Old drug, new tricks: polymer-based nanoscale systems for effective cytarabine delivery.

Cytarabine, an antimetabolite antineoplastic agent, has been utilized to treat various cancers. However, because of its short half-life, low stability, and limited bioavailability, achieving an optimal plasma concentration requires continuous intravenous administration, which can lead to toxicity in normal cells and tissues. Addressing these limitations is crucial to optimize the therapeutic efficacy of cytarabine while minimizing its adverse effects. The use of novel drug delivery systems, such as polymer-based nanocarriers have emerged as promising vehicles for targeted drug delivery due to their unique properties, including high stability, biocompatibility, and tunable release kinetics. In this review, we examine the application of various polymer-based nanocarriers, including polymeric nanoparticles, polymeric micelles, dendrimers, polymer-drug conjugates, and nano-hydrogels, for the delivery of cytarabine. The article highlights the limitations of conventional cytarabine administration which often lead to suboptimal therapeutic outcomes and systemic toxicity. The rationale for using polymer-based nanocarriers is discussed, highlighting their ability to overcome challenges by providing controlled drug release, improved stability, and enhanced targeting capabilities. In summary, this review offers a valuable resource for drug delivery scientists by providing insights into the design principles, formulation strategies, and potential applications of polymer-based nanocarriers that can enhance the therapeutic efficacy of cytarabine.

Kinetic and thermodynamic studies of novel acid phosphatase isolated and purified from Carthamus oxyacantha seedlings.

Acid phosphatase (ACP) is a key enzyme in the regulation of phosphate feeding in plants. In this study, a new ACP from C. oxyacantha was isolated to homogeneity and biochemically described for the first time. Specific activity (283 nkat/mg) was found after 2573 times purification fold and (17 %) yield. Using SDS-PAGE under denaturing and nondenaturing conditions, ACP was isolated as a monomer with a molecular weight of 36 kDa. LC-MS/MS confirmed the presence of this band, suggesting that C. oxycantha ACP is a monomer. The enzyme could also hydrolyze orthophosphate monoester with an optimal pH of 5.0 and a temperature of 50 °C. Thermodynamic parameters were also determined (Ea, ΔH°, ΔG°, and ΔS°). ACP activity was further studied in the presence of cysteine, DTT, SDS, EDTA, ß-ME, Triton-X-100 H2O2, and PMSF. The enzyme had a Km of 0.167 mM and an Ea of 9 kcal/mol for p-nitrophenyl phosphate. The biochemical properties of the C. oxyacantha enzyme distinguish it from other plant acid phosphatases and give a basic understanding of ACP in C. oxyacantha. The results of this investigation also advance our knowledge about the biochemical significance of ACP in C. oxyacantha. Thermal stability over a wide pH and temperature range make it more suitable for use in harsh industrial environments. However, further structural and physiological studies are anticipated to completely comprehend its important aspects in oxyacantha species.

Polyvinylpyrrolidone K-30-Based Crosslinked Fast Swelling Nanogels: An Impeccable Approach for Drug's Solubility Improvement.

Poor solubility is a global issue of copious pharmaceutical industries as large number of drugs in development stage as well as already marketed products are poorly soluble which results in low dissolution and ultimately dosage increase. Current study is aimed at developing a polyvinylpyrrolidone- (PVP-K30-) based nanogel delivery system for solubility enhancement of poorly soluble drug olanzapine (OLP), as solubilization enhancement is the most noteworthy application of nanosystems. Crosslinking polymerization with subsequent condensation technique was used for the synthesis of nanogels, a highly responsive polymeric networks in drug's solubility. Developed nanogels were characterized by percent entrapment efficiency, sol-gel, percent swelling, percent drug loaded content (%DLC), percent porosity, stability, solubility, in vitro dissolution studies, FTIR, XRD, and SEM analysis. Furthermore, cytotoxicity study was conducted on rabbits to check the biocompatibility of the system. Particle size of nanogels was found with 178.99 ± 15.32 nm, and in vitro dissolution study exhibited that drug release properties were considerably enhanced as compared to the marketed formulation OLANZIA. The solubility studies indicated that solubility of OLP was noticeably improved up to 36.7-fold in phosphate buffer of pH 6.8. In vivo cytotoxicity study indicated that prepared PVP-K30-based formulation was biocompatible. On the basis of results obtained, the developed PVP-K30-co-poly (AMPS) nanogel delivery system is expected to be safe, effective, and cost-effective for solubility improvement of poorly soluble drugs.

