Fibrils formed by proteins are vital components for cells. However, selective formation of xenogenous nanofibrils of small molecules on mammalian cells has yet to be observed. Here we report an unexpected observation of hydrogel/nanonets of a small D-peptide derivative in pericellular space. Surface and secretory phosphatases dephosphorylate a precursor of a hydrogelator to trigger the self-assembly of the hydrogelator and to result in pericellular hydrogel/nanonets selectively around the cancer cells that overexpress phosphatases. Cell based assays confirm that the pericellular hydrogel/nanonets block cellular mass exchange to induce apoptosis of cancer cells, including multidrug-resistance (MDR) cancer cells, MES-SA/Dx5. Pericellular hydrogel/nanonets of small molecules to exhibit distinct functions illustrates a fundamentally new way to engineer molecular assemblies spatiotemporally in cellular microenvironment for inhibiting cancer cell growth and even metastasis.
pericellular; hydrogel; nanofibrils; cancer; inhibition
Optical-resolution photoacoustic microscopy (OR-PAM) is an imaging modality with superb penetration depth and excellent absorption contrast. Here we demonstrate, for the first time, that this technique can advance quantitative analysis of conventional chromogenic histochemistry. Because OR-PAM can quantify the absorption contrast at different wavelengths, it is feasible to spectrally resolve the specific biomolecules involved in a staining color. Furthermore, the tomographic capability of OR-PAM allows for non-invasive volumetric imaging of a thick sample without microtoming it. By immunostaining the sample with different chromogenic agents, we further demonstrated the ability of OP-PAM to resolve different types of cells in a co-culture sample with imaging depths up to 1 mm. Taken together, the integration of OR-PAM with (immuno)histochemistry offers a simple and versatile technique with broad applications in cell biology, pathology, tissue engineering, and related biomedical studies.
photoacoustic microscopy; biomedical imaging; histochemistry; cell biology; tissue engineering
The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure-activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide-based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin-binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and stem cell fate.
anthrax toxin; multivalency in; periodic polypeptides in; protein engineering in; structure-activity relationships
We experimentally monitored, at the single-molecule level, the competition among reverse transcription, exponential amplification (RT-LAMP), and linear degradation (restriction enzymes) starting with Hepatitis C viral RNA molecules. We found significant heterogeneity in the rate of single-molecule amplification; introduction of the restriction enzymes affected both the rate and the “fate” (the binary outcome) of single-molecule amplification. While end-point digital measurements were primarily sensitive to changes in fate, the bulk real-time kinetic measurements were dominated by the rate of amplification of the earliest molecules, and not sensitive to fate of the rest of the molecules. We showed how this competition of reactions can be used for rapid HCV genotyping with either digital or bulk readout. This work advances our understanding of single-molecule dynamics in reaction networks and may help bring genotyping capabilities out of clinical labs and into limited-resource settings.
analytical methods; genotyping; global health; hepatitis C; single-molecule studies
Traditional micelle self-assembly is driven by the association of hydrophobic segments of amphiphilic molecules forming distinctive core-shell nanostructures in water. Here we report a surprising chaotropic anion-induced micellization of cationic ammonium-containing block copolymers. The resulting micelle nanoparticle consists of a large number of ion pairs (~60,000 in each hydrophobic core). Unlike chaotropic anions (e.g. ClO4−), kosmotropic anions (e.g. SO42−) were not able to induce micelle formation. A positive cooperativity was observed during micellization, where only a 3-fold change in ClO4− concentration was necessary for micelle formation, similar to our previously reported ultra-pH responsive behaviour. This unique ion pair-containing micelle provides a useful model system to study the complex interplay of non-covalent interactions (e.g. electrostatic, van der Waals and hydrophobic forces) during micelle self-assembly. This may lead to new fundamental insights and strategies for the future design of cooperative systems in molecular sensing and drug delivery applications.
