Synthesized Research Articles

Heterologous Biosynthesis of Taxifolin in Yarrowia lipolytica: Metabolic Engineering and Genome-Scale Metabolic Modeling.

Taxifolin, also known as dihydroquercetin (DHQ), is a flavonoid recognized for its potent antioxidant properties and a wide range of biological activities, including anti-tumor, antiviral, and immunomodulatory effects. Conventional extraction and chemical synthesis methods for taxifolin are often limited by low yields and associated environmental concerns. In this study, we investigated the heterologous biosynthesis of taxifolin in Yarrowia lipolytica through a combination of metabolic engineering and genome-scale metabolic modeling (GSM), complemented by flux balance analysis (FBA). We engineered Yarrowia lipolytica by introducing key biosynthetic genes and successfully synthesized taxifolin using naringenin (NAR) as a substrate, chosen for its low cost. Fermentation experiments demonstrated an optimal taxifolin yield of 10% at a substrate concentration of 200mg/L naringenin, with a maximum yield of 26.4mg/L taxifolin at 1g/L naringenin. To further enhance production, we applied a marker-free Cre-loxP-based gene integration method, allowing stable genomic integration of key genes, which increased taxifolin yield to 34.9mg/L at 1g/L naringenin. Additionally, intermediate metabolites eriodictyol (ERI) and dihydrokaempferol (DHK) accumulated to concentrations of 89.2mg/L and 21.7mg/L, respectively. Furthermore, we integrated metabolic data into a GSM and applied FBA to optimize the taxifolin biosynthetic pathway. Through Pareto frontier analysis, sensitivity analysis, flux variability analysis, and single gene deletion simulations, we identified key genetic modifications that significantly enhanced taxifolin yield. Overexpression of GND1 and IDP2 increased yields by 94% and 155%, respectively, while knockout of LIP2 led to a 46% increase. Using tri-baffled shake flasks to improve oxygen supply resulted in a 120% yield increase, whereas YPG medium decreased yield by 59%, validating our model's accuracy. To ensure stable and efficient gene expression, we integrated multi-copy constructs into the ribosomal DNA (rDNA) locus of Yarrowia lipolytica, doubling taxifolin production. These results demonstrate the effectiveness of GSM and FBA in addressing bottlenecks in microbial taxifolin biosynthesis and provide a basis for future optimization and large-scale production.

Understanding the role of oxidants for enhanced remediation of groundwater nitrate: An insight into surface modification

Rapid urbanization and excessive agricultural runoff caused nitrate levels in groundwater to exceed permissible limits, making drinking water toxic and unsafe for consumption. Numerous physicochemical and biological treatment methods have been explored to remove nitrate from water; however, adsorption, a surface phenomenon, has a wide range of applications because of its rapid rate of reaction, recyclability, and environmentally friendly synthesis method. In this direction, this study aimed to unravel the role of oxidants in the facile synthesis of a competent zirconium-based adsorbent to remove nitrate from groundwater. The wet oxidative method, a facile chemical synthesis process requires an oxidant, which adds the oxidative functionalities on the surface of the adsorbent, which offers excessive anchorage to the transition metal on the surface of the adsorbent during synthesis. The batch experiments were conducted to evaluate the effectiveness of the adsorbents in treating nitrate. The maximum adsorption capacity of competent adsorbent was 113.97 mg/g at 300 K, which is considerably high compared to 62.83 mg/g of raw activated carbon and other existing adsorbents. The sorption capacity is reduced with an increase in temperature, which favors adsorption at lower temperatures. Adsorbents were successfully applied to test the groundwater samples showing increased removal efficiency. About 97 % desorption was obtained using 0.5 M NaOH, which facilitates the adsorbents for reuse. The developed adsorbent shows promising effectiveness in removing nitrate and could be used at a large scale.