Identification and Inhibition of the Druggable Allosteric Site of SARS-CoV-2 NSP10/NSP16 Methyltransferase through Computational Approaches.

Since its emergence in early 2019, the respiratory infectious virus, SARS-CoV-2, has ravaged the health of millions of people globally and has affected almost every sphere of life. Many efforts are being made to combat the COVID-19 pandemic's emerging and recurrent waves caused by its evolving and more infectious variants. As a result, novel and unexpected targets for SARS-CoV-2 have been considered for drug discovery. 2'-O-Methyltransferase (nsp10/nsp16) is a significant and appealing target in the SARS-CoV-2 life cycle because it protects viral RNA from the host degradative enzymes via a cap formation process. In this work, we propose prospective allosteric inhibitors that target the allosteric site, SARS-CoV-2 MTase. Four drug libraries containing ~119,483 compounds were screened against the allosteric site of SARS-CoV-2 MTase identified in our research. The identified best compounds exhibited robust molecular interactions and alloscore-score rankings with the allosteric site of SARS-CoV-2 MTase. Moreover, to further assess the dynamic stability of these compounds (CHEMBL2229121, ZINC000009464451, SPECS AK-91811684151, NCI-ID = 715319), a 100 ns molecular dynamics simulation, along with its holo-form, was performed to provide insights on the dynamic nature of these allosteric inhibitors at the allosteric site of the SARS-CoV-2 MTase. Additionally, investigations of MM-GBSA binding free energies revealed a good perspective for these allosteric inhibitor-enzyme complexes, indicating their robust antagonistic action on SARS-CoV-2 (nsp10/nsp16) methyltransferase. We conclude that these allosteric repressive agents should be further evaluated through investigational assessments in order to combat the proliferation of SARS-CoV-2.

Isolation, Characterization, and Medicinal Potential of Polysaccharides of Morchella esculenta.

Mushroom polysaccharides are active medicinal compounds that possess immune-modulatory and anticancer properties. Currently, the mushroom polysaccharides krestin, lentinan, and polysaccharopeptides are used as anticancer drugs. They are an unexplored source of natural products with huge potential in both the medicinal and nutraceutical industries. The northern parts of Pakistan have a rich biodiversity of mushrooms that grow during different seasons of the year. Here we selected an edible Morchella esculenta (true morels) of the Ascomycota group for polysaccharide isolation and characterization. Polysaccharopeptides and polysaccharides from this mushroom were isolated using the green chemistry, hot water treatment method. Fourier transform infrared spectroscopy revealed the sugar nature and possible beta-glucan type structure of these polysaccharides. Antioxidant assays showed that the deproteinized polysaccharides have moderate free radical scavenging activity. These isolated polysaccharides exhibited good acetylcholinesterase (AChE) and butyryl cholinesterase (BChE) inhibition activities. Therefore, these polysaccharides may be valuable for the treatment of Alzheimer's and Parkinson's diseases. Further bioassays are needed to discover the true potential of M. esculenta polysaccharides for medicinal purposes.

Identification of Potential HCV Inhibitors Based on the Interaction of Epigallocatechin-3-Gallate with Viral Envelope Proteins.

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.

Important Flavonoids and Their Role as a Therapeutic Agent.

Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.

Nanogels as drug-delivery systems: a comprehensive overview.

Nanogels have attracted considerable attention as nanoscopic drug carriers, particularly for site-specific or time-controlled delivery of bioactive mediators. A high diversity of polymer systems and the simple modification of their physicochemical features have provided multipurpose forms of nanogel preparations. Nanogels have outstandingly high stability, drug loading ability, biologic consistence, good permeation capability and can be responsive to environmental stimuli. Great potential has been shown by nanogels in many fields including delivery of genes, chemotherapy drugs, diagnosis, targeting of specific organs and several others. This review focuses mainly on different types of nanogels, methods of preparation including methods of drug loading, different modes of biodegradation mechanisms as well as main mechanisms of drug release from nanogels. Recent applications of nanogels are also briefly discussed and exemplified.

