The crane fly glycosylated triketide δ-lactone cornicinine elicits akinete differentiation of the cyanobiont in aquatic Azolla fern symbioses.

The restriction of plant-symbiont dinitrogen fixation by an insect semiochemical had not been previously described. Here we report on a glycosylated triketide δ-lactone from Nephrotoma cornicina crane flies, cornicinine, that causes chlorosis in the floating-fern symbioses from the genus Azolla. Only the glycosylated trans-A form of chemically synthesized cornicinine was active: 500 nM cornicinine in the growth medium turned all cyanobacterial filaments from Nostoc azollae inside the host leaf-cavities into akinetes typically secreting CTB-bacteriocins. Cornicinine further inhibited akinete germination in Azolla sporelings, precluding re-establishment of the symbiosis during sexual reproduction. It did not impact development of the plant Arabidopsis thaliana or several free-living cyanobacteria from the genera Anabaena or Nostoc but affected the fern host without cyanobiont. Fern-host mRNA sequencing from isolated leaf cavities confirmed high NH4-assimilation and proanthocyanidin biosynthesis in this trichome-rich tissue. After cornicinine treatment, it revealed activation of Cullin-RING ubiquitin-ligase-pathways, known to mediate metabolite signaling and plant elicitation consistent with the chlorosis phenotype, and increased JA-oxidase, sulfate transport and exosome formation. The work begins to uncover molecular mechanisms of cyanobiont differentiation in a seed-free plant symbiosis important for wetland ecology or circular crop-production today, that once caused massive CO2 draw-down during the Eocene geological past.

Structure-Activity Relationship of Benzophenazine Derivatives for Homogeneous and Heterogenized Photooxygenation Catalysis.

Singlet oxygen is a powerful oxidant used in various applications, such as organic synthesis, medicine, and environmental remediation. Organic and inorganic photosensitizers are commonly used to generate this reactive species through energy transfer with the triplet ground state of oxygen. We describe here a series of novel benzophenazine derivatives as a promising class of photosensitizers for singlet oxygen photosensitization. In this study, we investigated the structure-activity relationship of these benzophenazine derivatives. Akin to a molecular compass, the southern fragment was first functionalized with either aromatic tertiary amines, alkyl tertiary amines, aromatic sulfur groups, alkyl sulfur groups, or cyclic ethers. Enhanced photophysical properties (in terms of triplet excited-state lifetime, absorption wavelength, triplet state energy, and O2 quenching capabilities) were obtained with cyclic ether and sulfur groups. Conversely, the presence of an amine moiety was detrimental to the photocatalysts. The western and northern fragments were also investigated and slightly undesirable to negligible changes in photophysical properties were observed. The most promising candidate was then immobilized on silica nanoparticles and its photoactivity was evaluated in the citronellol photooxidation reaction. These results provide insights into the design of efficient photosensitizers for singlet oxygen generation and the development of heterogeneous systems.

Photo-Catalyzed α-Arylation of Enol Acetate Using Recyclable Silica-Supported Heteroleptic and Homoleptic Copper(I) Photosensitizers.

Earth-abundant photosensitizers are highly sought after for light-mediated applications, such as photoredox catalysis, depollution and energy conversion schemes. Homoleptic and heteroleptic copper(I) complexes are promising candidates in this field, as copper is abundant and the corresponding complexes are easily obtained in smooth conditions. However, some heteroleptic copper(I) complexes suffer from low (photo)stability that leads to the gradual formation of the corresponding homoleptic complex. Such degradation pathways are detrimental, especially when recyclability is desired. This study reports a novel approach for the heterogenization of homoleptic and heteroleptic Cu complexes on silica nanoparticles. In both cases, the photophysical properties upon surface immobilization were only slightly affected. Excited-state quenching with aryl diazonium derivatives occurred efficiently (108 -1010  M-1 s-1 ) with heterogeneous and homogeneous photosensitizers. Moderate but almost identical yields were obtained for the α-arylation of enol acetate using the homoleptic complex in homogeneous or heterogeneous conditions. Importantly, the silica-supported photocatalysts were recycled with moderate loss in photoactivity over multiple experiments. Transient absorption spectroscopy confirmed that excited-state electron transfer occurred from the homogeneous and heterogeneous homoleptic copper(I) complexes to aryl diazonium derivatives, generating the corresponding copper(II) center that persisted for several hundreds of microseconds, compatible with photoredox catalysis applications.

