Photoinduced Ligand-to-Metal Charge Transfer in Base-Metal Catalysis.

The absorption of light by photosensitizers has been shown to offer novel reactive pathways through electronic excited state intermediates, complementing ground state mechanisms. Such strategies have been applied in both photocatalysis and photoredox catalysis, driven by generating reactive intermediates from their long-lived excited states. One developing area is photoinduced ligand-to-metal charge transfer (LMCT) catalysis, in which coordination of a ligand to a metal center and subsequent excitation with light results in the formation of a reactive radical and a reduced metal center. This mini review concerns the foundations and recent developments in ligand-to-metal charge transfer in transition metal catalysis focusing on the organic transformations made possible through this mechanism.

Silvestrol, a potent anticancer agent with unfavourable pharmacokinetics: Current knowledge on its pharmacological properties and future directions for the development of novel drugs.

Cancer remains a leading cause of death, with increasing incidence. Conventional treatments offer limited efficacy and cause significant side effects, hence novel drugs with improved pharmacological properties and safety are required. Silvestrol (SLV) is a flavagline derived from some plants of the Aglaia genus that has shown potent anticancer effects, warranting further study. Despite its efficacy in inhibiting the growth of several types of cancer cells, SLV is characterized by an unfavorable pharmacokinetics that hamper its use as a drug. A consistent research over the recent years has led to develop novel SLV derivatives with comparable pharmacodynamics and an ameliorated pharmacokinetic profile, demonstrating potential applications in the clinical management of cancer. This comprehensive review aims to highlight the most recent data available on SLV and its synthetic derivatives, addressing their pharmacological profile and therapeutic potential in cancer treatment. A systematic literature review of both in vitro and in vivo studies focusing on anticancer effects, pharmacodynamics, and pharmacokinetics of these compounds is presented. Overall, literature data highlight that rationale chemical modifications of SLV are critical for the development of novel drugs with high efficacy on a broad variety of cancers and improved bioavailability in vivo. Nevertheless, SLV analogues need to be further studied to better understand their mechanisms of action, which can be partially different to SLV. Furthermore, clinical research is still required to assess their efficacy in humans and their safety.

Expedited Proton Relay in Enzyme-Inspired Cobaloximes Facilitates Organic Transformations.

Developing a water-soluble, oxygen-tolerant, and acid-stable synthetic H2 production catalyst is vital for renewable energy infrastructure. To access such an effective catalyst, we strategically incorporated enzyme-inspired, multicomponent outer coordination sphere elements around the cobaloxime (Cl-Co-X) core with suitable axial coordination (X). Our cobaloximes with axial imidazole or L-histidine coordination in photocatalytic HAT including the construction of anilines via a non-canonical cross-coupling approach is found superior compared to commonly used cobaloxime catalysts. The reversible Co(II)/Co(I) process is influenced by the axial N ligand's nature. Imidazole/ L-histidine with a higher pKa promptly produces H2 upon irradiation, leading to the improved reactivity compared to previously employed axial (di)chloride or pyridine analogue.

Scaffold-Hopping Strategies in Aurone Optimization: A Comprehensive Review of Synthetic Procedures and Biological Activities of Nitrogen and Sulfur Analogues.

Aurones, particular polyphenolic compounds belonging to the class of minor flavonoids and overlooked for a long time, have gained significative attention in medicinal chemistry in recent years. Indeed, considering their unique and outstanding biological properties, they stand out as an intriguing reservoir of new potential lead compounds in the drug discovery context. Nevertheless, several physicochemical, pharmacokinetic, and pharmacodynamic (P3) issues hinder their progression in more advanced phases of the drug discovery pipeline, making lead optimization campaigns necessary. In this context, scaffold hopping has proven to be a valuable approach in the optimization of natural products. This review provides a comprehensive and updated picture of the scaffold-hopping approaches directed at the optimization of natural and synthetic aurones. In the literature analysis, a particular focus is given to nitrogen and sulfur analogues. For each class presented, general synthetic procedures are summarized, highlighting the key advantages and potential issues. Furthermore, the biological activities of the most representative scaffold-hopped compounds are presented, emphasizing the improvements achieved and the potential for further optimization compared to the aurone class.

Unambiguous Characterization of Commercial Natural (Dihydro)phenanthrene Compounds Is Vital in the Discovery of AMPK Activators.

These days, easy access to commercially available (poly)phenolic compounds has expanded the scope of potential research beyond the field of chemistry, particularly in the area of their bioactivity. However, the quality of these compounds is often overlooked or not even considered. This issue is illustrated in this study through the example of (dihydro)phenanthrenes, a group of natural products present in yams, as AMP-activated protein kinase (AMPK) activators. A study conducted in our group on a series of compounds, fully characterized using a combination of chemical synthesis, NMR and MS techniques, provided evidence that the conclusions of a previous study were erroneous, likely due to the use of a misidentified commercial compound by its supplier. Furthermore, we demonstrated that additional representatives of the (dihydro)phenanthrene phytochemical classes were able to directly activate AMPK, avoiding the risk of misinterpretation of results based on analysis of a single compound alone.