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives.

Steviosides, rebaudiosides and their analogues constitute a major class of naturally occurring biologically active diterpene compounds. The wide spectrum of pharmacological activity of this group of compounds has developed an interest among medicinal chemists to synthesize, purify, and analyze more selective and potent isosteviol derivatives. It has potential biological applications and improves the field of medicinal chemistry by designing novel drugs with the ability to cope against resistance developing diseases. The outstanding advancement in the design and synthesis of isosteviol and its derivative has proved its effectiveness and importance in the field of medicinal chemical research. The present review is an effort to integrate recently developed novel drugs syntheses from isosteviol and potentially active pharmacological importance of the isosteviol derivatives covering the recent advances.

pH/Thermo-Dual Responsive Tunable In Situ Cross-Linkable Depot Injectable Hydrogels Based on Poly(N-Isopropylacrylamide)/Carboxymethyl Chitosan with Potential of Controlled Localized and Systemic Drug Delivery.

In the current study, cytocompatible in situ cross-linkable pH/thermo-dual responsive injectable hydrogels were prepared based on poly(N-isopropylacrylamide) and carboxymethyl chitosan, i.e., poly(CMCS-g-NIPAAm). The prepared formulations were aimed to be used as drug depot of 5-fluorouracil (5-FU) after subcutaneous administration in vivo. The phase transition from sol-gel state under physiologic temperature range was analyzed and confirmed by tube titling and optical transmittance measurements. The viscoelastic properties of gel formulations were confirmed by rheology determination via time sweep, temperature, and continuous ramp test. Oscillatory swelling cycles confirmed temperature effect and structural changes. pH and temperature sensitivity of dual responsive gels were analyzed at different pH and temperature programs. In vitro drug release profile displayed that developed formulations have the highest release in acidic pH at 25°C. The safety of blank gel formulations was evaluated against L929 cell lines via MTT assay and confirmed cytocompatibility with no detectable toxicity. In vitro cytotoxic potential of drug-loaded gels against HeLa and MCF-7 cancer cell lines confirmed that 5-FU has controlled cytotoxic potential in depot form in comparison to free 5-FU solution. The IC50 values for free 5-FU (21 ± 05 µg/ml and 18 ± 66 µg/ml) were found higher in comparison to the loaded form. The copolymer structure formation was confirmed by NMR and FTIR spectroscopic analysis. TG and DSC analysis proved the thermal stability and phase transition temperatures of pure and copolymer samples, while SEM analysis showed the porous nature of in situ formed hydrogels. It was concluded from the results that the developed formulations have pH/temperature sensitivity with potential of systemic and intratumoral controlled drug delivery properties.

Increasing the Strength and Production of Artemisinin and Its Derivatives.

Artemisinin is a natural sesquiterpene lactone obtained from the Artemisia annua herb. It is widely used for the treatment of malaria. In this article, we have reviewed the role of artemisinin in controlling malaria, spread of resistance to artemisinin and the different methods used for its large scale production. The highest amount of artemisinin gene expression in tobacco leaf chloroplast leads to the production of 0.8 mg/g of the dry weight of the plant. This will revolutionize the treatment and control of malaria in third world countries. Furthermore, the generations of novel derivatives of artemisinin- and trioxane ring structure-inspired compounds are important for the treatment of malaria caused by resistant plasmodial species. Synthetic endoperoxide-like artefenomel and its derivatives are crucial for the control of malaria and such synthetic compounds should be further explored.

Molecular docking and biological evaluation of some thioxoquinazolin-4(3H)-one derivatives as anticancer, antioxidant and anticonvulsant agents.

BACKGROUND: The quinazoline are an important class of medicinal compounds that possess a number of biological activities like anticancer, anticonvulsant and antioxidant etc. RESULTS: We evaluated the previously synthesized quinazoline derivatives 1-3 for their anticancer activities against three cancer cell lines (HepG2, MCF-7, and HCT-116). Among the tested compounds, quinazolines 1 and 3 were found to be more potent than the standard drug Vinblastine against HepG2 and MCF-7 cell lines. All the tested compounds had less antioxidant activity and did not exhibit any anticonvulsant activity. Also, molecular docking studies were performed to get an insight into the binding modes of the compounds with human cyclin-dependent kinase 2, butyrylcholinesterase enzyme, human gamma-aminobutyric acid receptor. These compounds showed better docking properties with the CDK2 as compared to the other two enzymes. CONCLUSIONS: The overall study showed that thioxoquinazolines are suitable antitumor agents and they should be explored for other biological activities. Modification in the available lot of quinazoline and synthesis of its novel derivatives is essential to explore the potential of this class of compounds. The increase in the threat and with the emergence of drug resistance, it is important to explore and develop more efficacious drugs.