Efficient Method of (S)-Nicotine Synthesis

Improved methods for the synthesis of nicotine are of great importance due to the wide range of applications of synthetic nicotine, which is free from contamination with nitrosamines. Herein, we present a four-step chemical synthesis of (S)-nicotine, involving the reduction in myosmine, enantiomeric separation of nornicotine, and subsequent methylation of the appropriate enantiomer of nornicotine obtained. The reduction in myosmine was investigated using both electrochemical and chemical approaches, achieving up to 90% yields of pure nornicotine. To achieve the enantioseparation of nornicotine, its diastereomeric salts with chiral acids, specifically, N-lauroyl-(R)-alanine, were obtained in a mixture of methyl tert-butyl ether (MTBE) and chloroform, which led to the isolation of (S)-nornicotine with 92% ee. The structures of the obtained salts were determined by the X-ray diffraction (XRD) technique, which helped to explain the origin of enantiodiscrimination during the crystallization. The described methodology allows efficient regeneration of the reagents and solvents used, leading to cost-effective production of (S)-nicotine suitable for industrial-scale applications.

Visible Light-Induced Photocatalyst-Free Diastereoselective Iodosulfonylation of Cyclopropenes in Water.

This study presents a greener approach to the visible-light-induced micellar-catalyzed diastereoselective iodosulfonylation of cyclopropenes in a water medium. Remarkably, this process operates without a photocatalyst. Instead, it utilizes an electron-donor-acceptor complex formed between sulfonyl chloride and sodium iodide. This method is highly efficient and broadly applicable for both aromatic and aliphatic sulfonyl chlorides. Furthermore, this protocol enables the transformation of iodosulfonated cyclopropanes into sulfonated cyclopropenes, highlighting its substantial value as a versatile and powerful tool in synthetic chemistry.

Chemoselective Anaerobic Dehydrogenation of Alcohols By Using Visible Light and a Positively Charged Deazaflavin Catalyst Regenerated by Acetonitrile Solvent

Three series of novel deazaflavinum salts differing in their substitutions at positions 5 (R = H, phenyl or mesityl), 7 and 8 (R = OMe, Me, H or Cl) were synthesized as potential catalysts of a novel chemoselective visible light–mediated anaerobic oxidation of primary and secondary alcohols to carbonyl compounds. This mild procedure uses acetonitrile as a solvent, which acts simultaneously as a sacrificial electron acceptor (in place of the oxygen usually used in photooxidation reactions) and therefore the reaction does not need any additives. Structural and properties‐versus‐catalytic activity studies identified 5‐mesityl‐7,8‐dimethoxy‐3‐methyldeazaflavinium chloride (3a‐Cl) as the most potent catalyst. 3a‐Cl was effective in non‐deuterated acetonitrile (CH3CN), unlike its original 5‐phenyl analogue 2a‐Cl, which is efficient only in deuterated solvent (CD3CN). This difference arises because the regeneration of the 2a‐Cl catalyst is slower in CH3CN than in CD3CN. Our method using the optimized 3a‐Cl photocatalyst and CH3CN as a sacrificial oxidant and solvent in one is a useful addition to synthetic organic chemistry. Anaerobic conditions prevent side oxygenation reactions and overoxidations that usually occur in air or oxygen. This property makes this method suitable for dehydrogenations of alcohols that possess additional group(s) sensitive to oxygenation.

Bioimaging potential: Comparative study of ZnO nanoparticles synthesized via green and chemical routes

Zinc Oxide Nanoparticles (ZnO NPs) were synthesized through chemical and green synthesis methods employing Ficus religiosa (peepal) leaf extract. The synthesized nanoparticles underwent comprehensive characterization using various techniques such as Powder X-ray Diffractometry (PXRD), Fourier-transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), Photoluminescence (PL), UV–visible Spectroscopy, and Spectroscopic Ellipsometry. The PXRD analysis confirmed a hexagonal wurtzite structure with excellent crystallinity in the product. UV–visible studies indicated band gap energies of 3.13 eV and 2.7 eV for green-synthesized and chemically synthesized ZnO NPs, respectively. There was notable augmentation in the fluorescence characteristics of ZnO NPs derived through green synthesis when compared to chemically synthesized NPs. This observed enhancement in fluorescence renders the green-synthesized ZnO NPs particularly advantageous for bio-imaging.

A Comprehensive Review on Construction of Biologically Active α‐Carbolines From Synthetic And Natural Origin.