micelle self-assembly; anti-Hofmeister effect; amphiphilic block copolymers; ion pairs
chirality; interfaces; liquid crystals; peptides; supramolecular organization
We report on a therapeutic approach using thermo-responsive multi-fingered drug eluting devices. These therapeutic grippers referred to as theragrippers are shaped using photolithographic patterning and are composed of rigid poly(propylene fumarate) segments and stimuli responsive poly (N-isopropylacrylamide-co-acrylic acid) hinges. They close above 32°C allowing them to spontaneously grip onto tissue when introduced from a cold state into the body. Due to porosity in the grippers, theragrippers could also be loaded with fluorescent dyes and commercial drugs such as mesalamine and doxorubicin, which eluted from the grippers for up to seven days with first order release kinetics. In an in vitro model, theragrippers enhanced delivery of doxorubicin as compared to a control patch. We also released theragrippers into a live pig and visualized release of dye in the stomach. The design of such tissue gripping drug delivery devices offers an effective strategy for sustained release of drugs with immediate applicability in the gastrointestinal tract.
Drug Delivery; Hydrogels; Actuators; Polymers; Diffusion; Soft-Robotics
adsorption free energy; amelogenin; force spectroscopy; hydroxyapatite; molecular dynamics
A copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes provides di- and trisubstituted allenes. This extremely mild and rapid transformation is highly tolerant of several functional groups.
allenes; carbenes; copper; diazo compounds; flow chemistry
Ground-state molecular vibrations can be hybridized through strong coupling with the vacuum field of a cavity optical mode in the infrared region, leading to the formation of two new coherent vibro-polariton states. The spontaneous Raman scattering from such hybridized light–matter states was studied, showing that the collective Rabi splitting occurs at the level of a single selected bond. Moreover, the coherent nature of the vibro-polariton states boosts the Raman scattering cross-section by two to three orders of magnitude, revealing a new enhancement mechanism as a result of vibrational strong coupling. This observation has fundamental consequences for the understanding of light-molecule strong coupling and for molecular science.
optical cavity; Raman scattering; strong coupling; vibrations; vibro-polariton states
Half a century after Schill and Lüttringhaus carried out the first directed synthesis of a catenane, a plethora of strategies now exist for the construction of molecular Hopf links (singly interlocked rings), the simplest type of catenane. The precision and effectiveness with which suitable templates and/or noncovalent interactions can arrange building blocks has also enabled the synthesis of intricate and often beautiful higher order interlocked systems, including Solomon links, Borromean rings, and a Star of David catenane. This Review outlines the diverse strategies that exist for synthesizing catenanes in the 21st century and examines their emerging applications and the challenges that still exist for the synthesis of more complex topologies.
catenanes; interlocked molecules; links; supramolecular chemistry; template synthesis
The diuranium(III) compound [UN′′2]2(μ-η6:η6-C6H6) (N′′=N(SiMe3)2) has been studied using variable, high-pressure single-crystal X-ray crystallography, and density functional theory. In this compound, the low-coordinate metal cations are coupled through π- and δ-symmetric arene overlap and show close metal=CH contacts with the flexible methyl CH groups of the sterically encumbered amido ligands. The metal–metal separation decreases with increasing pressure, but the most significant structural changes are to the close contacts between ligand CH bonds and the U centers. Although the interatomic distances are suggestive of agostic-type interactions between the U and ligand peripheral CH groups, QTAIM (quantum theory of atoms-in-molecules) computational analysis suggests that there is no such interaction at ambient pressure. However, QTAIM and NBO analyses indicate that the interaction becomes agostic at 3.2 GPa.
