Synthetic Modification Research Articles

Design, synthesis, and applications of ring-functionalized histidines in peptide-based medicinal chemistry and drug discovery.

Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.

Potential health risks of mRNA-based vaccine therapy: A hypothesis

Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (nms-mRNAs) is impeded. Sustained presence of nms-mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the nms-mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of nms-mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.

Applications of Bacteria Decorated with Synthetic DNA Constructs.

The advent of DNA nanotechnology has revolutionized the way DNA has been perceived. Rather than considering it as the genetic material alone, DNA has emerged as a versatile synthetic scaffold that can be used to create a variety of molecular architectures. Modifying such self-assembled structures with bio-molecular recognition elements has further expanded the scope of DNA nanotechnology, opening up avenues for using synthetic DNA assemblies to sense or regulate biological molecules. Recent advancements in this field have lead to the creation of DNA structures that can be used to modify bacterial cell surfaces and endow the bacteria with new properties. This mini-review focuses on the ways by which synthetic modification of bacterial cell surfaces with DNA constructs can expand the natural functions of bacteria, enabling their potential use in various fields such as material engineering, bio-sensing, and therapy. The challenges and prospects for future advancements in this field are also discussed.

Stabilization of Functional DNA Structures with Mild Photochemical Methods.

A significant barrier to biological applications of DNA structures is their instability to nucleases. UV-mediated thymine dimerization can crosslink and stabilize DNA nanostructures, but its effect on DNA strand hybridization fidelity and function is unclear. In this work, we first compare a number of methods for DNA irradiation with different wavelengths of light and different photosensitizers. We demonstrate that all approaches can achieve nuclease protection; however, the levels of DNA off-target crosslinking and damage vary. We then describe mild irradiation conditions intended to safeguard DNA against nuclease degradation. We demonstrate up to 25× increase in serum stability while minimizing off-target damage and maintaining functions such as hybridization efficiency, gene silencing, aptamer binding, and DNA nanostructure formation. Our methodology requires no complex instruments beyond a UV light source and no synthetic modification of the DNA itself, allowing for applications in numerous areas of nucleic acid therapy and nanotechnology.

Structural basis of transcription recognition of a hydrophobic unnatural base pair by T7 RNA polymerase

Bacteriophage T7 RNA polymerase (T7 RNAP) is widely used for synthesizing RNA molecules with synthetic modifications and unnatural base pairs (UBPs) for a variety of biotechnical and therapeutic applications. However, the molecular basis of transcription recognition of UBPs by T7 RNAP remains poorly understood. Here we focused on a representative UBP, 7-(2-thienyl)-imidazo[4,5-b]pyridine (Ds) and pyrrole 2-carbaldehyde (Pa), and investigated how the hydrophobic Ds–Pa pair is recognized by T7 RNAP. Our kinetic assays revealed that T7 RNAP selectively recognizes the Ds or Pa base in the templates and preferentially incorporates their cognate unnatural base nucleotide substrate (PaTP or DsTP) over natural NTPs. Our structural studies reveal that T7 RNAP recognizes the unnatural substrates at the pre-insertion state in a distinct manner compared to natural substrates. These results provide mechanistic insights into transcription recognition of UBP by T7 RNAP and provide valuable information for designing the next generation of UBPs.

A ligand insertion mechanism for cooperative NH3 capture in metal-organic frameworks.

Ammonia is a critical chemical in agriculture and industry that is produced on a massive scale via the Haber-Bosch process1. The environmental impact of this process, which uses methane as a fuel and feedstock for hydrogen, has motivated the need for more sustainable ammonia production2-5. However, many strategies that use renewable hydrogen are not compatible with existing methods for ammonia separation6-9. Given their high surface areas and structural and chemical versatility, metal-organic frameworks (MOFs) hold promise for ammonia separations, but most MOFs bind ammonia irreversibly or degrade on exposure to this corrosive gas10,11. Here we report a tunable three-dimensional framework that reversibly binds ammonia by cooperative insertion into its metal-carboxylate bonds to form a dense, one-dimensional coordination polymer. This unusual adsorption mechanism provides considerable intrinsic thermal management12, and, at high pressures and temperatures, cooperative ammonia uptake gives rise to large working capacities. The threshold pressure for ammonia adsorption can further be tuned by almost five orders of magnitude through simple synthetic modifications, pointing to a broader strategy for the development of energy-efficient ammonia adsorbents.