Abstractα‐Carboline is an important scaffold present in various synthetic and naturally obtained bioactive compounds possessing a wide range of pharmacological properties. Hence, in the current comprehensive review, we intend to present the main routes to the synthesis of α‐carboline analogs based on various pathways such as pyrrole, benzene, and pyridine ring annulation. The pathways include either or combinations of transition metal‐catalyzed amination/arylation, Graebe‐Ullmann reaction (thermal pyrolysis, photochemical cyclization), Diels‐Alder cycloaddition and condensation reactions, N‐Heterocyclic carbene catalysed reactions, decarboxylative annulation, etc. of substituted benzene, pyridine, quinoline, and indole derivatives in order to compare the potential of synthetic routes of this series and consolidate the development, current status and perspectives for the design of α‐carboline analogs. Various pharmacological and spectroscopy functions of the compounds belonging to this class are summarized herewith. It also discusses the synthesis of functionalized bioactive naturally obtained hetero‐annulated α‐carbolines.

Exploring the Modelling of Gold Anisotropic Nanoparticles’ Optical Properties as a Promising Tool for Detection Systems Design

Gold nanoparticles have been a central topic in the last few decades due to their excellent optical properties that can be exploited in many applications, including food analysis, materials science, and biomedicine. The basis of these unique optical properties is the phenomenon known as localized surface plasmon (LSP), which relays in the collective oscillation of the conduction band electrons in the nanoparticle when excited by electromagnetic radiation. The optical properties of the nanoparticles are critical for selecting the best nanomaterials for each application, a key factor for optimum performance, and can be tuned due to their dependence on the geometry and size of the nanoparticles, as well as the polarization of the light beam. Here, we conducted simulations to study the tunable optical properties and local electric field distribution of three types of gold nanoparticles, cubes (AuNC), boxes (AuNB), and triangular prisms (AuNT), which have relatively simple synthetic routes. Finally, we compared these results with experimental data and described possible synthetic routes to discuss the positive and negative aspects of using each type of nanoparticle for potential applications.

Towards the synthesis of UDP-apiofuranose

AbstractApiose is a rare sugar present in cell-wall glycans of all higher plants. Apiosyltransferases use uridine diphosphate-α-d-apiofuranose (UDP-Api) to biosynthesize apiose-containing pectic polysaccharides, namely rhamnogalacturonan-II (RG-II) and apiogalacturonan. However, the study of apiosyltransferases is hampered by the limited availability of UDP-Api. Here, we report the challenging chemical synthesis of α-apiosyl 1-phosphate as the key intermediate towards UDP-Api synthesis. Various protecting group patterns and synthetic routes, including phosphoglycosylation, phosphorylation of the hemiacetal, and phosphorylation of the anomeric bromide were screened. The latter strategy enabled the synthesis of apiosyl 1-phosphate with good α-selectivity (α:β = 5:1). Additionally, we describe a pyrophosphate coupling reaction of the synthesized glycosyl 1-phosphate with commercially available uridine-monophosphate morpholidate to obtain UDP-Api. This test reaction was monitored by 31P-NMR spectroscopy, which showed formation of the desired product and its partial hydrolysis due to an unwanted intramolecular cyclisation typical of 1,2-cis UDP-sugars. Graphical abstract

Tuning antibacterial efficacy against Pseudomonas aeruginosa by using green AgNPs in chitosan thin films as a plastic alternative

Nanotechnology advancements have facilitated the development of eco-friendly strategies to combat bacterial infections caused by antibiotic-resistant pathogens. This study promotes a green method for the synthesis of silver nanoparticles (AgNPs) utilizing Eucalyptus globulus leaf extracts as an alternative to traditional colloidal AgNPs obtained through chemical synthesis, investigating their antibacterial efficacy against Pseudomonas aeruginosa and their impact on the expression of bacterial virulence factors (pyocyanin, pyoverdine, rhamnolipids). This work demonstrates that: i. while colloidal AgNPs showed ineffective up to 120 μM, green AgNPs had a bactericidal effect already at 20 μM, without impacting bacterial virulence factors at sub-inhibitory concentrations; ii. the polyphenolic shell surrounding green AgNPs could play a crucial role in the antibacterial mechanisms, with a pro-oxidant action confirmed by a greater sensitivity to hydrogen peroxide (H2O2); iii. AgNPs improved the antibacterial properties of chitosan when incorporated into thin films. Consequently, an environmentally friendly nanocomposite film with antibacterial and antibiofilm properties was produced, which holds promise for application in food packaging to mitigate the emergence of microbial contamination in food products.