Organic Reactions Enabled by Mechanical Force-Induced Single Electron Transfer.

Mechanochemical reactions, achieved through milling, grinding, or other mechanical actions, have emerged as a solvent-free alternative to traditional solution-based chemistry. Mechanochemistry not only provides the opportunity to eliminate bulk solvent use, reducing waste generation, but also unveils a new reaction strategy which enables the realization of reactions previously inaccessible in solution. While the majority of organic reactions facilitated by mechanical force traditionally follow two-electron transfer pathways similar to their solution-based counterparts, the field of mechanochemically induced single-electron transfer (SET) reactions has witnessed rapid development. This review outlines examples of mechanochemical reactions facilitated by the SET process, focusing on the reagents that initiate SET, thereby positioning mechanochemistry as a burgeoning field within the realm of single-electron chemistry.

Recent Advances in the Domino Annulation Reaction of Quinone Imines.

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.

Essential Oils: Chemistry and Pharmacological Activities-Part II.

The importance of essential oils and their components in the industrial sector is attributed to their chemical characteristics and their application in the development of products in the areas of cosmetology, food, and pharmaceuticals. However, the pharmacological properties of this class of natural products have been extensively investigated and indicate their applicability for obtaining new drugs. Therefore, this review discusses the use of these oils as starting materials to synthesize more complex molecules and products with greater commercial value and clinic potential. Furthermore, the antiulcer, cardiovascular, and antidiabetic mechanisms of action are discussed. The main mechanistic aspects of the chemopreventive properties of oils against cancer are also presented. The data highlight essential oils and their derivatives as a strategic chemical group in the search for effective therapeutic agents against various diseases.

Increasing Profitability of Ethanol Photoreforming by Simultaneous Production of H2 and Acetal.

Often, H2 is produced photocatalytically at the expense of sacrificial agents. When a sacrificial agent is selectively oxidized, this allows coupling of H2 production with synthesis of value-added organic compounds. Herein, it is argued that the conversion of bioethanol into 1,1-diethoxyethane with simultaneous H2 production increases the economic viability of photocatalysis and suggests a semiconductor material that is the most relevant for this purpose.

Magnetic Aerogels for Room-Temperature Catalytic Production of Bis(indolyl)methane Derivatives.

The potential of aerogels as catalysts for the synthesis of a relevant class of bis-heterocyclic compounds such as bis(indolyl)methanes was investigated. In particular, the studied catalyst was a nanocomposite aerogel based on nanocrystalline nickel ferrite (NiFe2O4) dispersed on amorphous porous silica aerogel obtained by two-step sol-gel synthesis followed by gel drying under supercritical conditions and calcination treatments. It was found that the NiFe2O4/SiO2 aerogel is an active catalyst for the selected reaction, enabling high conversions at room temperature, and it proved to be active for three repeated runs. The catalytic activity can be ascribed to both the textural and acidic features of the silica matrix and of the nanocrystalline ferrite. In addition, ferrite nanocrystals provide functionality for magnetic recovery of the catalyst from the crude mixture, enabling time-effective separation from the reaction environment. Evidence of the retention of species involved in the reaction into the catalyst is also pointed out, likely due to the porosity of the aerogel together with the affinity of some species towards the silica matrix. Our work contributes to the study of aerogels as catalysts for organic reactions by demonstrating their potential as well as limitations for the room-temperature synthesis of bis(indolyl)methanes.

Synthesis and Biological Properties of Fluorescent Strigolactone Mimics Derived from 1,8-Naphthalimide.

Strigolactones (SLs) have potential to be used in sustainable agriculture to mitigate various stresses that plants have to deal with. The natural SLs, as well as the synthetic analogs, are difficult to obtain in sufficient amounts for practical applications. At the same time, fluorescent SLs would be useful for the mechanistic understanding of their effects based on bio-imaging or spectroscopic techniques. In this study, new fluorescent SL mimics containing a substituted 1,8-naphthalimide ring system connected through an ether link to a bioactive furan-2-one moiety were prepared. The structural, spectroscopic, and biological activity of the new SL mimics on phytopathogens were investigated and compared with previously synthetized fluorescent SL mimics. The chemical group at the C-6 position of the naphthalimide ring influences the fluorescence parameters. All SL mimics showed effects similar to GR24 on phytopathogens, indicating their suitability for practical applications. The pattern of the biological activity depended on the fungal species, SL mimic and concentration, and hyphal order. This dependence is probably related to the specificity of each fungal receptor-SL mimic interaction, which will have to be analyzed in-depth. Based on the biological properties and spectroscopic particularities, one SL mimic could be a good candidate for microscopic and spectroscopic investigations.