Tyrosinase Inhibitors Naturally Present in Plants and Synthetic Modifications of These Natural Products as Anti-Melanogenic Agents: A Review

Tyrosinase is a key enzyme target to design new chemical ligands against melanogenesis. In the current review, different chemical derivatives are explored which have been used as anti-melanogenic compounds. These are different chemical compounds naturally present in plants and semi-synthetic and synthetic compounds inspired by these natural products, such as kojic acid produced by several species of fungi; arbutin-a glycosylated hydroquinone extracted from the bearberry plant; vanillin-a phenolic aldehyde extracted from the vanilla bean, etc. After enzyme inhibition screening, various chemical compounds showed different therapeutic effects as tyrosinase inhibitors with different values of the inhibition constant and IC50. We show how appropriately designed scaffolds inspired by the structures of natural compounds are used to develop novel synthetic inhibitors. We review the results of numerous studies, which could lead to the development of effective anti-tyrosinase agents with increased efficiency and safety in the near future, with many applications in the food, pharmaceutical and cosmetics industries.

Quantitative NMR spectroscopy reveals solvent effects in the photochemical degradation of thymoquinone

Thymoquinone, a monoterpene natural product isolated from Nigella sativa, has demonstrated potent antioxidant, cytotoxic, anticancer, and anti-inflammatory activity, making it a compound of great therapeutic potential and scientific interest. However, as a photochemically labile compound that can dimerize or decompose into other compounds upon irradiation, its clinical administration and synthetic modifications are greatly limited by its instability in the presence of light. Therefore, it is crucial to have a reliable way to quantify decreases in thymoquinone concentration as an indicator of photodegradation to provide insight into the chemical use of the compound. Here, we employed quantitative 1H nuclear magnetic resonance (NMR) spectroscopy as well as computational time-dependent density functional theory (TD-DFT) calculations to identify the effect of solvation on the photochemical degradation of thymoquinone under ultraviolet light (UV). We found that the rate of photochemical degradation of thymoquinone is highly solvent dependent, and that greatest photodegradation occurs in chloroform. The results presented here are informative for future solvent selection related to the isolation and experimental usage of the compound in solution.

Red-light photoswitching of indigos in polymer thin films.

Through simple synthetic derivatisation, the parent indigo dye becomes a red-light E-Z photoswitch exhibiting negative photochromism and tuneable thermal isomerisation kinetics. These attributes make indigo derivatives extremely attractive for applications related to materials and living systems. However, there is a lack of knowledge in translating indigo photoswitching dynamics from solution to solid state - the environment crucial for most applications. Herein, we study the photoswitching performance of six structurally distinct indigo derivatives in five polymers of varying rigidity. Three key strategies are identified to enable efficient photoswitching under red (660 nm) light: (i) choosing a soft polymer matrix to minimise its resistance toward the isomerisation, (ii) creating free volume around the indigo molecules through synthetic modifications, and (iii) applying low dye loading (<1% w/w) to inhibit aggregation. These strategies are shown to improve both photostationary state distributions and the thermal stability of the Z isomer. When all three strategies are implemented, the isomerisation performance (>80% Z form in the photostationary state) is nearly identical to that in solution. These findings thus pave the way for designing new red-light photochromic materials based on indigos.

Keeping the chromophores crossed: evidence for null exciton splitting.