The Combination of Graphitic Carbon Nitride (gC3N4) and Supercritical Carbon Dioxide for Green Photooxidation of Benzylic Alcohols

AbstractThe research focuses on the innovative use of graphite‐like carbon nitride (gC3N4) catalysts along with supercritical carbon dioxide (scCO2) for the green synthesis of valuable organic compounds. Having explored different synthetic routes for gC3N4 and the obtained samples efficiency in the photocatalytic oxidation of benzyl alcohol with molecular oxygen in scCO2, we identified the most effective catalyst bearing ether linkers between layers of a graphite‐like structure. This catalyst facilitates the production of benzaldehyde and benzoic acid derivatives, highlighting the potential for sustainable industrial applications. The study's emphasis on a metal‐free catalyst and a zero‐waste process underlines its contribution to environmentally friendly chemical practices. The proposed approach offers a more sustainable and efficient alternative to traditional processes in small‐scale chemical production.

An ACE2 PET imaging agent derived from 18F/Cl exchange of MLN-4760 under phase transfer catalysis

BackgroundAngiotensin-converting enzyme-2 (ACE2) acts as a key regulatory molecule and important therapeutic target in the pathological remodeling of numerous organs and diseases. In this study, a rapid, simple, and efficient synthetic route with a catalytic, 18F-for-Cl (18F/Cl) exchange scheme was designed for the preparation of 18F-labeled MLN-4760, and its targeting ability was investigated in a humanized ACE2 mouse model.ResultsA novel 18F-labeled MLN-4760 radioligand, abbreviated as 18F-MLN-4760, was successfully synthesized by the 18F/Cl exchange-labeling, and was purified by SepPak C18 columns with a radiochemical yield of 30% and a radiochemical purity of 29.89%. Target distribution of 18F-MLN-4760 in several organs with high ACE2 expression was observed by PET imaging with good stability over 120 min. The biodistribution data showed that the uptake of 18F-MLN-4760 in ACE2-overexpressing organs and tissues was highly specific, and immunohistochemistry confirmed the same results of ACE2 expression and biodistribution in the major organs (heart, liver, lungs, and kidneys). There was a good correlation between the uptake in the organs with high ACE2 expression and ACE2 expression levels (r = 0.935).Conclusion18F-MLN-4760 was successfully synthesized via 18F/Cl exchange under phase transfer catalysis, and served as a potential probe for ACE2-targeted PET imaging.

Total Synthesis of Euphorbialoid A.

Euphorbialoid A (1) belongs to the rare diterpenoid family of premyrsinanes and exhibits potent anti-inflammatory effects. The 5/7/6/3-membered carbocycle (ABCD-ring) of 1 contains 11 contiguous stereocenters and seven oxygen-containing functional groups. Moreover, four of the six hydroxy groups of 1 are concentrated in the southern sector and flanked by four structurally different acyl groups. The dense array of various functional groups with disparate reactivities on the tetracyclic ABCD-ring presents a daunting challenge for the chemical synthesis of 1. As a reflection of its formidable complexity, synthesis of 1 or any other premyrsinane diterpenoids has not yet been reported. Here, we devised a novel strategy comprising two stages and achieved the first total synthesis of 1 (35 steps as the longest linear sequence). In the first stage, the ABCD-ring was expeditiously assembled by integrating three powerful transformations: (1) Pt-doped TiO2-catalyzed radical coupling to attach a northern chain to a 6/3-membered CD-ring, (2) Pd-catalyzed decarboxylative asymmetric allylation to construct a quaternary carbon with a southern chain, and (3) a Co-mediated Pauson-Khand reaction to cyclize the two chains into the 5/7-membered AB-ring. In the second stage, three-dimensional structures of the ABCD-ring intermediates were utilized to stereoselectively fabricate the A-ring and site-selectively append the four different acyl groups. In the present total synthesis, we revealed the significance of orchestrating the multistep reaction sequence and incorporating cyclic protective groups. The overall strategy and tactics provide new insights into designing synthetic routes to premyrsinanes and densely oxygenated terpenoids decorated with diverse acyl groups.

