Control of Dynamic Chirality in Donor-Acceptor Fluorophores.

Very recently, the control of dynamic chirality has emerged as a powerful strategy to design chiral functional materials. In this context, we describe herein a molecular design in which a tethered configurationally stable binaphthyl chiral unit efficiently controls the dynamic chirality of donor-acceptor fluorophores, involving diverse indolocarbazoles as electron donors and terephthalonitrile as an electron acceptor. The high conformational discrimination in such a molecular system suggested by density functional theory calculations is experimentally probed using electronic and vibrational circular dichroism and confirmed by the crystallization of these chiral molecules in gel and their single crystal X-ray diffraction analysis. In addition to extending the scope of dynamic chirality control to donor-acceptor fluorophores, this work also highlights the positive effect of the configurationally stable chiral inductor on the magnitude of the dissymmetry factors of the active dynamically chiral fluorophores, both in ground and excited states, through chiral perturbation.

Deuteration and Tritiation of Pharmaceuticals by Non-Directed Palladium-Catalyzed C-H Activation in Heavy and Super-Heavy Water.

Deuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non-directed homogeneous Pd-catalysis. Aromatic C-H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D2O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non-directed homogeneous Pd catalysis for H/T exchange on three different pharmaceuticals by using T2O as isotopic source, demonstrating the applicability to the synthesis of radiotracers.

CinNapht AIE(E)gens for selective imaging of lipid droplets.

This article describes the synthesis and photophysical properties of Aggregation-Induced Emission (enhancement) luminogens derivated from CinNaphts dyes. These fluorophores can be obtained in good yields in a single SNAr step of a fluorinated CinNapht derivative by incorporating hindered aromatic amines. They exhibit AIE(E) behavior associated with solid-state fluorescence covering an emission range from 563 to 722 nm. One carbazole derivative demonstrates a remarkable efficiency in imaging lipid droplets in living cells through an original photophysical mechanism.

Stable π-Extended Thio[7]helicene-Based Diradical with Predominant Through-Space Spin-Spin Coupling.

In this work, a novel π-extended thio[7]helicene scaffold was synthesized, where the α-position of the thiophene unit could be functionalized with bulky phenoxy radicals after considerable synthetic attempts. This open-shell helical diradical, ET7H-R, possesses high stability in the air, nontrivial π conjugation, persistent chirality, and a high diradical character (y0 of 0.998). The key feature is a predominant through-space spin-spin coupling (TSC) between two radicals at the helical terminals. Variable-temperature continuous-wave electron spin resonance (cw-ESR) and superconducting quantum interference device (SQUID) magnetometry in the solid state reveal a singlet ground state with a nearly degenerate triplet state of ET7H-R. These results highlight the significance of a stable helical diradicaloid as a promising platform for investigating intramolecular TSCs.

Unprecedented perspectives on the application of CinNapht fluorophores provided by a "late-stage" functionalization strategy.

A simple and easy-to-implement process based on a nucleophilic aromatic substitution reaction with a wide variety of nucleophiles on a fluorinated CinNapht is described. This process has the key advantage of introducing multiple functionalities at a very late stage, thus providing access to new applications including the synthesis of photostable and bioconjugatable large Stokes shift red emitting dyes and selective organelle imaging agents, as well as AIEE-based wash-free lipid droplet imaging in live cells with high signal-to-noise ratio. The synthesis of bench-stable CinNapht-F has been optimized and can be reproduced on a large scale, making it an easy-to-store starting material that can be used at will to prepare new molecular imaging tools.

Chiral perturbation on single benzene-based fluorophores: A structure/(chir)optical activity relationship study.

In this paper, we describe the synthesis and the (chir)optical properties of a novel series of circularly polarized luminescent emitters. These molecules involve a compact single benzene-based donor-acceptor fluorophore composed of two cyclic alkylamines as electron donors and a phthalonitrile moiety as electron acceptor linked to a configurationally stable BINOL acting as a chiral perturbation unit. These new compounds display fair quantum yields (up to 66%) with emission maxima around 500 nm in toluene solutions, and the study of their chiroptical properties has shown that the cyclic alkylamine's ring size affects significantly the luminescence dissymmetry factors, reaching 2.2 × 10-3 for the larger cyclic alkylamine moieties.

A C-H activation-based enantioselective synthesis of lower carbo[n]helicenes.