Fundamental understanding of the supramolecular assemblies of organic chromophores and the development of design strategies have seen endless ripples of interest owing to their exciting photophysical properties and optoelectronic applications. The independent discovery of dye aggregates by Jelley and Scheibe was the commencement of the remarkable advancement in the field of aggregate photophysics. Subsequent research warranted an exceptional model for defining the exciton interactions in aggregates, proposed by Davydov, Kasha and co-workers, independently, based on the long-range Coulombic coupling. Fascinatingly, the orthogonally cross-stacked molecular transition dipole arrangement was foretold by Kasha to possess null exciton interaction leading to spectroscopically uncoupled molecular assembly, which lacked an experimental signature for decades. There have been several attempts to identify and probe atypical molecular aggregates for decoding their optical behaviour. Herein, we discuss the recent efforts in experimentally verifying the unusual exciton interactions supported with quantum chemical computations, primarily focusing on the less explored null exciton splitting. Exciton engineering can be realized through synthetic modifications that can additionally offer control over the assorted non-covalent interactions for orchestrating precise supramolecular assembly, along with molecular editing. The task of attaining a minimal excitonic coupling through an orthogonally cross-stacked crystalline architecture envisaged to offer a monomer-like optical behaviour was first reported in 1,7-dibromoperylene-3,4,9,10-tetracarboxylic tetrabutylester (PTE-Br2). The attempt to stitch molecules covalently in an orthogonal fashion to possess null excitonic character culminated in a spiro-conjugated perylenediimide dimer exhibiting a monomer-like spectroscopic signature. The computational and experimental efforts to map the emergent properties of the cross-stacked architecture are also discussed here. Using the null aggregates formed by the interference effects between CT-mediated and Coulombic couplings in the molecular array is another strategy for achieving monomer-like spectroscopic properties in molecular assemblies. Moreover, identifying supramolecular assemblies with precise angle-dependent properties can have implications in functional material design, and this review can provide insights into the uncharted realm of null exciton splitting.

Mussel-Based Biomimetic Strategies in Musculoskeletal Disorder Treatment: From Synthesis Principles to Diverse Applications

Musculoskeletal disorders are the second leading cause of disability worldwide, posing a huge global burden to the public sanitation system. Currently, tissue engineering-based approaches act as effective strategies, which are, however, challenging in limited application scenarios. Mussel-based biomimetic materials, exhibit numerous unique properties such as intense adhesion, biocompatibility, moisture resistance, and injectability, to name only a few, and have attracted extensive research interest. In particular, featuring state-of-the-art properties, mussel-inspired biomaterials have been widely explored in innumerable musculoskeletal disorder treatments including osteochondral defects, osteosarcoma, osteoarthritis, ligament rupture, and osteoporosis. Nevertheless, a comprehensive and timely discussion of their applications in musculoskeletal disorders is insufficient. In this review, we emphasize on (1) the main categories and characteristics of mussel foot proteins and their fundamental mechanisms for the spectacular adhesion in mussels; (2) the diverse synthetic methods and modification of various polymers; and (3) the emerging applications of mussel-biomimetic materials, the future perspectives, and challenges, especially in the area of musculoskeletal disorder. We envision that this review will provide a unique and insightful perspective to improve the development of a new generation of mussel biomimetic strategies.

Synthetic approaches, modification ability and biological activity of 1,3,4-thiadiazole based [5+5] annelated heterosystems: Mini-review

Condensed bicyclic systems with thiadiazole core being annelated to other five-membered heterocycles such as 1,3-thiazole, imidazole or 1,2,4-triazole occupy prominent place in medicinal chemistry because of their broad spectrum of pharmacological activities. The combination of several heterocycles into a bicyclic system commonly provides much more interest in the enhanced activity profile of its analogs than their parent separate constituents. In this review, we summarized the literature data about the main approaches for obtaining and possible directions of structural modification of the most common 1,3,4-thiadiazole containing [5+5] annelated heterosystems as promising objects for modern medicinal chemistry.

