Oleksandr

Small pseudopeptidic cages show enhanced chloride binding and transport across a lipid membrane at acidic pH. This increases their cytotoxicity towards lung adenocarcinoma cells in environments mimicking those surrounding solid tumors.

Abstract

Acidic microenvironments in solid tumors are a hallmark of cancer. Inspired by that, we designed a family of pseudopeptidic cage‐like anionophores displaying pH‐dependent activity. When protonated, they efficiently bind chloride anions. They also transport chloride through lipid bilayers, with their anionophoric properties improving at acidic pH, suggesting an H⁺/Cl⁻ symport mechanism. NMR studies in DPC micelles demonstrate that the cages bind chloride within the lipid phase. The chloride affinity and the chloride‐exchange rate with the aqueous bulk solution are improved when the pH is lowered. This increases cytotoxicity towards lung adenocarcinoma cells at the pH of the microenvironment of a solid tumor. These properties depend on the nature of the amino‐acid side chains of the cages, which modulate their lipophilicity and interactions with the cell membrane. This paves the way towards using pH as a parameter to control the selectivity of cytotoxic ionophores as anticancer drugs.

Nature, Published online: 10 July 2019; doi:10.1038/s41586-019-1371-4

Prebiotic peptide formation is achieved through chemoselective, high-yielding ligation of α-aminonitriles in water, showing selectivity for α-peptide coupling and tolerance of all proteinogenic amino acid residues.

Organocapture, in which a small heterocycle captures reactive intermediates by reacting with them, thereby suppressing their hydrolysis and modulating their reactivity, could have facilitated the formation of biosynthetic networks in the absence of enzymes on the early earth.

Abstract

Organisms use enzymes to ensure a flow of substrates through biosynthetic pathways. How the earliest form of life established biosynthetic networks and prevented hydrolysis of intermediates without enzymes is unclear. Organocatalysts may have played the role of enzymes. Quantitative analysis of reactions of adenosine 5’‐monophosphate and glycine that produce peptides, pyrophosphates, and RNA chains reveals that organocapture by heterocycles gives hydrolytically stabilized intermediates with balanced reactivity. We determined rate constants for 20 reactions in aqueous solutions containing a carbodiimide and measured product formation with cyanamide as a condensing agent. Organocapture favors reactions that are kinetically slow but productive, and networks, over single transformations. Heterocycles can increase the metabolic efficiency more than two‐fold, with up to 0.6 useful bonds per fuel molecule spent, boosting the efficiency of life‐like reaction systems in the absence of enzymes.

Nonenzymatic template‐directed RNA polymerization using imidazole‐activated monomers has been studied for decades as an experimental model for sequence replication during the origin of life. This Minireview covers recent advances in our understanding of the mechanistic underpinnings of this key reaction, including the discovery of an unexpected covalent intermediate, as revealed by kinetic, structural, and chemical SAR approaches.

Abstract

The emergence of the replication of RNA oligonucleotides was a critical step in the origin of life. An important model for the study of nonenzymatic template copying, which would be a key part of any such pathway, involves the reaction of ribonucleoside‐5′‐phosphorimidazolides with an RNA primer/template complex. The mechanism by which the primer becomes extended by one nucleotide was assumed to be a classical in‐line nucleophilic‐substitution reaction in which the 3′‐hydroxyl of the primer attacks the phosphate of the incoming activated monomer with displacement of the imidazole leaving group. Surprisingly, this simple model has turned out to be incorrect, and the dominant pathway has now been shown to involve the reaction of two activated nucleotides with each other to form a 5′–5′‐imidazolium bridged dinucleotide intermediate. Here we review the discovery of this unexpected intermediate, and the chemical, kinetic, and structural evidence for its role in template copying chemistry.

Nature, Published online: 26 June 2019; doi:10.1038/s41586-019-1331-z

A solution-based living annulative π-extension polymerization technique produces graphene nanoribbons with simultaneous control over their length, width and edges, resulting in the synthesis of graphene nanoribbon block copolymers.

Nature, Published online: 12 June 2019; doi:10.1038/s41586-019-1288-y

This Perspective discusses the challenges associated with the prediction of chemical synthesis, in particular the reaction conditions required for organic transformations, and the role of machine-learning approaches in the prediction process.