actinides; density functional calculations; high-pressure chemistry; uranium; X-ray diffraction
We present a new approach for determining the strength of the dipolar solute-induced reaction field, along with the ground- and excited-state electrostatic dipole moments and polarizability of a solvated chromophore, using exclusively one-photon and two-photon absorption measurements. We verify the approach on two benchmark chromophores N,N-dimethyl-6-propionyl-2-naphthylamine (prodan) and coumarin 153 (C153) in a series of toluene/dimethyl sulfoxide (DMSO) mixtures and find that the experimental values show good quantitative agreement with literature and our quantum-chemical calculations. Our results indicate that the reaction field varies in a surprisingly broad range, 0–107 V cm−1, and that at close proximity, on the order of the chromophore radius, the effective dielectric constant of the solute–solvent system displays a unique functional dependence on the bulk dielectric constant, offering new insight into the close-range molecular interaction.
intramolecular charge transfer; molecular reaction field; solvatochromism; solvent effects; two-photon absorption spectroscopy
Defect engineering in metal–organic frameworks (MOFs) is an exciting concept for tailoring material properties, which opens up novel opportunities not only in sorption and catalysis, but also in controlling more challenging physical characteristics such as band gap as well as magnetic and electrical/conductive properties. It is challenging to structurally characterize the inherent or intentionally created defects of various types, and there have so far been few efforts to comprehensively discuss these issues. Based on selected reports spanning the last decades, this Review closes that gap by providing both a concise overview of defects in MOFs, or more broadly coordination network compounds (CNCs), including their classification and characterization, together with the (potential) applications of defective CNCs/MOFs. Moreover, we will highlight important aspects of “defect-engineering” concepts applied for CNCs, also in comparison with relevant solid materials such as zeolites or COFs. Finally, we discuss the future potential of defect-engineered CNCs.
coordination chemistry; defects engineering; heterogeneity; metal–organic frameworks; porous materials
Dodecaborate anions of the type B12X122− and B12X11Y2− (X=H, Cl, Br, I and Y=OH, SH, NH3+, NR3+) form strong (Ka up to 106 L mol−1, for B12Br122−) inclusion complexes with γ-cyclodextrin (γ-CD). The micromolar affinities reached are the highest known for this native CD. The complexation exhibits highly negative enthalpies (up to −25 kcal mol−1) and entropies (TΔS up to −18.4 kcal mol−1, both for B12I122−), which position these guests at the bottom end of the well-known enthalpy-entropy correlation for CDs. The high driving force can be traced back to a chaotropic effect, according to which chaotropic anions have an intrinsic affinity to hydrophobic cavities in aqueous solution. In line with this argument, salting-in effects revealed dodecaborates as superchaotropic dianions.
boron clusters; cyclodextrins; Hofmeister series; host–guest complexes; supramolecular chemistry
A highly-ordered 3D covalent fullerene framework is presented with a structure based on octahedrally functionalized fullerene building blocks in which every fullerene is separated from the next by six functional groups and whose mesoporosity is controlled by cooperative self-assembly with a liquid-crystalline block copolymer. The new fullerene-framework material was obtained in the form of supported films by spin coating the synthesis solution directly on glass or silicon substrates, followed by a heat treatment. The fullerene building blocks coassemble with a liquid-crystalline block copolymer to produce a highly ordered covalent fullerene framework with orthorhombic Fmmm symmetry, accessible 7.5 nm pores, and high surface area, as revealed by gas adsorption, NMR spectroscopy, small-angle X-ray scattering (SAXS), and TEM. We also note that the 3D covalent fullerene framework exhibits a dielectric constant significantly lower than that of the nonporous precursor material.
covalent frameworks; electron mobility; fullerenes; mesoporous materials; self-assembly
A π-conjugated twelve-porphyrin tube is synthesized in 32 % yield by a template-directed coupling reaction that joins together six porphyrin dimers, forming twelve new C=C bonds. The nanotube has two bound templates, enclosing an internal volume of approximately 4.5 nm3. Its UV/Vis/NIR absorption and fluorescence spectra resemble those of a previously reported six-porphyrin ring, but are red-shifted by approximately 300 cm−1, reflecting increased conjugation. Ultrafast fluorescence spectroscopy demonstrates extensive excited-state delocalization. Transfer of electronic excitation from an initially formed state polarized in the direction of the nanotube axis (z axis) to an excited state polarized in the xy plane occurs within 200 fs, resulting in a negative fluorescence anisotropy on excitation at 742 nm.