Recent Advancements in the Application of Artificial Intelligence in Drug Molecular Generation and Synthesis Planning

AbstractThe design and synthesis of drug molecules is a pivotal stage in drug development that traditionally requires significant investment in time and finances. However, the integration of artificial intelligence (AI) in drug design accelerates the identification of potential drug candidates, optimizes the drug development process, and contributes to more informed decision-making. The application of AI in molecular generation is changing the way researchers explore the chemical space and design novel compounds. It accelerates the process of drug discovery and materials science, enabling rapid exploration of the vast chemical landscapes for the identification of promising candidates for further experimental validation. The application of AI in predicting reaction products accelerates the synthesis planning process, contributes to the automation of synthetic chemistry tasks, and supports chemists in making informed decisions during drug discovery. This paper reviewed the recent advances in two interrelated areas: the application of AI in molecular generation and synthesis routes. It will provide insights into the innovative ways in which AI is transforming traditional approaches in drug development and predict its future progress in these key fields.

Natural products as drug leads: exploring their potential in drug discovery and development.

Natural products have been pivotal in drug discovery, offering a wealth of bioactive compounds that significantly contribute to therapeutic developments. Despite the rise of synthetic chemistry, natural products continue to play a crucial role due to their unique chemical structures and diverse biological activities. This study reviews and evaluates the potential of natural products in drug discovery and development, emphasizing the integration of traditional knowledge with modern drug discovery methodologies and addressing the associated challenges. A comprehensive literature search was conducted across PubMed/MedLine, Scopus, Web of Science, Google Scholar, and Cochrane Library, covering publications from 2000 to 2023. Inclusion criteria focused on studies related to natural products, bioactive compounds, medicinal plants, phytochemistry, and AI applications in drug discovery. Data were categorized into source, extraction methods, bioactivity assays, and technological advances. The current review underscores the historical and ongoing importance of natural products in drug discovery. Technological advancements in chromatographic and spectroscopic techniques have improved the isolation and structural elucidation of bioactive compounds. AI and machine learning have streamlined the identification and optimization of natural product leads. Challenges such as biodiversity sustainability and development complexities are discussed, alongside innovative approaches like biosynthetic engineering and metagenomics. Natural products remain a vital source of novel therapeutic agents, providing unique chemical diversity and specific biological activities. Integrating traditional knowledge with modern scientific methods is essential for maximizing the potential of natural products in drug discovery. Despite existing challenges, ongoing research and technological advancements are expected to enhance the efficiency and success of natural product-based drug development.

Triflic Acid‐Catalyzed Dehydrative Amination of 2‐Arylethanols with Weak N‐Nucleophiles in Hexafluoroisopropanol

AbstractThe catalytic deoxyamination of readily available 2‐arylethanols offers an appealing, simple, and straightforward means of accessing β‐(hetero)arylethylamines of biological interest. Yet, it currently represents a great challenge to synthetic chemistry. In most cases, the alcohol has to be either pre‐activated in situ or converted into a reactive carbonyl intermediate, limiting the substrate scope for some methods. Examples of direct dehydrative amination of 2‐arylethanols are thus still scarce. Here, we describe a catalytic protocol based on the synergy of triflic acid and hexafluoroisopropanol, which enables the direct and stereospecific amination of a broad array of 2‐arylethanols, and does not require any pre‐activation of the alcohol. This approach yields high value‐added products incorporating sulfonamide, amide, urea, and aniline functionalities. In addition, this approach was applied to the sulfidation of 2‐arylethanols. Mechanistic experiments and DFT computations indicate the formation of phenonium ions as key intermediates in the reaction.

