Experimental and theoretical comprehension of ESIPT fluorophores based on a 2-(2'-hydroxyphenyl)-3,3'-dimethylindole (HDMI) scaffold.

Excited-State Intramolecular Proton Transfer (ESIPT) emission is associated with intense single or multiple fluorescence in the solid-state, along with enhanced photostability and sensitivity to the close environment. As a result, ESIPT probes are attractive candidates for ratiometric sensing of a variety of substrates. A new family of ESIPT fluorophores is described herein, inspired by the well-known 2-(2'hydroxyphenyl)benzazole (HBX) organic scaffold. The connection of 3,3'-dimethylindole (or 3H-indole) derivatives with phenol rings triggers the formation of novel 2-(2'-hydroxyphenyl)-3,3'-dimethylindole (HDMI) fluorophores, capable of stimuli-responsive ESIPT emission. This brand new family of dyes displays redshifted emission, as compared to HBX, along with an unprecedented acid/base-mediated stabilization of different rotamers, owing to supramolecular interactions with methyl groups. These compounds are therefore highly sensitive to external stimuli, such as the presence of acid or base, where protonated and deprotonated species have specific optical signatures. Moreover, a new pyridine-functionalized HDMI dye displays acid-sensitive AIE properties. The photophysical properties of all compounds have also been studied using ab initio calculations to support experiments in deciphering the nature of the various radiative transitions observed and the related excited rotameric species.

Base- and sulfur-promoted oxidative lactonization of chalcone-acetate Michael adducts: access to pyran-2-ones.

A cost-effective, practical, straightforward and scalable synthesis of α-pyrones via base- and sulfur-promoted annulation of phenylacetates and chalcones is reported. Generated in situ from the starting components by using dbu as a base catalyst, the Michael adducts underwent a smooth oxidative cyclization into 3,4,6-triaryl-2-pyranones upon heating with DABCO and sulfur in DMSO. Extension to malonate in place of phenylacetates led to 4,6-diaryl-2-pyranone-2-carboxylates.

Synthesis and Characterization of a [1,2,6]Diazaphosphonine Oxide: An Example of a Photoswitchable Phosphorus-Containing Cyclic Azobenzene.

We report herein the synthesis and characterization of a phosphorus-containing cyclic azobenzene as a new photoswitchable scaffold. This backbone reveals high bidirectional photoswitching yields and high thermal stability for both isomers, with t1/2 > 90 days at 60 °C. Both E- and Z-isomers have been characterized by UV-vis spectroscopy and X-ray crystallography.

Lanthanide-Based Probes for Imaging Detection of Enzyme Activities by NIR Luminescence, T1- and ParaCEST MRI.

Applying a single molecular probe to monitor enzymatic activities in multiple, complementary imaging modalities is highly desirable to ascertain detection and to avoid the complexity associated with the use of agents of different chemical entities. We demonstrate here the versatility of lanthanide (Ln3+) complexes with respect to their optical and magnetic properties and their potential for enzymatic detection in NIR luminescence, CEST and T1 MR imaging, controlled by the nature of the Ln3+ ion, while using a unique chelator. Based on X-ray structural, photophysical, and solution NMR investigations of a family of Ln3+ DO3A-pyridine model complexes, we could rationalize the luminescence (Eu3+, Yb3+), CEST (Yb3+) and relaxation (Gd3+) properties and their variations between carbamate and amine derivatives. This allowed the design of L n L G a l 5 ${{{\bf L n L}}_{{\bf G a l}}^{5}}$ probes which undergo enzyme-mediated changes detectable in NIR luminescence, CEST and T1-weighted MRI, respectively governed by variations in their absorption energy, in their exchanging proton pool and in their size, thus relaxation efficacy. We demonstrate that these properties can be exploited for the visualization of ß-galactosidase activity in phantom samples by different imaging modalities: NIR optical imaging, CEST and T1-weighted MRI.

Crystal structure of poly[hexa-µ-bro-mido-bis{2-[1-(py-ri-din-2-yl)ethyl-idene-amino]ethanol-ato}tetracopper(II)].