Novel synthetic methodology of Diclofenac derivatives and its spectrochemical studies

To design the novel synthetic scheme, structural modification, characterization, and pharmacological evaluation of new derivatives of Diclofenac drugs is the main aim of the current research work. We describe the utility of novel reagents and green synthetic methodology to formulate the derivatives to enhance its biological action without undesirable effects. Diclofenac sodium is the phenylacetic acid salt and categorized under nonsteroidal anti-inflammatory drug (NSAID) with pain-relieving, antipyretic, and anti-inflammatory activity, but it has limits and adverse effects as gastrointestinal irritation, small intestine damage, nausea, platelet dysfunction and vertigo. Diclofenac amide derivatives are prepared with Sulphanilic acid and Naphthylamine by the following methods such as reflux and microwave irradiation method. Structural modification is carried out to build up the desired properties. The new synthesized derivatives were structurally characterized with the help of FT-IR, UV–Visible spectroscopy, and MS spectrometry techniques. Further we propose the pharmacological evaluation of Diclofenac derivatives will be carried out by in-vivo and invitro methods.

Selective photo-oxidative coupling of amines to form C–N bonds using post synthetic modification of MIL-68-NH2 with metal acetylacetonate

Significant attention has been paid to the conversion of benzylamine into very valuable organic intermediates via selective photocatalytic oxidation using modified MOFs with acetylacetonate linker.

Spin crossover in mixed-anion Fe(NH2trz)3(BF4)(SiF6)0.5 crystalline rod-shaped particles: the strength of the solid-liquid post synthetic modification.

A pure mixed-anion Fe(NH2trz)3(BF4)(SiF6)0.5 spin crossover complex is obtained implementing a solid-liquid post synthetic modification approach from the Fe(NH2trz)3(BF4)2 parent complex. This method allows obtaining highly crystalline powder samples incorporating homogeneous micrometric (1 μm long) rod-shaped particles. This compound presents an abrupt spin crossover behaviour with a narrow (10 K) hysteresis loop centred just above room temperature (320 K) which makes it very interesting for future integration into devices for various applications.

The development of chiral metal-organic frameworks for enantioseparation of racemates.

MIL-101(Cr), an achiral metal-organic framework, made up of a terephthalic acid ligand and a metal chromium ion was selected as a template. Its structural features are unsaturated Lewis acid sites that can be easily activated and it has an extremely high specific surface area, big pore size, and good thermal/chemical/water stability. This achiral framework was modified to introduce chirality within the structure to develop chiral metal-organic frameworks (CMOFs). Here, natural chiral ligands, amino acids (l-proline, l-thioproline and l-tyrosine), were selected for post synthetic modification (PSM) of MIL-101(Cr). This is a very simple, clean and facile methodology with respect to the reactants and reaction conditions. CMOFs 1-3 abbreviated as MIL-101-l-proline (CMOF-1), MIL-101-l-thioproline (CMOF-2) and MIL-101-l-tyrosine (CMOF-3) were prepared by introducing l-proline, l-thioproline and l-tyrosine as chiral moieties within the framework of (Cr). These CMOFs were characterized by FTIR, PXRD, SEM, and thermo gravimetric analysis. Chirality within these CMOFs 1-3 was established by circular dichroism (CD) and polarimetric methods. These three CMOFs 1-3 showed enantioselectivity towards RS-ibuprofen, RS-mandelic acid and RS-1-phenylethanol to varying extents. Their enantioselectivity towards racemates was studied by chiral HPLC and polarimetry.

Synthesis ofN-β-aminoacrylate substituted indolesviatBuOK catalyzed addition of indoles to ketenimines

tBuOK catalyzed aza-Mannich-type addition of indole N–H bonds to ketenimines to affordN-β-aminoacrylate substituted indoles is developed.

Detection of intact vancomycin-arginine as the active antibacterial conjugate in E. coli by whole-cell solid-state NMR.

