LC-MS and GC-MS Analyses on Green Algae Penicillus capitatus: Cytotoxic, Antimicrobial and Anticholinesterase Activity Screening Enhanced by Molecular Docking & Dynamics and ADME Studies.

In this comprehensive screening study, the chemical composition, and cytotoxic, antimicrobial, and anticholinergic activities of the green algae Penicillus capitatus, collected from Antalya-Türkiye, were determined as in vitro and in silico. GC-MS analysis of the hexane extract revealed a high content of fatty acids, with hexadecanoic acid constituting half of the total fatty acid content. LC-HRMS analysis of the DCM:MeOH extract identified ascorbic acid as the most abundant compound, followed by (-)-epigallocatechin and salicylic acid. The DCM:MeOH extract exhibited potent cytotoxicity against MDA-MB-231 and MCF7 breast cancer cell lines, outperforming doxorubicin with lower IC50 values and a higher selectivity index. Additionally, the extract demonstrated significant antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, along with selective inhibition of acetylcholinesterase (hAChE) over butyrylcholinesterase (hBChE). Molecular docking and dynamics studies revealed that apigenin-7-O-glucoside and epigallocatechin form stable interactions with estrogen receptor alpha (ERα) and hAChE, suggesting their potential as inhibitors. In silico ADME studies indicated favorable pharmacokinetic profiles for the detected compounds, supporting their potential as drug candidates. The promising cytotoxic activity of the P. capitatus extracts, coupled with significant antimicrobial properties and selective hAChE inhibition, highlights their therapeutic potential for breast cancer treatment, infection management, and neurodegenerative disease intervention.

Synthesis of Sorafenib-Ruthenium Complexes, Investigation of Biological Activities and Applications in Drug Delivery Systems as an Anticancer Agent.

Sorafenib, a multiple kinase inhibitor, is widely used as a first-line treatment for hepatocellular carcinoma. However, there is a need for more effective alternatives when sorafenib proves insufficient. In this study, we aimed to design a structure that surpasses sorafenib's efficacy, leading us to synthesize sorafenib-ruthenium complexes for the first time and investigate their properties. Our results indicate that the sorafenib-ruthenium complexes exhibit superior epidermal growth factor receptor (EGFR) inhibition compared to sorafenib alone. Interestingly, among these complexes, Ru3S demonstrated high activity against various cancer cell lines including sorafenib-resistant HepG2 cells while exhibiting significantly lower cytotoxicity than sorafenib in healthy cell lines. Further evaluation of cell cycle, cell apoptosis, and antiangiogenic effects, molecular docking, and molecular dynamics studies revealed that Ru3S holds great potential as a drug candidate. Additionally, when free Ru3S was encapsulated into polymeric micelles M1, enhanced cytotoxicity on HepG2 cells was observed. Collectively, these findings position Ru3S as a promising candidate for EGFR inhibition and warrant further exploration for drug development purposes.

Novel complex compounds of nickel with 3-(1-phenyl-2,3-dimethyl-pyrazolone-5)azopentadione-2,4: synthesis, NBO analysis, reactivity descriptors and in silico and in vitro anti-cancer and bioactivity studies.

A synthesized azo compound based on 4-amino antipyrine and its complexes with Ni(II) in solution and solid phase is reported. The structures of these compounds have been testified by IR and NMR spectroscopy. The combined experimental and theoretical approach was used. To study the structure and properties of the synthesized compound, as well as its possible complex formation with the Ni(II), ab initio quantum-chemical calculations were carried out using the Hartree-Fock (HF) method with the 6-31 G basis set and the electron density functional theory (DFT) method with hybrid three-parameter potential B3LYP and extended basis set 6-311++G(d,p) taking into account polarization and diffuse functions for all atoms. The geometric, energy, and electronic parameters were calculated and analyzed. The HOMO-LUMO energy gap has been calculated to determine chemical activity. Both complexes had effective inhibition against butyrylcholinesterase and acetylcholinesterase. IC50 values were found as 19.43 and 27.08 µM for AChE, 2.37 and 7.40 µM for BChE, respectively. For the anticancer outcome, high doses of compound E1 inhibited viability by about 40-45%, while this rate was around 65-70% for compound E2 at the same doses. Anticholinesterase and anticancer potential of compounds E1 and E2 also evaluated by in silico techniques. Both compounds show strong binding to VEGFR1, with E2 exhibiting superior inhibitory activity in hAChE and hBChE through shorter and stronger interactions. MD simulations suggest that E2 forms more stable complexes with hAChE and hBChE compared to E1, making it a promising candidate for further exploration in anticancer and anticholinesterase therapies.Communicated by Ramaswamy H. Sarma.