The reaction of the Schiff base 2-[1-(pyridin-2-yl)ethyl-idene-amino]-ethanol (HL), which is formed by reaction of 2-amino-ethanol and 2-acetyl-pyridine with CuBr2 in ethanol results in the isolation of the new polymeric complex poly[hexa-µ-bromido-bis-{2-[1-(pyridin-2-yl)ethyl-idene-amino]-ethano-lato}tetra-copper(II)], [Cu4Br6(C9H11N2O)2]n or [Cu4Br6 L 2]n. The asymmetric unit of the crystal structure of the polymeric [Cu4Br6 L 2]n complex is composed by four copper (II) cations, two monodeprotonated mol-ecules of the ligand, and six bromide anions, which act as bridges. The ligand mol-ecules act in a tridentate fashion through their azomethine nitro-gen atoms, their pyridine nitro-gen atoms, and their alcoholate O atoms. The crystal structure shows two types of geometries in the coordination polyhedrons around Cu2+ ions. Two copper cations are situated in a square-based pyramidal environment, while the two other copper cations adopt a tetra-hedral geometry. Bromides anions acting as bridges between two metal ions connect the units, resulting in a tetra-nuclear polymer compound.

Difluoro Dipyridomethene Boron Complexes: Synthesis, Characterization, and Ab Initio Calculations.

Molecular engineering studies on the meso-cyano difluoro dipyridomethene boron complexes are presented and two series (a and b) of novel fluorophores are extensively studied. Halogenated derivatives were reacted under Suzuki-Miyaura or Sonogashira cross coupling reactions to introduce electron-donating or electron-withdrawing functional groups on positions 1 and 2 of the aromatic ligand. All derivatives were obtained in 14-90% yields and studied in detail by structural, photophysical, and computational analyses. Both series display excellent emissive properties in solution with blue to orange fluorescence emission upon blue light absorption and promising features as solid emitters. All the spectroscopic measurements are supported and confirmed by first-principles theoretical calculations combining TD-DFT and CC2. Series b, featuring an aryl substituent onto position 1 of the aromatic core, showed significantly large Stokes shifts values.

Sodium sulfide-promoted regiodefined redox condensation of o-nitroanilines with aryl ketones to benzo[a]phenazines and quinoxalines.

Inexpensive sodium sulfide trihydrate was found to promote unprecedented 6e-regio-predefined redox condensation of o-nitroanilines with α-tetralones to benzo[a]phenazines. The method was also successfully extended to acetophenones and higher homologs as reducing partners to provide 2-phenylquinoxalines. Compared to traditional approaches toward benzo[a]phenazine and quinoxaline cores starting with o-phenylenediamines, the present strategy could afford these heterocycles with well-defined regiochemistry based on the structure of starting o-nitroanilines.

Sulfur- and Amine- Promoted Multielectron Autoredox Transformation of Nitromethane: Multicomponent Access to Thiourea Derivatives.

Thiourea derivatives are in-demand motifs in organic synthesis, medicinal chemistry and material science, yet redox methods for the synthesis that start from safe, simple, inexpensive and readily available feedstocks are scarce. In this article, we disclose the synthesis of these motifs using elemental sulfur and nitromethane as the starting materials. The method harnesses the multi-electron auto-redox property of nitromethane in the presence of sulfur and amines, delivering thiourea products without any added oxidant or reductant. Extension of this reaction to cyclizable amines and/or higher homologues of nitromethane led to a wide range of nitrogen heterocycles and thioamides. Operationally simple, the reactions are scalable, tolerate a wide range of functional groups, and can be employed for the direct functionalization of natural products. Mechanistically, the nitro group was found to act as an oxidant leaving group, being reduced to ammonia whereas sulfur, along with the role of a sulfur building block for the thiocarbonyl group, behaved as a complementary reductant, being oxidized to sulfate.

Enantioselective and Regiodivergent Synthesis of Dihydro-1,2-oxazines from Triene-Carbamates via Chiral Phosphoric Acid-Catalysis.

Conjugated trienes are fascinating building blocks for the rapid construction of complex polycyclic compounds. However, limited success has been achieved due to the challenging regioselectivity control. Herein, we report an enantio- and diastereoselective process allowing to regioselectively control the functionalization of NH-triene-carbamates. Synthesis of chiral cis-3,6-dihydro-2H-1,2-oxazines is achieved by a chiral phosphoric acid catalyzed Nitroso-Diels-Alder cycloaddition involving [(1E,3E,5E)-hexa-1,3,5-trien-1-yl]carbamates. Moreover, modular access to three different regioisomers with excellent diastereoselectivities and high to excellent enantioselectivities is obtained by a careful choice of the reaction conditions. A computational study reveals that the regioselectivity is influenced by the steric demand of the substituents at the 6-position of the triene, as well as noncovalent interactions between the two cycloaddition partners. Utility of each regioisomeric cycloadduct is highlighted by a variety of synthetic transformations.

Functional and structural insights into the multi-step activation and catalytic mechanism of bacterial ExoY nucleotidyl cyclase toxins bound to actin-profilin.

