Switching between Nonisoenergetic Dynamic Covalent Reactions Using Host-Guest Chemistry.

CO2 reacts with simple amines in the presence of water to generate dynamic combinatorial libraries of majority (i.e., ammonium carbamates) and minority (i.e., ammonium carbonates) nonisoenergetic covalent adducts. Over the past two decades, our laboratory has reported on a new class of cavitands, namely, dyn[n]arenes, from which a polyanionic macrocycle is a highly efficient receptor for linear polyammoniums that forms [2]pseudorotaxanes in water at neutral pH. Herein, we demonstrate that the formation of [2]pseudorotaxanes shifts the equilibrium of CO2 capture by polyamines in water toward the quasi-exclusive formation of carbonate adducts, providing the first example of a switch between two competitive and reversible covalent processes triggered by host-guest interactions. In addition, this supramolecular approach to CO2 capture exhibits enhanced capture efficiency by increasing the state of protonation of complexed vs uncomplexed polyamines. Altogether, we report here that a templating approach can divert the outcome of two reversible covalent chemistries involving nucleophilic additions and acid-base reactions, challenging therefore the common knowledge that noncovalent and covalent bonds operate in separate energy frames.

Everything You Always Wanted to Know about Poly-l-lysine Dendrigrafts (But Were Afraid to Ask).

Less than a decade ago, dendrigrafts of poly-l-lysine (DGLs) joined the family of polycationic dendritic macromolecules. Resulting from the iterative polycondensation of an N-carboxyanhydride in water, four generations of the dendrigraft can be obtained on a multigram scale and without chromatographic purification. DGLs share features with both dendrimers and hyperbranched polymers, but turned out to have unique biophysical and bioactive properties. The macromolecules-in their native form or functionalized-have been extensively characterized by various analytical and computational methods, and have already found numerous applications in the biomedical field, such as drug and gene delivery, biomaterials, tissue engineering, bioimaging, and biosensing. Despite a growing interest for DGLs, there is still plenty of room for further exciting developments that could result from a better exposure of these macromolecules, which is the ambition of this short review.

Digitizing Poly-l-lysine Dendrigrafts: From Experimental Data to Molecular Dynamics Simulations.

Despite the growing use of poly-l-lysine dendrigrafts in biomedical applications, a deeper understanding of the molecular level properties of these macromolecules is missing. Herein, we report a simple methodology for the construction of three-dimensional structures of poly-l-lysine dendrigrafts and the subsequent investigation of their structural features using microsecond molecular dynamics simulations. This methodology relies on the encoding of the polymers' experimental characterizations (i.e., composition, degrees of polymerization, branching ratios, charges) into alphanumeric strings that are readable by the Amber simulation package. Such an original approach opens avenues toward the in silico exploration of dendrigrafts and hyperbranched polymers.

On-Demand Cyclophanes: Substituent-Directed Self-Assembling, Folding, and Binding.

A family of p-cyclophanes based on bis- or tetrafunctionalized 1,4-bisthiophenol units linked by disulfide bridges was obtained by self-assembly on a gram scale and without any chromatographic purification. The nature of the functionalities borne by these so-called dyn[4]arenes plays a crucial role on their structural features as well as their molecular recognition abilities. Tuning these functions on demand yields tailored receptors for cations, anions, or zwitterions in organic or aqueous media.

Self-assembly of achiral building blocks into chiral cyclophanes using non-directional interactions.

The diastereoselective assembly of achiral constituents through a single spontaneous process into complex covalent architectures bearing multiple stereogenic elements still remains a challenge for synthetic chemists. Here, we show that such an extreme level of control can be achieved by implementing stereo-electronic information on synthetic organic building blocks and templates and that non-directional interactions (i.e., electrostatic and steric interactions) can transfer this information to deliver, after self-assembly, high-molecular weight macrocyclic species carrying up to 16 stereogenic elements. Beyond the field of supramolecular chemistry, this proof of concept should stimulate the on-demand production of highly structured polyfunctional architectures.

Mid-infrared Shack-Hartmann wavefront sensor fully cryogenic using extended source for endoatmospheric applications.