Arresting kinase suppressor of Ras in an inactive state.

Ras protein signaling pathways are important in controlling the plight of different types of cancer. Here we discussed the paper entitled "Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling" published in Nature journal on inactivating the kinase suppressor of Ras (KSR) protein using a small molecule as an inhibitor by Dhawan et al. A biphenyl ether analogue of a quinazoline binds in one of the binding pockets of KSR and results in stabilization of its inactive state. In this inactive state, KSR is unable to take part in the cascade of protein association to perform the signalling process.

Photosynthesis at the far-red region of the spectrum in Acaryochloris marina

Acaryochloris marina is an oxygenic cyanobacterium that utilizes far-red light for photosynthesis. It has an expanded genome, which helps in its adaptability to the environment, where it can survive on low energy photons. Its major light absorbing pigment is chlorophyll d and it has α-carotene as a major carotenoid. Light harvesting antenna includes the external phycobilin binding proteins, which are hexameric rods made of phycocyanin and allophycocyanins, while the small integral membrane bound chlorophyll binding proteins are also present. There is specific chlorophyll a molecule in both the reaction center of Photosystem I (PSI) and PSII, but majority of the reaction center consists of chlorophyll d. The composition of the PSII reaction center is debatable especially the role and position of chlorophyll a in it. Here we discuss the photosystems of this bacterium and its related biology.

The Search for Covalently Ligandable Proteins in Biological Systems.

This commentary highlights the recent article published in Nature, June 2016, titled: "Proteome-wide covalent ligand discovery in native biological systems". They screened the whole proteome of different human cell lines and cell lysates. Around 700 druggable cysteines in the whole proteome were found to bind the electrophilic fragments in both active and inactive states of the proteins. Their experiment and computational docking results agreed with one another. The usefulness of this study in terms of bringing a change in medicinal chemistry is highlighted here.

Bioactive Thiazine and Benzothiazine Derivatives: Green Synthesis Methods and Their Medicinal Importance.

Thiazines are a group of heterocyclic organic compounds that are still largely unexplored for their pharmacological activities. There are different available methods for the synthesis of thiazine derivatives in the literature. In this review, we discuss available methods of thiazine preparation through green synthesis methods. Beside their synthesis, many thiazine derivatives are biologically active and play an important role in the treatment of various diseases and show promising results of varying degrees, where they act as antibacterial, antifungal, antitumor, antimalarial, antineoplastic, antiviral, anti-inflammatory, analgesic and anticancer agents and thus they represent an interesting class of heterocyclic medicinal compounds worthy of further exploration.

Ibuprofen-loaded chitosan and chemically modified chitosans--release features from tablet and film forms.

The biopolymer chitosan was chemically modified in two sequences of reactions: (i) immobilization of methyl acrylate followed by cysteamine and (ii) the sequence of immobilization reactions involving ethylene sulfide, methyl acrylate and finally cysteamine. In both cases the pendant chains have attached nitrogen, oxygen and sulfur basic centers. The corresponding structures were characterized through elemental analysis, infrared spectroscopy, nuclear magnetic resonance in the solid state for carbon, thermogravimetry and scanning electron microscopy. The newly synthesized biopolymers have abilities to immobilize and controllably release the non-steroidal drug ibuprofen. The ibuprofen-loaded biomaterials as tablets or as films crosslinked with glutaraldehyde revealed that drug release is pH sensitive. The chemically modified chitosan may allow reduction of drug release in stomach fluids, since the functional groups cause a decrease in swelling rate at pH 1.2, opposite to the behavior that occurs at pH 7.4, that of nutritional fluid, where an increase of the rate of swelling occurs. In such conditions the negatively charge ibuprofen is electrostatically repelled by negative chitosan derivative surfaces.

Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).

This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K(i) and EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.