Integrated Approach of Life Cycle Assessment and Experimental Design in the Study of a Model Organic Reaction: New Perspectives in Renewable Vanillin-Derived Chemicals.

This work is focused on performing a quantitative assessment of the environmental impacts associated with an organic synthesis reaction, optimized using an experimental design approach. A nucleophilic substitution reaction was selected, employing vanillin as the substrate, a phenolic compound widely used in the food industry and of pharmaceutical interest, considering its antioxidant and antitumoral potential. To carry out the reaction, three different solvents have been chosen, namely acetonitrile (ACN), acetone (Ace), and dimethylformamide (DMF). The syntheses were planned with the aid of a multivariate experimental design to estimate the best reaction conditions, which simultaneously allow a high product yield and a reduced environmental impact as computed by Life Cycle Assessment (LCA) methodology. The experimental results highlighted that the reactions carried out in DMF resulted in higher yields with respect to ACN and Ace; these reactions were also the ones with lower environmental impacts. The multilinear regression models allowed us to identify the optimal experimental conditions able to guarantee the highest reaction yields and lowest environmental impacts for the studied reaction. The identified optimal experimental conditions were also validated by experimentally conducting the reaction in those conditions, which indeed led to the highest yield (i.e., 93%) and the lowest environmental impacts among the performed experiments. This work proposes, for the first time, an integrated approach of DoE and LCA applied to an organic reaction with the aim of considering both conventional metrics, such as reaction yield, and unconventional ones, such as environmental impacts, during its lab-scale optimization.

A General and Highly Versatile Heterogeneous Pd-Catalyzed Oxidative Aminocarbonylation of Alkynes with Aromatic and Aliphatic Amines.

An efficient heterogeneous catalytic system for the oxidative aminocarbonylation of alkynes and amines in the presence of CO/O2 to afford substituted propiolamides has been developed. The active nanocatalyst, [Pd/Mg3Al-LDH]-300(D), is composed by Pd nanoaggregates (2-3 nm average particle size) stabilized over a partially dehydrated [Mg3Al-LDH] matrix. The methodology has resulted widely applicable, being the first catalytic system, either homogeneous or heterogeneous, able to activate not only aliphatic amines but also poorly-nucleophilic aromatic amines. In fact, >60 substituted propiolamides have been synthesized in good to excellent isolated yields through this methodology, being 27 novel compounds. An important characterization effort (XRD, 27Al MAS NMR, TGA, TPD-CO2, BET area, XPS, HAADF-HRSTEM and HRTEM) and optimization of the synthesis conditions of the optimal catalyst has been performed. This study, together with a series of kinetic and mechanistic essays, indicates that the optimal catalyst is composed by Pd(0) species stabilized in a partially dehydrated/dehydroxylated LDH material with a Mg/Al molar ratio of 3 and a small crystallite size. All the experimental data indicates that the in situ formation of [PdI2] active species in the material surface together with the presence of a matrix with the optimal acid/base properties are key aspects of this process.

A New Method of Constructing Methyleneindene and Quinoline Frameworks from Methylenecyclopropanes.

In this paper, we have established an operationally convenient protocol for the rapid construction of polysubstituted methyleneindene and quinoline derivatives under mild conditions. This new synthetic method is achieved through the conversion of acetyl-substituted methylenecyclopropanes with TsOH·H2O and ortho-amino-substituted methylenecyclopropanes with aromatic aldehyde and TsOH·H2O, respectively. A variety of transformations of the obtained products was demonstrated. The plausible reaction mechanisms were also proposed.

Mechanistic insights into C(sp2)-H activation in 1-Phenyl-4-vinyl-1H-1,2,3-triazole derivatives: a theoretical study with palladium acetate catalyst.

CONTEXT: The activation of C-H bonds is a fundamental process in synthetic organic chemistry, which enables their replacement by highly reactive functional groups. Coordination compounds serve as effective catalysts for this purpose, as they facilitate chemical transformations by interacting with C-H bonds. A comprehensive understanding of the mechanism of activation of this type of bond lays the foundation for the development of efficient protocols for cross-coupling reactions. We explored the activation of C(sp2)-H bonds in 1-Phenyl-4-vinyl-1H-1,2,3-triazole derivatives with CH3, OCH3, and NO2 substituents in the para position of the phenyl ring, using palladium acetate as catalyst. The studied reaction is the first step for subsequent conjugation of the triazoles with naphthoquinones in a Heck-type reaction to create a C-C bond. The basic nitrogen atoms of the 1,2,3-triazole coordinate preferentially with the cationic palladium center to form an activated species. A concerted proton transfer from the terminal vinyl carbon to one of the acetate ligands with low activation energy is the main step for the C(sp2)-H activation. This study offers significant mechanistic insights for enhancing the effectiveness of C(sp2)-H activation protocols in organic synthesis. METHODS: All calculations were performed using the Gaussian 09 software package and density functional theory (DFT). The structures of all reaction path components were fully optimized using the CAM-B3LYP functional with the Def2-SVP basis set. The optimized geometries were analyzed by computing the second-order Hessian matrix to confirm that the corresponding minimum or transition state was located. To account for solvent effects, the Polarizable Continuum Model of the Integral Equation Formalism (IEFPCM) with water as the solvent was used.