The three-dimensional structure of carbohelicenes has fascinated generations of molecular chemists and has been exploited in a wide range of applications. Their strong circularly polarized luminescence has attracted considerable attention in recent years due to promising applications in new optical materials. Although the enantioselective synthesis of fused carbo- and heterohelicenes has been achieved, a direct catalytic enantioselective method allowing the synthesis of lower, non-fused carbo[n]helicenes (n = 4-6) is still lacking. We report here that Pd-catalysed enantioselective C-H arylation in the presence of a unique bifunctional phosphine-carboxylate ligand provides a simple and general access to these lower carbo[n]helicenes. Computational mechanistic studies indicate that both the C-H activation and reductive elimination steps contribute to the overall enantioselectivity. The observed enantio-induction seems to arise from a combination of non-covalent interactions and steric repulsion between the substrate and ligand during the two key reductive elimination steps. The photophysical and chiroptical properties of the synthesized scalemic [n]helicenes have been systematically studied.

Synthesis, structural characterization, and chiroptical properties of planarly and axially chiral boranils.

2-Amino[2.2]paracyclophane reacts with salicylaldehyde or 2-hydroxyacetophenone to yield imines that then give access to a new series of boranils (8b-d) upon complexation with BF2 . These novel boron-containing compounds display both planar and axial chiralities and were examined experimentally and computationally. In particular, their photophysical and chiroptical properties were studied and compared to newly prepared, simpler boranils (9a-d) exhibiting axial chirality only. Less sophisticated chiral architectures were shown to demonstrate overall stronger circularly polarized luminescence (CPL) activity.

Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes.

Bioorthogonal click-and-release reactions are powerful tools for chemical biology, allowing, for example, the selective release of drugs in biological media, including inside animals. Here, we developed two new families of iminosydnone mesoionic reactants that allow a bioorthogonal release of electrophilic species under physiological conditions. Their synthesis and reactivities as dipoles in cycloaddition reactions with strained alkynes have been studied in detail. Whereas the impact of the pH on the reaction kinetics was demonstrated experimentally, theoretical calculations suggest that the newly designed dipoles display reduced resonance stabilization energies compared to previously described iminosydnones, explaining their higher reactivity. These mesoionic compounds react smoothly with cycloalkynes under physiological, copper-free reaction conditions to form a click pyrazole product together with a released alkyl- or aryl-isocyanate. With rate constants up to 1000 M-1 s-1, this click-and-release reaction is among the fastest described to date and represents the first bioorthogonal process allowing the release of isocyanate electrophiles inside living cells, offering interesting perspectives in chemical biology.

A Polymer Prodrug Strategy to Switch from Intravenous to Subcutaneous Cancer Therapy for Irritant/Vesicant Drugs.

Chemotherapy is almost exclusively administered via the intravenous (IV) route, which has serious limitations (e.g., patient discomfort, long hospital stays, need for trained staff, high cost, catheter failures, infections). Therefore, the development of effective and less costly chemotherapy that is more comfortable for the patient would revolutionize cancer therapy. While subcutaneous (SC) administration has the potential to meet these criteria, it is extremely restrictive as it cannot be applied to most anticancer drugs, such as irritant or vesicant ones, for local toxicity reasons. Herein, we report a facile, general, and scalable approach for the SC administration of anticancer drugs through the design of well-defined hydrophilic polymer prodrugs. This was applied to the anticancer drug paclitaxel (Ptx) as a worst-case scenario due to its high hydrophobicity and vesicant properties (two factors promoting necrosis at the injection site). After a preliminary screening of well-established polymers used in nanomedicine, polyacrylamide (PAAm) was chosen as a hydrophilic polymer owing to its greater physicochemical, pharmacokinetic, and tumor accumulation properties. A small library of Ptx-based polymer prodrugs was designed by adjusting the nature of the linker (ester, diglycolate, and carbonate) and then evaluated in terms of rheological/viscosity properties in aqueous solutions, drug release kinetics in PBS and in murine plasma, cytotoxicity on two different cancer cell lines, acute local and systemic toxicity, pharmacokinetics and biodistribution, and finally their anticancer efficacy. We demonstrated that Ptx-PAAm polymer prodrugs could be safely injected subcutaneously without inducing local toxicity while outperforming Taxol, the commercial formulation of Ptx, thus opening the door to the safe transposition from IV to SC chemotherapy.