ExoY virulence factors are members of a family of bacterial nucleotidyl cyclases (NCs) that are activated by specific eukaryotic cofactors and overproduce cyclic purine and pyrimidine nucleotides in host cells. ExoYs act as actin-activated NC toxins. Here, we explore the Vibrio nigripulchritudo Multifunctional-Autoprocessing Repeats-in-ToXin (MARTX) ExoY effector domain (Vn-ExoY) as a model for ExoY-type members that interact with monomeric (G-actin) instead of filamentous (F-actin) actin. Vn-ExoY exhibits moderate binding affinity to free or profilin-bound G-actin but can capture the G-actin:profilin complex, preventing its spontaneous or VASP- or formin-mediated assembly at F-actin barbed ends in vitro. This mechanism may prolong the activated cofactor-bound state of Vn-ExoY at sites of active actin cytoskeleton remodelling. We present a series of high-resolution crystal structures of nucleotide-free, 3'-deoxy-ATP- or 3'-deoxy-CTP-bound Vn-ExoY, activated by free or profilin-bound G-actin-ATP/-ADP, revealing that the cofactor only partially stabilises the nucleotide-binding pocket (NBP) of NC toxins. Substrate binding induces a large, previously-unidentified, closure of their NBP, confining catalytically important residues and metal cofactors around the substrate, and facilitating the recruitment of two metal ions to tightly coordinate the triphosphate moiety of purine or pyrimidine nucleotide substrates. We validate critical residues for both the purinyl and pyrimidinyl cyclase activity of NC toxins in Vn-ExoY and its distantly-related ExoY from Pseudomonas aeruginosa, which specifically interacts with F-actin. The data conclusively demonstrate that NC toxins employ a similar two-metal-ion mechanism for catalysing the cyclisation of nucleotides of different sizes. These structural insights into the dynamics of the actin-binding interface of actin-activated ExoYs and the multi-step activation of all NC toxins offer new perspectives for the specific inhibition of class II bacterial NC enzymes.

DABCO-Catalyzed DMSO-Promoted Sulfurative 1,2-Diamination of Phenylacetylenes with Elemental Sulfur and o-Phenylenediamines: Access to Quinoxaline-2-thiones.

The oxidative amination of alkynes typically requires transition metal catalysts and strong oxidants. Herein, we alternatively utilize DABCO as a sulfur-activating catalyst to achieve the sulfurative 1,2-diamination of phenylacetylenes with elemental sulfur and o-phenylenediamines. DMSO was found to be particularly suitable for use as a terminal oxidant for this three-component process. A mechanistic study has shown that this cascade reaction is triggered by the addition of active sulfur species to the triple bond of phenylacetylenes.

Sulfur-Promoted Oxidative Cyclization of Pentan-1-ones: Direct Access to Tetrasubstituted Furans from Deoxybenzoins and Chalcones.

Furan is an important heterocyclic scaffold in natural product, bioorganic, and medicinal chemistry as well as in materials science. The system S8/DABCO/DMSO was found to efficiently mediate the oxidative cyclization of 1,2,3,5-tetraarylpentan-1-ones A, which were obtained in situ as the Michael adducts of chalcones 1 and deoxybenzoins 2, to furan 3. The strategy provided convenient and direct access to tetrasubstituted furans 3 from readily available starting materials with high functional group tolerance.

Sulfur-Promoted Oxidative Condensation of Chalcones with Unsubstituted Cyanoacetamide in DMSO: Access to 3-Cyanopyrid-2-ones.

Elemental sulfur and DABCO were found to be an excellent combination to promote a one-pot cascade of condensation-oxidative cyclization of chalcones and unsubstituted cyanoacetamide in DMSO to provide 3-cyanopyrid-2-ones.

Light-Promoted Basic Nitrogen Unmasking in Arene Ruthenium Complexes Derived from Z-Configured 2,2'-Azobispyridine.

Two novel 2,2'-azobispyridine derivatives bearing N-dialkylamino substituents at position 4,4' were synthesized and their E-Z photoswitching behavior was characterized by combination of 1 H- and 13 C NMR spectroscopy, UV-Vis absorption and DFT calculations. Both isomers act as ligands towards arene-RuII centers, leading either to E-configured 5-membered chelates (involving coordination of nitrogen atoms from N=N bond and pyridine) or to the uncommon Z-configured 7-membered chelates (involving coordination of nitrogen atoms from both pyridines). The latter show good stability in the dark, allowing single crystal X-ray diffraction study to be reported here for the first time. All synthesized Z-configured arene-RuII complexes undergo irreversible photo-isomerization to their corresponding E isomers with rearrangement of their coordination pattern. This property was advantageously exploited for the light-promoted unmasking of a basic nitrogen atom of the ligand.