Novel quinazoline-chromene hybrids as anticancer agents: Synthesis, biological activity, molecular docking, dynamics and ADME studies.

In this study, new quinazoline-chromene hybrid compounds were synthesized. The cytotoxic effects on cell viability of the hybrid compounds were tested against A549 human lung adenocarcinoma and BEAS-2B healthy bronchial epithelial cell lines in vitro. In addition, the ability of the active compounds to inhibit cell migration was tested. Molecular docking studies were performed to evaluate the ligand-protein interactions, and molecular dynamics simulations were performed to determine the interactions and stability of ligand-protein complexes. In silico absorption, distribution, metabolism, and excretion (ADME) studies were conducted to estimate the drug-likeness of the compounds. Compounds 4 (IC50 = 51.2 µM) and 5 (IC50 = 44.2 µM) were found to be the most active agents against A549 cells. They are found to be more selective against A549 cells than the reference drug doxorubicin. They also have the ability to significantly inhibit cell migration. They have the best docking scores against epidermal growth factor receptor (EGFR) (-11.300 and -11.226 kcal/mol) and vascular endothelial growth factor receptor 2 (VEGFR2) (-10.987 and -11.247 kcal/mol), respectively. In MD simulations, compounds 4 and 5 have strong hydrogen bond interactions above 80% of simulation times and showed a low ligand root mean square deviation (RMSD) around 2 Å. According to the ADME analysis, compounds 4 and 5 exhibit excellent drug-likeness and pharmacokinetic characteristics.

Synthesis and Anticancer Activity of Novel Derivatives of α,ß-Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells.

Herein, new derivatives of α,ß-unsaturated ketones based on oleanolic acid (4 a-i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4 a-i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC50 values on PC3 cell lines were 4 b (7.785 µM), 4 c (8.869 µM), and 4 e (8.765 µM). The results of the ADME calculations showed that the drug-likeness parameters were within the defined ranges according to Lipinski's and Jorgensen's rules. For the most potent compounds 4 b, 4 c, and 4 e, a molecular docking analysis using the induced fit docking (IFD) protocol was performed against three protein targets (PARP, PI3K, and mTOR). Based on the IFD scores, compound 4 b had the highest calculated affinity for PARP1, while compound 4 c had higher affinities for mTOR and PI3K. The MM-GBSA calculations showed that the most potent compounds had high binding affinities and formed stable complexes with the protein targets. Finally, a 50 ns molecular dynamics simulation was performed to study the behavior of protein target complexes under in silico physiological conditions.

New Anthranilic Acid Hydrazones as Fenamate Isosteres: Synthesis, Characterization, Molecular Docking, Dynamics & in Silico ADME, in Vitro Anti-Inflammatory and Anticancer Activity Studies.

In this study, twenty new anthranilic acid hydrazones 6-9 (a-e) were synthesized and their structures were characterized by Fourier-transform Infrared (FT-IR), Nuclear Magnetic Resonance (1 H-NMR - 13 C-NMR), and High-resolution Mass Spectroscopy (HR-MS). The inhibitory effects of the compounds against COX-II were evaluated. IC50 values of the compounds were found in the range of >200-0.32 µM and compounds 6e, 8d, 8e, 9b, 9c, and 9e were determined to be the most effective inhibitors. Cytotoxic effects of the most potent compounds were investigated against human hepatoblastoma (Hep-G2) and human healthy embryonic kidney (Hek-293) cell lines. Doxorubicin (IC50 : 8.68±0.16 µM for Hep-G2, 55.29±0.56 µM for Hek-293) was used as standard. 8e is the most active compound, with low IC50 against Hep-G2 (4.80±0.04 µM), high against Hek-293 (159.30±3.12), and high selectivity (33.15). Finally, molecular docking and dynamics studies were performed to understand ligand-protein interactions between the most potent compounds and COX II, Epidermal Growth Factor Receptor (EGFR), and Transforming Growth Factor beta II (TGF-ßII). The docking scores were calculated in the range of -10.609--6.705 kcal/mol for COX-II, -8.652--7.743 kcal/mol for EGFR, and -10.708--8.596 kcal/mol for TGF-ßII.

