designed and synthesized as a new family of carbon nanorings. The synthesis was accomplished by the Ni(0)-mediated Yamamoto-coupling of chiral spirobifluorene building blocks. The structures of the cyclic 3-, 4-, and 5-mers were determined by X-ray crystallographic analysis. These carbon nanorings exhibited a strong violet colored emission with high quantum yields in solution (95%, 93%, and 94% for 3-, 4-, and 5-mer, respectively). Other spectroscopic properties, including their chiroptical properties, were also investigated. The g-values for circularly polarized luminescence were found to be in the order of 10⁻³. Characteristic spiroconjugation induced by multiple (≧3) bifluorenyl units, for example the even-odd effect of the number of units in the matching of the signs of the orbitals, was also indicated by DFT calculations.

Chiral cyclic [n]spirobifluorenylenes consisting of helically arranged quaterphenyl rods, illustrating partial units of woven patterns, were designed and synthesized as a new family of carbon nanorings.     

Stereoselective synthesis of triply isotope-labeled Ser, Cys, and Ala: amino acids for stereoarray isotope labeling technology

Efficient access to highly enantioselective isotope-labeled serine, cysteine, and alanine for stereoarray isotope labeling (SAIL) is described.     

Three-metal-center spin interactions through the intercalation of metal azaporphines and porphines into an organic pillared coordination box

Discrete homo Cu-Cu-Cu and hetero Cu-Pd-Cu or Cu-Co-Cu metal arrays are prepared within an organic-pillared coordination box by inserting M(ii)-azaporphine/porphine cartridges (M = Cu(ii), Pd(ii) or Co(ii)), where the metal arrays show unique spin interactions in ESR: in particular, Deltam(s) = 3 for the Cu-Cu-Cu array.     

CH/pi hydrogen bonds determine the selectivity of the Src homology 2 domain to tyrosine phosphotyrosyl peptides: an ab initio fragment molecular orbital study

The CH/pi hydrogen bond is a weak molecular force occurring between CH groups (soft acids) and pi-systems (soft bases), and has been recognized to be important in the interaction of proteins with their specific ligands. For instance, it is well known that Src homology-2 protein (SH2) recognizes its specific pTyr peptide in two key regions, pTyr-binding region and specificity-determining region, by the use of attractive molecular forces, including the CH/pi hydrogen bond. We hypothesized that the CH/pi hydrogen bond plays a key role in determining the selectivity of SH2 proteins, and studied this issue by the ab initio fragment molecular orbital (FMO) method. The FMO calculations were carried out, at the HF/6-31G* and MP2/6-31G* level, for SH2 domains of Src, Grb2, P85alpha(N), Syk, and SAP, in complex with corresponding pTyr peptides. CH/pi hydrogen bonds have in fact been found to be important in stabilizing the structure of the complexes. We conclude that the CH/pi hydrogen bond plays an indispensable role in the recognition of SH2 domains with their specific pTyr peptides, thus playing a vital role in the signal transduction system.     

Defect-Free Synthesis of a Fully π-Conjugated Helical Ladder Polymer and Resolution into a Pair of Enantiomeric Helical Ladders**

Fully π-conjugated ladder polymers with a spiral geometry represent a new class of helical polymers with great potential for organic nanodevices, but there is no precedent for an optically active helical ladder polymer totally composed of achiral units. We now report the defect-free synthesis and resolution of a fully π-conjugated helical ladder polymer with a rigid helical cavity, which has been achieved by quantitative and chemoselective acid-promoted alkyne benzannulations of a rationally designed, random-coil achiral polymer followed by chromatographic enantioseparation. Because of a sufficiently high helix-inversion barrier, the isolated excess one-handed helical ladder polymer with a degree of polymerization of more than 15 showed a strong circular dichroism with a dissymmetry factor of up to 1.7×10⁻² and is thermally stable, maintaining its optical activity in solution even at 100 °C, as well-supported by molecular dynamics simulation.