Cocrystallization-Induced Spontaneous Deracemization: A General Thermodynamic Approach to Deracemization.

Processes leading to enantiomerically pure compounds are of utmost importance, in particular for the pharmaceutical industry. Starting from a racemic mixture, crystallization-induced diastereomeric transformation allows in theory for 100 % transformation of the desired enantiomer. However, this method has the inherent limiting requirement for the organic compound to form a salt. Herein, this limitation is lifted by introducing cocrystallization in the context of thermodynamic deracemization, with the process applied to a model chiral fungicide. We report a new general single thermodynamic deracemization process based on cocrystallization for the deracemization of (R,S)-4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)pentan-3-one. This study demonstrates the feasibility of this novel approach and paves the way to further development of such processes.

Capturing the Monomeric (L)CuH in NHC-Capped Cyclodextrin: Cavity-Controlled Chemoselective Hydrosilylation of α,ß-Unsaturated Ketones.

The encapsulation of copper inside a cyclodextrin capped with an N-heterocyclic carbene (ICyD) allowed both to catch the elusive monomeric (L)CuH and a cavity-controlled chemoselective copper-catalyzed hydrosilylation of α,ß-unsaturated ketones. Remarkably, (α-ICyD)CuCl promoted the 1,2-addition exclusively, while (ß-ICyD)CuCl produced the fully reduced product. The chemoselectivity is controlled by the size of the cavity and weak interactions between the substrate and internal C-H bonds of the cyclodextrin.

Biosynthesis of the nickel-pincer nucleotide cofactor of lactate racemase requires a CTP-dependent cyclometallase.

Bacterial lactate racemase is a nickel-dependent enzyme that contains a cofactor, nickel pyridinium-3,5-bisthiocarboxylic acid mononucleotide, hereafter named nickel-pincer nucleotide (NPN). The LarC enzyme from the bacterium Lactobacillus plantarum participates in NPN biosynthesis by inserting nickel ion into pyridinium-3,5-bisthiocarboxylic acid mononucleotide. This reaction, known in organometallic chemistry as a cyclometalation, is characterized by the formation of new metal-carbon and metal-sulfur σ bonds. LarC is therefore the first cyclometallase identified in nature, but the molecular mechanism of LarC-catalyzed cyclometalation is unknown. Here, we show that LarC activity requires Mn2+-dependent CTP hydrolysis. The crystal structure of the C-terminal domain of LarC at 1.85 Å resolution revealed a hexameric ferredoxin-like fold and an unprecedented CTP-binding pocket. The loss-of-function of LarC variants with alanine variants of acidic residues leads us to propose a carboxylate-assisted mechanism for nickel insertion. This work also demonstrates the in vitro synthesis and purification of the NPN cofactor, opening new opportunities for the study of this intriguing cofactor and of NPN-utilizing enzymes.

Enantio-, Regio- and Chemoselective Copper-Catalyzed 1,2-Hydroborylation of Acylsilanes.

Enantioselective synthesis of synthetically significant (α-hydroxyallyl)silanes, (α-hydroxyaryl)silanes, and (α-hydroxyalkyl)silanes is reported. The present copper-catalyzed 1,2-selective hydroborylation of acylsilanes affords the aforementioned products in high yields and with high enantiomeric excesses. This robust and scalable additive-free catalytic system relies on the use of low copper(II) acetate and diphosphine ligand loadings at room temperature in the presence of a commercially available and bench-stable hydride source.