The introduction of new and improved antibacterial agents based on facile synthetic modifications of existing antibiotics represents a promising strategy to deliver urgently needed antibacterial candidates to treat multi-drug resistant bacterial infections. Using this strategy, vancomycin was transformed into a highly active agent against antibiotic-resistant Gram-negative organisms in vitro and in vivo through the addition of a single arginine to yield vancomycin-arginine (V-R). Here, we report detection of the accumulation of V-R in E. coli by whole-cell solid-state NMR using 15N-labeled V-R. 15N CPMAS NMR revealed that the conjugate remained fully amidated without loss of arginine, demonstrating that intact V-R represents the active antibacterial agent. Furthermore, C{N}REDOR NMR in whole cells with all carbons at natural abundance 13C levels exhibited the sensitivity and selectivity to detect the directly bonded 13C-15N pairs of V-R within E. coli cells. Thus, we also present an effective methodology to directly detect and evaluate active drug agents and their accumulation within bacteria without the need for potentially perturbative cell lysis and analysis protocols.

Synthetic modification of dehydrozingerone and their biological evaluation for anti-tubercular and anti-inflammatory potency

The current research effort focuses on dehydrozingerone (DHZ, 1), a secondary metabolite discovered in the rhizome of Zingiber officinale. Here, we designed and synthesized the diaryl ether derivatives in high yields (80–93%) using substituted arylboronic acids and copper-promoted arylation of phenol. For anti-microbial activity against clinically significant infectious strains of Mycobacterium tuberculosis (ATCC 27294) and H37Ra (ATCC 25177), as well as against Gram-positive and Gram-negative bacteria (B. subtilis ATCC 6633, E. faecalis ATCC 29212, P. aeruginosa ATCC 9027, Escherichia coli ATCC 11105). 16 g/ml MIC value and mycobacterial potential. Compound 7 was the most active of all the compounds, with a MIC Value of 4 g/ml. Additionally, pro-inflammatory cytokines were checked for across the board in the compounds (1–16). IL6 and TNF- are produced by LPS-stimulated RAW 264.7 cells in a dose-dependent manner.

Phytochemical Screening, Anti-obesity and Hepatoprotective Activities of Ethanol Leaf Extract of Jatropha tanjorensis in Wistar Rats

Aim: The objective of this study is to assess Jatropha tanjorensis's phytochemical components, anti-obesity and hepatoprotective properties.&#x0D; Methods: 35 albino Wistar rats were placed into five groups of seven rats each. Each group received the following treatment: Group A served as the control group, and extract doses of 100 mg/kg and 150 mg/kg were given to groups B and C, respectively. Doses of 200 mg/kg and 250 mg/kg of J. tanjorensis extract were given to groups D and E. Using accepted methods, the phytochemical components, anti-obesity, and hepatoprotective properties of J. tanjorensis were identified.&#x0D; Results: J. tanjorensis was found to include biochemical building blocks like alkaloids, flavonoids, tannins, cardiac glycosides, anthraquinones, and saponins after undergoing a qualitative phytochemical screening. With the exception of group C, the results showed a substantial (P&lt; 0.05) drop in cholesterol levels when compared to the control group. Group A's HDL concentration levels increased significantly (P&lt; 0.05) when compared to the other groups.In treated group D (8.70±6.54) after extract administrations, ALP levels were significantly (p 0.05) lower than in the normal control group (15.00±8.00). Although there was a considerable decline in other groups, the ALT activity was found to be significantly lower in treatment group E (5.33±1.33). Treatment groups B (14.003.61) and E (14.003.61) saw a minor but significant decline in AST activity, but treatment groups C (24.33±3.53) and D (36.67±17.34) saw a more significant increase.&#x0D; Conclusion: The study concludes that plant extracts may be used to treat metabolic disorders like obesity and cardiovascular diseases because they have the potential to lower cholesterol and have hepatoprotective effects. Additionally, phytochemicals may be used as drug precursors, templates for synthetic modification, and pharmacological probes.