Nature Communications, Published online: 23 May 2019; doi:10.1038/s41467-019-10300-2

Molecular switches that can access more than just a few states are difficult to realize. Here, the authors use scanning tunnelling microscopy and spectroscopy to show that a surface-bound Li@C60 endofullerene can be switched between 14 molecular states—distinguished by the location of the Li atom inside the fullerene cage—by resonant tunnelling through the superatom molecular orbitals.

An out‐of‐equilibrium state of a synthetic molecular machine is used to control catalysis. A rotaxane is transiently converted from a catalytically inactive state into an active form by CCl₃CO₂H. Deprotonation by the rotaxane promotes decarboxylation of the acid, thereby returning the system to its original state and stopping catalysis. This process allows temporal control of a coupled biomimetic reduction reaction.

Abstract

We report on catalysis by a fuel‐induced transient state of a synthetic molecular machine. A [2]rotaxane molecular shuttle containing secondary ammonium/amine and thiourea stations is converted between catalytically inactive and active states by pulses of a chemical fuel (trichloroacetic acid), which is itself decomposed by the machine and/or the presence of additional base. The ON‐state of the rotaxane catalyzes the reduction of a nitrostyrene by transfer hydrogenation. By varying the amount of fuel added, the lifetime of the rotaxane ON‐state can be regulated and temporal control of catalysis achieved. The system can be pulsed with chemical fuel several times in succession, with each pulse activating catalysis for a time period determined by the amount of fuel added. Dissipative catalysis by synthetic molecular machines has implications for the future design of networks that feature communication and signaling between the components.

A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids

A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids, Published online: 22 April 2019; doi:10.1038/s41557-019-0255-4

The highly charged phosphodiester chemistry of the natural nucleic acids DNA and RNA has been widely considered to be indispensable for their function as informational molecules. Now, synthetic genetic polymers with an uncharged alkyl phosphonate backbone chemistry have been shown to enable genetic information transfer and evolution.

Closed-loop recycling of plastics enabled by dynamic covalent diketoenamine bonds

Closed-loop recycling of plastics enabled by dynamic covalent diketoenamine bonds, Published online: 22 April 2019; doi:10.1038/s41557-019-0249-2

It is difficult to recover materials for re-manufacturing and re-use from plastics that are compounded with colourants, fillers and flame retardants. Now, it has been shown that alternative plastics based on dynamic covalent poly(diketoenamine)s depolymerize in strong aqueous acids and enable triketone and amine monomers to be isolated and upcycled into new plastics.

Self‐control: Introducing a molecule into a plasmonic nanocavity allows self‐induced electrostatic catalysis to emerge. This approach is also exploited to modify the spin‐crossover transition temperature of metal complexes, the prime example of molecular switches, paving the way towards single‐molecule chemical control.

Abstract

The potential of strong interactions between light and matter remains to be further explored within a chemical context. Towards this end herein we study the electromagnetic interaction between molecules and plasmonic nanocavities. By means of electronic structure calculations, we show that self‐induced catalysis emerges without any external stimuli through the interaction of the molecular permanent and fluctuating dipole moments with the plasmonic cavity modes. We also exploit this scheme to modify the transition temperature T _1/2 of spin‐crossover complexes as an example of how strong light–matter interactions can ultimately be used to control a materials responses.

Probing by autocatalysis: A new molecular autocatalytic reaction scheme based on a H₂O₂‐mediated deprotection of a boronate ester probe into a redox cycling compound is described (see scheme representing the autocatalytic process based on the cross‐activation of two catalytic loops), generating an exponential signal gain in the presence of O₂ and a reducing agent or enzyme.