Covalent Grafting of BPin functions on Carbon Nanotubes and Chan-Lam-Evans Post-Functionalization.

The chemical functionalization of carbon nanotubes is often a prerequisite prior to their use in various applications. The covalent grafting of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (BPin) functional groups directly on the surface of multi- and single-walled carbon nanotubes, activated by nucleophilic addition of nBuLi, was carried out. Thermogravimetric analysis (TGA) coupled with mass spectrometry, Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ions mass spectrometry (ToF-SIMS) confirmed the efficiency of this methodology and proved the integrity and covalent grafting of the BPin functional groups. These groups were further reacted with various nucleophiles in the presence of a copper(II) source in the conditions of the aerobic Chan-Lam-Evans coupling. The resulting materials were characterized by TGA, XPS and ToF-SIMS. This route is efficient, reliable and among the scarce reactions that enable the direct grafting of heteroatoms at carbonaceous material surfaces.

Carbon-Nanotube-Appended PAMAM Dendrimers Bearing Iron(II) α-Keto Acid Complexes: Catalytic Non-Heme Oxygenase Models.

Poly(amidoamine) dendrimers grafted on carbon nanotubes have been appended with iron(II)-α-keto acid (benzoylformate) complex of polypyridyl ligand to design artificial non-heme oxygenase model. This nano-enzyme was applied for selective catalytic oxidation of organic molecules. Although the carbon nanotubes serve as a robust heterogeneous platform, the amine terminals of dendrimers provide catalysts binding sites and the amide bonds provide a necessary second coordination sphere similar to the enzymatic polypeptide chains. Such a hybrid design prevented the deactivation of the primary active sites leading to 8 times faster oxidative decarboxylation rates than those of its homogeneous analogue. An electrophilic iron(IV)-oxo intermediate has been intercepted, which catalyzes the selective oxidation of alcohols to aldehydes and incorporates single oxygen atoms into sulfides and olefins by using aerial oxygen with multiple turnover numbers. The catalyst was consecutively regenerated three times by mild chemical treatment and showed negligible loss of activity.

Synthesis and Catalytic Applications of Multi-Walled Carbon Nanotube-Polyamidoamine Dendrimer Hybrids.

Polyamidoamine (PAMAM) dendrimers were covalently immobilized on multi-walled carbon nanotubes (MWNT) by two "grafting to" strategies. We demonstrate the existence of non-covalent interactions between the two components but outline the superiority of our two grafting approaches, namely xanthate and click chemistry. MWNT surfaces were functionalized with activated ester and propargylic moieties prior to their reaction with PAMAM or azido-PAMAM dendrimers, respectively. The grafting of PAMAM generations 0 to 3 was evaluated with X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). The versatility of our hybrids was demonstrated by post-functionalization sequences involving copper alkyne-azide cycloaddition (CuAAC). We synthesized homogeneous supported iridium complexes at the extremities of the dendrimers. In addition, our materials were used as templates for the encapsulation of Pd nanoparticles (NPs), validating our nanocomposites for catalytic applications. The palladium-based catalyst was active for carbonylative coupling over five consecutive runs without loss of activity.

Copper-Catalyzed One-Pot Borylative Aldolisation ß-Fluoride Elimination for the Formal Addition of Acrylates to Carbonyl Moieties.

Herein, we report the copper-catalyzed domino borylation/aldolisation of methyl 2-fluoroacrylate with carbonyl compounds followed by an elimination to give Morita-Baylis-Hillman (MBH) analogues. The optimal conditions described were shown to be compatible with a wide range of aldehydes and ketones. Unprecedented MBH adducts derived from ketones were efficiently synthesized.

Molecular Engineering of Trifunctional Supported Catalysts for the Aerobic Oxidation of Alcohols.