Adaptive optics provide real-time compensation for atmospheric turbulence. The correction quality relies on a key element: the wavefront sensor. We have designed an adaptive optics system in the mid-infrared range providing high spatial resolution for ground-to-air applications, integrating a Shack-Hartmann infrared wavefront sensor operating on an extended source. This paper describes and justifies the design of the infrared wavefront sensor, while defining and characterizing the Shack-Hartmann wavefront sensor camera. Performance and illustration of field tests are also reported.

The dark side of disulfide-based dynamic combinatorial chemistry.

During the last two decades, disulfide-based dynamic combinatorial chemistry has been extensively used in the field of molecular recognition to deliver artificial receptors for molecules of biological interest. Commonly, the nature of library members and their relative amounts are provided from HPLC-MS analysis of the libraries, allowing the identification of potential binders for a target (bio)molecule. By re-investigating dynamic combinatorial libraries generated from a simple 2,5-dicarboxy-1,4-dithiophenol building block in water, we herein demonstrated that multiple analytical tools were actually necessary in order to comprehensively describe the libraries in terms of size, stereochemistry, affinity, selectivity, and finally to get a true grasp on the different phenomena at work within dynamic combinatorial systems.

RNA relics and origin of life.

A number of small RNA sequences, located in different non-coding sequences and highly preserved across the tree of life, have been suggested to be molecular fossils, of ancient (and possibly primordial) origin. On the other hand, recent years have revealed the existence of ubiquitous roles for small RNA sequences in modern organisms, in functions ranging from cell regulation to antiviral activity. We propose that a single thread can be followed from the beginning of life in RNA structures selected only for stability reasons through the RNA relics and up to the current coevolution of RNA sequences; such an understanding would shed light both on the history and on the present development of the RNA machinery and interactions. After presenting the evidence (by comparing their sequences) that points toward a common thread, we discuss a scenario of genome coevolution (with emphasis on viral infectious processes) and finally propose a plan for the reevaluation of the stereochemical theory of the genetic code; we claim that it may still be relevant, and not only for understanding the origin of life, but also for a comprehensive picture of regulation in present-day cells.

Lost in (Clinical) Translation: Recent Advances in Heparin Neutralization and Monitoring.

The heparin family, which includes unfractionated heparin, low-molecular heparin, and fondaparinux, is a class of drugs clinically used as intravenous blood thinners. To date, issues related to both the reversal of anticoagulation and the blood level determination of the anticoagulant at the point-of-care remain: while the only U.S. Food and Drug Administration (FDA) approved antidote for heparin displays serious efficacy and safety drawbacks, the current assays for heparin monitoring are indirect measurements subject to their own limitations and variations. Herein, we provide an update on the numerous recent chemical approaches to tackle these issues, from which it is clear that some new antidotes and sensors for heparin certainly have the potential to exceed current clinical standards. This review aims to review a field that requires close collaborations between physicians, biologists, and chemists in order to foster advances toward clinical translation.

Dendrigraft of Poly-l-lysine as a Promising Candidate To Reverse Heparin-based Anticoagulants in Clinical Settings.

By using a combination of experimental and computational experiments, we demonstrated that a second-generation dendrigraft of poly-l-lysine neutralizes the anticoagulant activity of unfractionated heparin, low-molecular-weight heparin, and fondaparinux more efficiently than protamine does in human plasma, making this synthetic polymer a promising surrogate of this problematic protein in clinical settings.

Wetting the lock and key enthalpically favours polyelectrolyte binding.

By using a combination of readily accessible experimental and computational experiments in water, we explored the factors governing the association between polyanionic dyn[4]arene and a series of α,ω-alkyldiammonium ions of increasing chain length. We found that the lock-and-key concept based on the best match between the apolar and polar regions of the molecular partners failed to explain the observed selectivities. Instead, the dissection of the energetic and structural contributions demonstrated that the binding events were actually guided by two crucial solvent-related phenomena as the chain length of the guest increases: the expected decrease of the enthalpic cost of guest desolvation and the unexpected increase of the favourable enthalpy of complex solvation. By bringing to light the decisive enthalpic impact of complex solvation during the binding of polyelectrolytes by inclusion, this study may provide a missing piece to a puzzle that one day could display the global picture of molecular recognition in water.