Investigation of the relationship of groundwater quality and irrigation: the case of Mardin Kiziltepe Plain (Mesopotamia) in Turkey.

Underground water resources are one of the most valuable vital resources for mankind. Groundwater is used as drinking water and for agricultural irrigation. However, in recent years, it has been exposed to dangerous pollution, mainly due to man-made reasons. The study area is located in the Upper Mesopotamian region, where dry agriculture has been practiced since ancient times, which has semi-arid characteristics and where important civilizations lived. In this direction, the changes in groundwater quality were investigated with seasonal, annual samples taken from selected wells in Mardin Kiziltepe Plain in Upper Mesopotamia region and representing the plain in general and were subjected to water quality classifications. Statistical analyses were carried out on EC and NO3- parameters, which are important in determining the quality of groundwater. The results obtained were interpreted, evaluated in terms of drinking and agricultural uses, and it was observed that there were no non-standard values. In addition, the study area will be opened for irrigation in the near future within the framework of GAP, the largest integrated irrigation project in Turkey. This study, which is the first scientific research to be carried out before intensive irrigation, will be the first memory that will provide a very important data set for the region and will be recorded. In addition, the results of the study will be the basis for the comparison of the research to be carried out after the transition to irrigated agriculture depending on the GAP and the pre-irrigation data.

Synthesis and Comprehensive in Vivo Activity Profiling of Olean-12-en-28-ol, 3ß-Pentacosanoate in Experimental Autoimmune Encephalomyelitis: A Natural Remyelinating and Anti-Inflammatory Agent.

Multiple sclerosis (MS) treatment has received much attention, yet there is still no certain cure. We herein investigate the therapeutic effect of olean-12-en-28-ol, 3ß-pentacosanoate (OPCA) on a preclinical model of MS. First, OPCA was synthesized semisynthetically and characterized. Then, the mice with MOG35-55-induced experimental autoimmune/allergic encephalomyelitis (EAE) were given OPCA along with a reference drug (FTY720). Biochemical, cellular, and molecular analyses were performed in serum and brain tissues to measure anti-inflammatory and neuroprotective responses. OPCA treatment protected EAE-induced changes in mouse brains maintaining blood-brain barrier integrity and preventing inflammation. Moreover, the protein and mRNA levels of MS-related genes such as HLD-DR1, CCL5, TNF-α, IL6, and TGFB1 were significantly reduced in OPCA-treated mouse brains. Notably, the expression of genes, including PLP, MBP, and MAG, involved in the development and structure of myelin was significantly elevated in OPCA-treated EAE. Furthermore, therapeutic OPCA effects included a substantial reduction in pro-inflammatory cytokines in the serum of treated EAE animals. Lastly, following OPCA treatment, the promoter regions for most inflammatory regulators were hypermethylated. These data support that OPCA is a valuable and appealing candidate for human MS treatment since OPCA not only normalizes the pro- and anti-inflammatory immunological bias but also stimulates remyelination in EAE.

Synthesis of ursolic acid arylidene-hydrazide hybrid compounds and investigation of their cytotoxic and antimicrobial effects.

In this study, 13 new hybrid compounds (7a-m) were synthesised starting from ursolic acid, and their cytotoxic activities were investigated on the BEAS-2B and A549 cell lines. In addition, the synthesised compounds were tested against Staphylococcus aureus, Escherichia coli, and Candida albicans to determine their anti-microbial properties. The hybrid compounds that exhibited the lowest cytotoxicity against the BEAS-2B were 7k, 7b, and 7g. The cytotoxicity of the compounds against A549 was evaluated, the IC50 value of 7k, 7b, and 7g are found as 0.15 µM, 0.31 µM, and 0.26 µM, respectively. The results showed that the selectivity of 7k was 7 times higher than doxorubicin against the A549 cells. According to the antimicrobial activity studies 7c is found as the most effective compound against S. aureus. Almost all compounds showed a similar inhibition potential against E. coli and C. albicans.