We describe a simple and general method for the preparation and molecular engineering of supported trifunctional catalysts and their application in the representative Cu/TEMPO/NMI-catalyzed aerobic oxidation of benzyl alcohol. The methodology allows in one single step to immobilize, with precise control of surface composition, both pyta, Cu(I) , TEMPO, and NMI sites on azide-functionalized silica particles. To optimize the performance of the heterogeneous trifunctional catalysts, synergistic interactions are finely engineered through modulating the degree of freedom of the imidazole site as well as tuning the relative surface composition, leading to catalysts with an activity significantly superior to the corresponding homogeneous catalytic system.

Easy preparation of enantiomerically enriched heteroaromatic alcohols through lipase-catalyzed acylation with succinic anhydride under unconventional activation.

This study reports the lipase-catalyzed resolution of heteroaromatic secondary alcohols by succinic anhydride under different activation conditions by convenient procedure with succinic anhydride. The effects of succinic anhydride and the nature of the heteroatom are discussed in standard conditions in the kinetic resolution with lipases. The results recorded under microwave activation and ultrasonication is compared. (R)-4-chromanol was obtained in optically pure form (ee > 99%) with a high selectivity E > 200 by Pseudomonas cepacia lipase (PCL) in diethyl ether, using microwave radiation and under ultrasonication. The reaction time is reduced compared to the conventional heating with a better control of the selectivity of the lipase PCL. A significant effect of the nature of the heteroatoms on the reactivity and selectivity of the lipase with succinic anhydride has been disclosed, regardless the conditions of activation. This method proved to be clean, fast, interesting alternative, and facilitates the use of a cyclic anhydride, by microwave or ultrasound especially with secondary alcohols. The process is a valuable prerequisite for the preparative scale production of enantiomerically heteroaromatic alcohols in sustainable chemistry.

Synthesis of Novel ß-Keto-Enol Derivatives Tethered Pyrazole, Pyridine and Furan as New Potential Antifungal and Anti-Breast Cancer Agents.

Recently, a new generation of highly promising inhibitors bearing ß-keto-enol functionality has emerged. Reported herein is the first synthesis and use of novel designed drugs based on the ß-keto-enol group embedded with heterocyclic moieties such as pyrazole, pyridine, and furan, prepared in a one-step procedure by mixed Claisen condensation. All the newly synthesized compounds were characterized by FT-IR, ¹H-NMR, (13)C-NMR, ESI/LC-MS, elemental analysis, and evaluated for their in vitro antiproliferative activity against breast cancer (MDA-MB241) human cell lines and fungal strains (Fusarium oxysporum f.sp albedinis FAO). Three of the synthesized compounds showed potent activity against fungal strains with IC50 values in the range of 0.055-0.092 µM. The results revealed that these compounds showed better IC50 values while compared with positive controls.

One-step double covalent functionalization of reduced graphene oxide with xanthates and peroxides.

Radical functionalization of reduced graphene oxide has been achieved by reaction with a xanthate in the presence of peroxide as a radical initiator. X-ray photoelectron spectroscopy, bulk elemental analyses, and thermogravimetric analyses showed that the xanthate grafting is covalent and efficient. The synthesis and use of seven xanthates and three peroxides showed that the highest grafting yield is obtained when xanthate and peroxide are introduced in stoichiometric amounts. It also revealed that the peroxide used as radical initiator is grafted at the graphenic surface during the functionalization. The method presented in this contribution therefore allows bifunctionalized reduced graphene oxide samples to be easily obtained in one single step. This method leads to undamaged graphene sheets with higher dispersibility than the pristine sample.

Versatile Cu(I)/Pd(0) dual catalysis for the synthesis of quaternary α-allylated carbonyl compounds: development, mechanistic investigations and scope.

We report herein a versatile cooperative dual catalysis reaction based on a Cu(I)/Pd(0) system. Mechanistic investigation shows that every component plays a crucial role in determining the reaction outcome. The reaction is successfully extended to various substrates; such as α,ß-unsaturated ketones, malonates and coumarins. The strategy tolerates different substitution patterns and affords good yields for each family of substrates.