Enantioselective [1,2]-Stevens rearrangement of quaternary ammonium salts. A mechanistic evaluation.

Using a supramolecular asymmetric ion pairing strategy, an enantioselective [1,2]-Stevens is feasible on substrates devoid of stereogenic quaternary nitrogen atoms.

Diastereoselective Synthesis of a Dyn[3]arene with Distinct Binding Behaviors toward Linear Biogenic Polyamines.

The extension of the family of dyn[ n]arenes toward a three-membered macrocycle is reported. Through a templated approach, a single diastereoisomer of a dyn[3]arene that bears six carboxyl groups could be isolated by precipitation in 59-63% yield and excellent purity (≥95%). A combination of experimental and computational experiments in water at physiological pH revealed that the macrocycle could bind parent biogenic polyamines with a unique diversity of surface-binding modes. Whereas no binding event could be accurately measured with 1,3-diaminopropane, spermidine formed a classical stoichiometric complex with the dyn[3]arene in the millimolar concentration range. On the other hand, the data obtained for spermine could only be attributed to a more complex binding event with the formation of a 2:1 complex at high [host]/[guest] ratios and redistribution toward a 1:1 complex upon further addition of guest.

Chirality sensing and discrimination of lysine derivatives in water with a dyn[4]arene.

The asymmetric deformation of a dyn[4]arene upon the binding of various lysine derivatives leads to distinct induced circular dichroism outputs in buffered water, which can be exploited not only for the determination of their enantiomeric excesses, but also for their classification by linear discriminant analysis.

Expanding diversity in dynamic combinatorial libraries: simultaneous exchange of disulfide and thioester linkages.

Dynamic combinatorial libraries have been prepared which feature two simultaneous covalent exchange reactions in aqueous solution at neutral pH. This allows for diversity, not only of the subunits that are linked, but also of the linkage itself.

A KISS (keep it simple, sensor) array for glycosaminoglycans.

Herein, we demonstrate that it is possible to design a sensor array with one multivalent cationic receptor (a dendrigraft of lysine) and one fluorescent anionic indicator (a fluorescein-labeled peptide). Depending on the loading of the indicator on the receptor, negatively charged glycosaminoglycans (GAGs) induce a positive or negative variation of the fluorescent signal as they displace the indicators from the receptor or they compact the indicators on the receptor's surface, respectively. This unique strategy allows not only the blind identification of pure GAGs with a level of accuracy of 100%, but also the differentiation of mixtures.

Monitoring clinical levels of heparin in human blood samples with an indicator-displacement assay.

We report that a "tree-like" polymer of lysine is able to form a multi-ligand complex with a fluorescently labelled peptide, leading to the almost complete extinction of the optical signal that can be restored upon the introduction of heparin. This simple system allows, for the first time, the turn-ON fluorescent sensing of the anticoagulant in human blood at clinically relevant levels.

Conformational preference and configurational control of highly symmetric spirobi[dibenzazepinium] cation.

[formula: see text] Stereodynamics were detected in solution for salts of the simple spirobi[dibenzazepinium] cation in favor of the homochiral (D2) conformer as evidenced by chiral TRISPHAT and BINPHAT counterions; asymmetric induction was furthermore observed in 1H and 15N NMR spectroscopy.

One-step stereoselective synthesis and NMR chiral shift properties of a novel hexacoordinated phosphorus cation.

[reaction: see text] Tropolone, binol, and PCl(5) react in CH(2)Cl(2) at reflux to generate in one step a novel C(2)-symmetric hexacoordinated phosphorus cation of configuration controlled by the binol ligand. It behaves as an efficient NMR chiral shift agent for chiral anionic phosphate and borate anions.

Efficient NMR enantiodifferentiation of chiral quats with BINPHAT anion.

Hexacoordinated phosphorus BINPHAT anion is an efficient NMR chiral shift agent for quaternary ammonium cations (quats) leading to large separations (DeltaDeltadelta up to 0.29 ppm) of the proton signals of the enantiomers. [reaction: see text]