Interactions of Phenylalanine Derivatives with Human Tyrosinase: Lessons from Experimental and Theoretical tudies.

The pigmentation of the skin, modulated by different actors in melanogenesis, is mainly due to the melanins (protective pigments). In humans, these pigments' precursors are synthetized by an enzyme known as tyrosinase (TyH). The regulation of the enzyme activity by specific modulators (inhibitors or activators) can offer a means to fight hypo- and hyper-pigmentations responsible for medical, psychological and societal handicaps. Herein, we report the investigation of phenylalanine derivatives as TyH modulators. Interacting with the binuclear copper active site of the enzyme, phenylalanine derivatives combine effects induced by combination with known resorcinol inhibitors and natural substrate/intermediate (amino acid part). Computational studies including docking, molecular dynamics and free energy calculations combined with biological activity assays on isolated TyH and in human melanoma MNT-1 cells, and X-ray crystallography analyses with the TyH analogue Tyrp1, provide conclusive evidence of the interactions of phenylalanine derivatives with human tyrosinase. In particular, our findings indicate that an analogue of L-DOPA, namely (S)-3-amino-tyrosine, stands out as an amino phenol derivative with inhibitory properties against TyH.

A Structure-Activity Investigation of the Fungal Metabolite (-)-TAN-2483B: Inhibition of Bruton's Tyrosine Kinase.

The natural product (-)-TAN-2483B is a fungal secondary metabolite which displays promising anti-cancer and immunomodulatory activity. Our previous syntheses of (-)-TAN-2483B and sidechain analogues uncovered inhibitory activity against Bruton's tyrosine kinase (Btk), an established drug target for various leukaemia and immunological diseases. A structure-based computational study using ensemble docking and molecular dynamics was performed to determine plausible binding modes for (-)-TAN-2483B and analogues in the Btk binding site. These hypotheses guided the design of new analogues which were synthesised and their inhibitory activities determined, providing insights into the structural determinants of the furopyranone scaffold that confer both activity and selectivity for Btk. These findings offer new perspectives for generating optimised (-)-TAN-2483B-based kinase inhibitors for the treatment of leukaemia and immunological diseases.

Synthesis and biological evaluation of novel benzothiazole derivatives as potential anticancer and antiinflammatory agents.

Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks. Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers. Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 µM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties. Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study's mechanistic exploration, highlighting B7's simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.

Green synthesis of reduced graphene oxide by using tropical microalgae and its application in biophotovoltaic devices.

The successful commercialization of algal biophotovoltaics (BPV) technology hinges upon a multifaceted approach, encompassing factors such as the development of a cost-efficient and highly conductive anode material. To address this issue, we developed an environmentally benign method of producing reduced graphene oxide (rGO), using concentrated Chlorella sp. UMACC 313 suspensions as the reducing agent. The produced rGO was subsequently coated on the carbon paper (rGO-CP) and used as the BPV device's anode. As a result, maximum power density was increased by 950% for Chlorella sp. UMACC 258 (0.210 mW m-2) and 781% for Synechococcus sp. UMACC 371 (0.555 mW m-2) compared to bare CP. The improved microalgae adhesion to the anode and improved electrical conductivity of rGO brought on by the effective removal of oxygen functional groups may be the causes of this. This study has demonstrated how microalgal-reduced GO may improve the efficiency of algal BPV for producing bioelectricity.

Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors.

In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and drug-likeness consideration provided valuable support in selecting 5-methyl-2H-benzo[h]imidazo[1,5,4-de]quinoxalin-7(3H)-one as a candidate molecule. It was synthesized in a four-step sequence starting from 2,3-dichloronaphthalene-1,4-dione and evaluated as an inhibitor of electric eel acetylcholinesterase (eeAChE), human recombinant AChE (hAChE), and horse serum butyrylcholinesterase (BChE), together with other analogs obtained by the same synthesis. The candidate molecule showed a slightly lower inhibitory potential against eeAChE but better inhibitory activity against hAChE than discorhabdin G, with a higher selectivity for AChEs than for BChE. It acted as a reversible competitive inhibitor, as previously observed for the natural alkaloid. The findings from the in vitro assay were relatively consistent with the data available from the AutoDock Vina and Protein-Ligand ANTSystem (PLANTS) calculations.