CuI/Pd0 cooperative dual catalysis: tunable stereoselective construction of tetra-substituted alkenes.

This paper describes a tunable and stereoselective dual catalytic system that uses copper and palladium reagents. This cooperative silylcupration and palladium-catalyzed allylation readily affords trisubstituted alkenylsilanes. Fine-tuning the reaction conditions allows selective access to one stereoisomer over the other. This new methodology tolerates different substituents on both coupling partners with high levels of stereoselectivity. The one-pot reaction involving a Cu(I)/Pd(0) cooperative dual catalyst directly addresses the need to develop more time-efficient and less-wasteful synthetic pathways.

Valorization of Chicken Viscera as Natural Raw Material Source: Application to Hydrolysis of Fatty Esters for Sewage Treatment.

"Chicken viscera" constitutes very abundant domestic wastes interestingly investigated in the present paper. The efficiency of this crude slaughter co-product of high protein component, as biocatalyst, for the hydrolysis of fatty acid esters was reported and that, without any pre-treatment. The crude chicken intestine powder (CIP) has shown a high reactivity for the hydrolysis of fatty esters. Two biocatalyst preparations were independently explored for the bioresolution of sec-phenyl alkyl carbinol esters: the CIP preparation and the crude chicken intestine acetone powder CIAP preparation. The last one has shown good catalytic activity during the bio-hydrolysis in biphasic medium. Furthermore, the direct hydrolysis of milk fat using CIAP (500 mg) reveals the elimination of fats present in 50 ml of treated milk. These results open up very interesting prospects for the use of this biowaste for the treatment of milk fat.

Enhancing Tsuji-Trost deallylation in living cells with an internal-nucleophile coumarin-based probe.

In recent years, bioorthogonal uncaging reactions have been developed to proceed efficiently under physiological conditions. However, limited progress has been made in the development of protecting groups combining stability under physiological settings with the ability to be quickly removed via bioorthogonal catalysis. Herein, we present a new water-soluble coumarin-derived probe bearing an internal nucleophilic group capable of promoting Tsuji-Trost deallylation under palladium catalysis. This probe can be cleaved by a bioorthogonal palladium complex at a faster rate than the traditional probe, namely N-Alloc-7-amino-4-methylcoumarin. As the deallylation process proved to be efficient in mammalian cells, we envision that this probe may find applications in chemical biology, bioengineering, and medicine.

A novel approach to pH-Responsive targeted cancer Therapy: Inhibition of FaDu cancer cell proliferation with a pH low insertion Peptide-Conjugated DGAT1 inhibitor.

Targeting enzymes involved in lipid metabolism is increasingly recognized as a promising anticancer strategy. Efficient inhibition of diacylglycerol O-transferase 1 (DGAT1) can block fatty acid (FA) storage. This, in turn, triggers an increase in free polyunsaturated FA concentration, leading to peroxidation and ferroptosis. In this study, we report the development of a pH-sensitive peptide (pHLIP)-drug conjugate designed to selectively deliver DGAT1 inhibitors to cancer cells nested within the acidic microenvironment of tumors. We utilized two previously established pHLIP sequences for coupling with drugs. The study of DGAT1 conjugates in large unilamellar vesicles (LUVs) of different compositions did not reveal enhanced pH-dependent insertion compared to POPC LUVs. However, using in vitro 3D tumor spheroids, significant antiproliferative effects were observed upon exposure to pHLIP-T863 (DGAT1 inhibitor) conjugates, surpassing the inhibitory activity of T863 alone. In conclusion, our study provides the first evidence that pHLIP-based conjugates with DGAT1 inhibitors have the potential to specifically target the acidic compartment of tumors. Moreover, it sheds light on the limitations of LUV models in capturing the pH-dependency of such conjugates.