Phytochemical analysis and molecular docking studies of two endemic varieties of Salvia sericeotomentosa.

The use of medicinal plants for treating various diseases dates back thousands of years and has been a part of many cultures around the world. Various parts of plants, including roots, leaves, and flowers, and their extracts have been used to develop remedies to cure different ailments like fever, pain, inflammation, infections, among others. In this research, the aerial parts of both Salvia varieties were extracted with ethanol and water to obtain infusion and decoction, separately. S. sericeotomentosa var. hatayica Celep & Dogan (SH) and Salvia sericeotomentosa Rech. f. var. sericeotomentosa (ST) plants were chemically analyzed for polar compounds using LC-HRMS for the first time. All SH and ST extracts were found to be very rich in rosmarinic acid, salvianolic acid B, hispidulin-7-O-glucoside, and caffeic acid. The study also investigated the antiinflammatory and carbonic anhydrase inhibition properties of the most abundant secondary metabolites extracted from SH and ST. In silico studies were conducted for the first time to explore the effects of these metabolites on TNF-α, iNOS, and human carbonic anhydrase isoenzymes (hCAI and hCAII). Salvianolic acid B should be considered a strong antiinflammatory agent and a carbonic anhydrase I and II inhibitors due to low binding energy scores with the tested enzymes (TNF-α: -12.391 kcal/mol), (iNOS: -7.547 kcal/mol), (hCAI: -7.877 kcal/mol), and (hCAII: -4.312 kcal/mol).

Effects of NaOH, thermal, and combined NaOH-thermal pretreatments on the biomethane yields from the anaerobic digestion of walnut shells.

Anaerobic digestion (AD) of walnut shells (WS) results in only a limited biomethane yield because of their high fibre content, which ultimately represents an essentially nonbiodegradable lignocellulosic biomass. In the present study, thermal (i.e. 50-250 °C), alkaline (i.e. 1-5% w/w NaOH) and combined alkaline-thermal (i.e. 4% w/w NaOH + 150 °C thermal) pretreatment methods have been applied to increase the anaerobic biodegradation of WS. The highest biomethane yields of 159.9 ± 6.8 mL CH4.g VS-1 and 169.8 ± 6.8 mL CH4.g VS-1 were achieved after pretreatment at both 250 °C and with 4% NaOH. After combined NaOH-thermal pretreatments, the AD process showed the largest total VFA concentration (i.e. 1280.1 mg Hac L-1) but a relatively high lag phase (i.e. 3.90 days) compared to thermal and NaOH pretreatments alone, from which the highest biomethane yield (i.e. 192.4 ± 8.2 mL CH4.g VS-1 ) was achieved at the end of the AD process. The highest biomethane yield from the combined NaOH-thermal pretreated WS was corroborated by the corresponding highest SCOD/TCOD ratio (i.e. 0.37 ± 0.02) and the highest lignocellulosic fibre removal (i.e. 41.1 ± 2.7% cellulose, 35.6 ± 1.8% hemicellulose, and 58.7 ± 3.2% lignin). The cumulative biomethane yields were further simulated via a modified Gompertz model. This study provides a promising strategy in the sense that the biomethane yield of WS containing large amounts of lignin can be significantly increased via thermal, NaOH, and combined NaOH-thermal pretreatment methods.

Enhanced lignocellulosic component removal and biomethane potential from chestnut shell by a combined hydrothermal-alkaline pretreatment.