Abstract

Herein, a new molecular autocatalytic reaction scheme based on a H₂O₂‐mediated deprotection of a boronate ester probe into a redox cycling compound is described, generating an exponential signal gain in the presence of O₂ and a reducing agent or enzyme. For such a purpose, new chemosensing probes built around a naphthoquinone/naphthohydroquinone redox‐active core, masked by a self‐immolative boronic ester protecting group, were designed. With these probes, typical autocatalytic kinetic traces with characteristic lags and exponential phases were obtained by using either UV/Visible or fluorescence optical detection, or by using electrochemical monitoring. Detection of concentrations as low as 0.5 μm H₂O₂ and 0.5 nm of a naphthoquinone derivative were achieved in a relatively short time (<1 h). From kinetic analysis of the two cross‐activated catalytic loops associated with the autocatalysis, the key parameters governing the autocatalytic reaction network were determined, indirectly showing that the analytical performances are currently limited by the slow nonspecific self‐deprotection of boronate probes. Collectively, the present results demonstrate the potential of this new exponential molecular amplification strategy, which, owing to its generic nature and modularity, is quite promising for coupling to a wide range of bioassays involving H₂O₂ or redox cycling compounds, or for use as a new building block in the development of more complex chemical reaction networks.

Two high‐yielding strategies are used to prepare nanohoop [2]rotaxanes, which owing to the π‐rich macrocycle are highly emissive. Metal coordination leads to molecular shuttling and modulates fluorescence in both organic and aqueous conditions. A self‐immolative [2]rotaxane was designed that self‐destructs in the presence of an analyte, eliciting a strong fluorescent turn‐on response, serving as proof‐of‐concept for a molecular sensor.

Abstract

The unique optoelectronic properties and smooth, rigid pores of macrocycles with radially oriented π systems render them fascinating candidates for the design of novel mechanically interlocked molecules with new properties. Two high‐yielding strategies are used to prepare nanohoop [2]rotaxanes, which owing to the π‐rich macrocycle are highly emissive. Then, metal coordination, an intrinsic property afforded by the resulting mechanical bond, can lead to molecular shuttling as well as modulate the observed fluorescence in both organic and aqueous conditions. Inspired by these findings, a self‐immolative [2]rotaxane was then designed that self‐destructs in the presence of an analyte, eliciting a strong fluorescent turn‐on response, serving as proof‐of‐concept for a new type of molecular sensing material. More broadly, this work highlights the conceptual advantages of combining compact π‐rich macrocyclic frameworks with mechanical bonds formed via active‐template syntheses.

Selective anion binding in water represents a significant challenge for artificial receptors operating by non-covalent interactions. In this paper, we report two easily accessible, highly symmetric, and compact tetraurea macrocycles that stack to form columnar aggregates with an electropositive interior for anion binding. Micromolar affinity and selective chloride binding have been achieved in 60% water/acetonitrile because of urea-binding sites being located within a solvent-excluding microenvironment afforded by macrocycle aggregation.

Nonenzymatic template‐directed RNA polymerization using imidazole‐activated monomers has been studied for decades as an experimental model for sequence replication during the origin of life. This Minireview covers recent advances in our understanding of the mechanistic underpinnings of this key reaction, including the discovery of an unexpected covalent intermediate, as revealed by kinetic, structural, and chemical SAR approaches.

Abstract

The emergence of the replication of RNA oligonucleotides was a critical step in the origin of life. An important model for the study of nonenzymatic template copying, which would be a key part of any such pathway, involves the reaction of ribonucleoside‐5′‐phosphorimidazolides with an RNA primer/template complex. The mechanism by which the primer becomes extended by one nucleotide was assumed to be a classical in‐line nucleophilic‐substitution reaction in which the 3′‐hydroxyl of the primer attacks the phosphate of the incoming activated monomer with displacement of the imidazole leaving group. Surprisingly, this simple model has turned out to be incorrect, and the dominant pathway has now been shown to involve the reaction of two activated nucleotides with each other to form a 5′–5′‐imidazolium bridged dinucleotide intermediate. Here we review the discovery of this unexpected intermediate, and the chemical, kinetic, and structural evidence for its role in template copying chemistry.

The molecular Lego movie

The molecular Lego movie, Published online: 22 March 2019; doi:10.1038/s41557-019-0243-8

The structure of self-assembled aggregates depends critically on the manner in which the building blocks organize themselves. Now, such a self-assembly process has been monitored in situ using liquid-phase transition electron microscopy, unveiling a new pathway of vesicle formation.