Catalyst-Free Synthesis of Functionalized 4-Substituted-4H-Benzo[d][1,3]oxazines via Intramolecular Cyclization of ortho-Amide-N-tosylhydrazones.

Functionalized 4-aryl-4H-benzo[d][1,3]oxazines are synthesized under transition-metal-free conditions using ortho-amide-N-tosylhydrazones. This synthetic method uses readily available N-tosylhydrazones as the diazo compound precursors and involves an intramolecular ring closure reaction mediated by a protic polar additive (iPrOH). A wide range of functionalized oxazines are obtained by this straightforward method in good to excellent yields. Furthermore, the viability of our strategy is illustrated by the gram-scale elaboration of a bromo-substituted 4H-benzo[d][1,3]oxazine and its post-functionalization by palladium-catalyzed cross-couplings.

Fluorinated 2-Azetines: Synthesis, Applications, Biological Tests, and Development of a Catalytic Process.

An efficient and straightforward phosphine-promoted tandem aza-Michael addition/intramolecular Wittig reaction was developed for the synthesis of polyfunctionalized 2-azetines. After demonstrating that this transformation could be made catalytic in phosphine through in situ reduction of phosphine oxide with phenylsilane, different post-transformation steps have been demonstrated, including an original [2 + 2] photodimerization. Preliminary biological tests highlighted that these fluorinated 1,2-dihydroazete-2,3-dicarboxylates exhibited significant cytotoxicity against the human tumor cell line.

From the Spectroscopic Reassessment of Authentic Alkaloid Samples to the Molecular Networking-Guided Discovery of Criophylline-Related Analogues from Callichilia inaequalis.

The molecular network-guided exploration of the alkaloid extract of Callichilia inaequalis stems revealed a cluster attributed tentatively to dimeric monoterpene indole alkaloids of the rare criophylline subtype, initiating the dual study reported herein. A patrimonial-themed portion of this work was aimed at performing a spectroscopic reassessment of criophylline (1), a monoterpene bisindole alkaloid for which the nature of the inter-monomeric connectivity and configurational assignments have remained dubious. A targeted isolation of the entity annotated as criophylline (1) was undertaken to strengthen the available analytical evidence. An extensive set of spectroscopic data was acquired from the authentic sample of criophylline (1a) isolated earlier by Cavé and Bruneton. These spectroscopic studies proved the samples to be identical, and the complete structure of criophylline could be assigned, half a century after it was first isolated. The absolute configuration of andrangine (2) was also ascertained based on a TDDFT-ECD approach from the authentic sample. The forward-looking aspect of this investigation resulted in the characterization of two new criophylline derivatives from C. inaequalis stems, namely, 14'-hydroxycriophylline (3) and 14'-O-sulfocriophylline (4). Their structures, including absolute configurations, were elucidated by analysis of NMR and MS spectroscopic data and by ECD analysis. Notably, 14'-O-sulfocriophylline (4) is the first sulfated monoterpene indole alkaloid to have been reported. The antiplasmodial activity against the chloroquine-resistant strain of Plasmodium falciparum FcB1 was determined for criophylline and its two new analogues.

Anti-Cancer and Radio-Sensitizing Properties of New Bimetallic (N-Heterocyclic Carbene)-Amine-Pt(II) Complexes.

Bioactive NHC-transition metal complexes have shown promise as anti-cancer agents, but their potential use as radiosensitizers has been neglected so far. We disclose here a new series of bimetallic platinum(II) complexes displaying NHC-type bridging ligands, (bis-NHC)[trans-Pt(RNH2)I2]2, that have been synthesized via a simple, two-step procedure. They display cytotoxicity in the micromolar range on cancerous cell lines, accumulate in cells, and bind to genomic DNA, by inducing DNA damages. Notably, these bimetallic complexes demonstrate significant radiosensitizing effects on both ovarian cells A2780 and nonsmall lung carcinoma cells H1299. Further investigations revealed that bimetallic species make irradiation-induced DNA damages more persistent by inhibiting repair mechanisms. Indeed, a higher and persistent accumulation of both γ-H2AX and 53BP1 foci post-irradiation was detected, in the presence of the NHC-Pt complexes. Overall, we provide the first in vitro evidence for the radiosensitizing properties of NHC-platinum complexes, which suggests their potential use in combined chemo-radio therapy protocols.

Unifying the configuration of historical alkaloids from Borreria capitata through an extensive spectroscopic reinvestigation.

Reinvestigation of the structure of borrecapine and borreline through extensive spectroscopic analysis of their authentic samples led to the assignment of their absolute configurations. Newly acquired spectroscopic data determined that the previously assigned relative configuration for borrecapine was incorrect and that the claimed absolute configuration of borreline should be revised to its enantiomer.