fluorescence anisotropy; nanotubes; polycycles; synthetic methods; template synthesis
The G-quadruplex (G4) is a non-canonical nucleic acid structure which regulates important cellular processes. RNA G4s have recently been shown to exist in human cells and be biologically significant. Described herein is a new approach to detect and map RNA G4s in cellular transcripts. This method exploits the specific control of RNA G4–cation and RNA G4–ligand interactions during reverse transcription, by using a selective reverse transcriptase to monitor RNA G4-mediated reverse transcriptase stalling (RTS) events. Importantly, a ligation-amplification strategy is coupled with RTS, and enables detection and mapping of G4s in important, low-abundance cellular RNAs. Strong evidence is provided for G4 formation in full-length cellular human telomerase RNA, offering important insights into its cellular function.
cations; G-quadruplexes; ligand effects; reverse transcription; RNA structures; telomerase RNA
Rate and equilibrium constants for the reaction between N-aryl triazolium N-heterocyclic carbene (NHC) precatalysts and substituted benzaldehyde derivatives to form 3-(hydroxybenzyl)azolium adducts under both catalytic and stoichiometric conditions have been measured. Kinetic analysis and reaction profile fitting of both the forward and reverse reactions, plus onwards reaction to the Breslow intermediate, demonstrate the remarkable effect of the benzaldehyde 2-substituent in these reactions and provide insight into the chemoselectivity of cross-benzoin reactions.
2-substituent effect; kinetics; mechanistic studies; N-heterocyclic carbenes; organocatalysis
Protein design will ultimately allow for the creation of artificial enzymes with novel functions and unprecedented stability. To test our current mastery of nature’s approach to catalysis, a Zn(II) metalloenzyme was prepared using de novo design. α3DH3 folds into a stable single-stranded three-helix bundle and binds Zn(II) with high affinity using His3O coordination. The resulting metalloenzyme catalyzes the hydration of CO2 better than any small molecule model of carbonic anhydrase and with an efficiency within 1400-fold of the fastest carbonic anhydrase isoform, CAII, and 11-fold of CAIII.
de novo design; metalloenzyme; protein design; carbonic anhydrase; zinc enzyme
An unprecedented gold-catalyzed diastereoselective cycloisomerization of 1,6-diynes bearing an alkylidene cyclopropane moiety has been developed. This methodology enables rapid access to a variety of 1,2-trimethylenenorbornanes, important building blocks in the preparations of abiotic and sesquiterpene core structures.
gold catalysis; cycloisomerization; 1, 6-diyne; cyclopropylidene; synthetic methods
Organic chemists and metabolic engineers use largely orthogonal technologies to construct essential small molecules like pharmaceuticals and commodity chemicals. While chemists have leveraged the unique capabilities of biological catalysts for small molecule production, metabolic engineers have not likewise integrated reactions from organic synthesis with the metabolism of living organisms. Here we report a method for alkene hydrogenation that utilizes a palladium catalyst and hydrogen gas generated directly by a living microorganism. This biocompatible transformation, which requires both catalyst and microbe and can be used on a preparative scale, represents a new strategy for chemical synthesis that combines organic chemistry and metabolic engineering.
biocompatible chemistry; hydrogenation; metabolism; palladium; catalysis
We report a stereodivergent, asymmetric total synthesis of (−)-clusianone in six steps from commercial materials. We implement a challenging cationic cyclization forging a bond between two sterically encumbered quaternary carbons. Mechanistic studies point to the unique ability of formic acid to bring about successful cyclization to the clusianone framework.
PPAPs; natural products; cationic cyclization; alkylative dearomatization; formic acid
on-wire lithography; molecular electronics; nanowire; click chemistry; SERS
bond graphs; bond order; bond valence; Lewis formulas; oxidation state