A Supramolecular Approach to Engineering Living Cells with Enzymes for Adaptive and Recyclable Cascade Synthesis

Biocatalytic transformation in nature is inherently dynamic, spontaneous, and adaptive, enabling complex chemical synthesis and metabolism. These processes often involve supramolecular recognition among cells, enzymes, and biomacromolecules, far surpassing the capabilities of isolated cells and enzymes used in industrial synthesis. Inspired by nature, here we design a supramolecular approach to equip living cells with these capacities, enabling recyclable, efficient cascade reactions. Our two‐step "plug‐and‐play" methodology begins by coating Escherichia coli cells with guest‐containing polymers (SupraBAC) via supramolecular charge interactions, followed by the introduction of β‐cyclodextrin‐functionalized host enzymes through host‐guest chemistry, creating a robust cell‐enzyme complex. This supramolecular coating not only protects cells from various stresses, such as UV radiation, heat, and organic solvents, but also facilitates the overexpression of intracellular enzymes and the attachment of extracellular enzymes within and on SupraBAC. This combination results in efficient multienzyme cascade synthesis, enabling two‐ and three‐step reactions in one pot. Importantly, the multienzyme system can be recycled up to five times without significant loss of activity. Our findings introduce a versatile, adaptive supramolecular coating for whole‐cell catalysts, offering a sustainable and efficient solution for complex synthesis in both chemistry and industrial biotechnology.

Electroless Synthesis of Cobalt Nanowires in Magnetic Field and their Characterization by Resonant Magnetometry Methods

In this paper, a simple and effective low-temperature electroless chemical method that provides the synthesis of cobalt micro- and nanowires due to the processes of self-organization of magnetic cobalt nanoparticles under the influence of a magnetic field, using the technology of chemical synthesis of magnetic nanoparticles and nanowires is proposed. Cobalt nanoparticles have magnetic dipole moments. An external magnetic field forces them to be oriented parallel to it. Dipole-dipole interactions between magnetic nanoparticles lead to attraction between cobalt nanoparticles leading to their self-organization into nanowires, reducing their total energy. The resulting smaller nanoparticles fill the gaps between the ordered nanoparticles, leading to the formation of smooth cobalt nanowires. The magnetic and structural properties of the synthesized and commercial nanowires polarized by a magnetic field in the epoxy matrix were studied using the resonant radio-frequency magnetometry and electron microscopy methods. These methods are of interest for optimizing the coercive force of cobalt nanowires with a view to their possible use in creating permanent magnets that do not use rare earth elements, as well as in information processing devices and sensors.

Antimicrobial Peptides: A Promising Solution to the Rising Threat of Antibiotic Resistance

The demand for developing novel antimicrobial drugs has increased due to the rapid appearance and global spread of antibiotic resistance. Antimicrobial peptides (AMPs) offer distinct advantages over traditional antibiotics, such as broad-range efficacy, a delayed evolution of resistance, and the capacity to enhance human immunity. AMPs are being developed as potential medicines, and current computational and experimental tools aim to facilitate their preclinical and clinical development. Structural and functional constraints as well as a more stringent regulatory framework have impeded clinical translation of AMPs as possible therapeutic agents. Although around four thousand AMPs have been identified so far, there are some limitations of using these AMPs in clinical trials due to their safety in the host and sometimes limitations in the biosynthesis or chemical synthesis of some AMPs. Overcoming these obstacles may help to open a new era of AMPs to combat superbugs without using synthetic antibiotics. This review describes the classification, mechanisms of action and immune modulation, advantages, difficulties, and opportunities of using AMPs against multidrug-resistant pathogens and highlights the need and priorities for creating targeted development strategies that take into account the most cutting-edge tools currently available. It also describes the barriers to using these AMPs in clinical trials.

Green and chemical synthesis of TiO2 nanoparticles: An In-depth comparative analysis and photoluminescence study

Titania nanoparticles were synthesized by sol-gel method using chemical and natural solvents. Isopropanol is used as a chemical solvent for the reduction of ions. Further, Jasminum and Magnolia champaca flower extracts were individually used as natural solvents which acts as both reducing and stabilizing agents. The role of natural solvents over chemical solvents on the structure, phase, morphology, and optical properties of TiO2 nanoparticles were investigated. Synthesis using natural solvents led to rutile phase of TiO2 nanoparticles while, chemical synthesis produced anatase phase. Green synthesis yielded larger crystallite size TiO2 compared to chemical synthesis. Synthesized TiO2 exhibited PL emission centered at 397 nm with excitation 325 nm associated with weak emissions noticed at 450 nm, 470 nm, and 520 nm.