This study proposes new perspectives for the management and biorefinery of wastes deriving from the agri-food sector such as chestnut shell (CS), which was here used as an organic feedstock for biomethane production through anaerobic digestion (AD). 1-5% alkaline (i.e. NaOH and KOH), hydrothermal (i.e. at 100 °C) and combined hydrothermal-alkaline pretreatments were employed to enhance the CS biodegradability prior to biochemical methane potential (BMP) tests conducted under mesophilic conditions. The hydrothermally-pretreated CS with 3% NaOH achieved the highest biomethane yield of 253 (±9) mL CH4·g VS-1 coupled to a volatile solid reduction of 48%. The hydrothermal-alkaline pretreatment positively affected both delignification and hemicellulose polymerization, promoting an approximately 2.4-fold higher substrate biodegradability compared to the untreated CS, which only reached a CH4 production of 104 (±5) mL CH4·g VS-1. AD proceeded via volatile fatty acid accumulation, subsequently followed by methane production that was effectively simulated via the modified Gompertz kinetic having a R2 of 0.974-0.999. Among the physical-chemical parameters characterizing the CS, the soluble chemical oxygen demand (sCOD) was highly correlated with the BMP showing a Pearson coefficient of 0.952. The cumulative biomethane yield, the sCOD and the cellulose, hemicellulose and lignin amount of CS were also processed through the least square method, obtaining a useful regression equation to predict the BMP. The economic assessment indicated that the hydrothermal-alkaline pretreatment is a cost-effective method to improve the BMP of CS, also for future full-scale applications.

Anaerobic digestion of hazelnut (Corylus colurna) husks after alkaline pretreatment and determination of new important points in Logistic model curves.

In this study, anaerobic digestion (AD) of hazelnut (Corylus colurna) husks (HH) was investigated by NaOH pretreatment at 1-6% w/w concentrations. The highest methane yield was 278.45 ± 7.85 mL/g volatile solid (VS), and this was obtained in a 4% NaOH pretreated reactor. In this reactor, the methane yield increased by 162.2% compared to that in the control. The concentrations of volatile fatty acids (VFAs) varied during the digestion process according to the different NaOH pretreatment results. The highest lignosellulosic solubilizations were obtained in a 6% NaOH pretreated reactor. Furthermore, in the second part of kinetic studies, it was defined critical points for cumulative methane yield (CMY) in the Logistic model (LM). These points were the absolute acceleration point (PAA), maximum acceleration point (PAM), inflection point (PI), maximum deceleration point (PDM), and asymptotic deceleration point (PDA). Using these points on the CMY curves, the AD process of HH was mathematically interpreted and explained.

Biogas potential of hazelnut shells and hazelnut wastes in Giresun City.

In recent years, the world's natural energy resources unable to meet the increasing energy needs. In Turkey and in the world, there is an increasing need for renewable energy. One of the renewable energy sources is biogas energy. In this study, the biogas potential of Giresun, which is also known as coastal city, can be formed from 2 different organic wastes are experimentally calculated. Organic wastes included in the calculation; hazelnut shells (HS) and hazelnut wastes (HW). Production experiments were investigated in two ways: untreated and thermal pretreatment. In addition, biogas yield was examined at room temperature (23 °C), at mesophilic temperature (39 °C), and at thermophilic temperature (60 °C). As a result, the highest biogas yield was found at temperatures of 60 °C and under thermal pretreatment conditions. Under these conditions, annual biogas production potential of Giresun city was found as 38.21 GW h/yr.

Synthesis of Oleanolic Acid Analogues and Their Cytotoxic Effects on 3T3 Cell Line.

BACKGROUND: Oleanolic acid (OA) is a known natural compound with many important biological activities. Thirteen oleanolic acid derivatives linked at C-3 and C-28 were synthesized and their structures were confirmed by 1H- and 13C NMR and mass spectral analyses. Among them, compounds 4, 6, 8-10, 12, 13 were synthesized for the first time. They were evaluated for their cytotoxic activity. They showed proliferative effect at low concentrations while cytotoxic effect was observed at high concentrations in a dose dependent manner. METHODS: We have first synthesized compounds 1 and 2 from the reaction of methyl iodide and OA. Compound 1 was reduced with LiAlH4 to give compound 3, and compound 2 gave compound 9 with MOMBr as a new compound. The compound 10 was then obtained from the reduction of compound 9 with LiAlH4 as a new oleanolic acid derivative. A diol derivative 11 was synthesized from OA and LiAlH4 at the room temperature. Compound 4 was obtained from the reaction of compound 3 with CBr4 as a new analogue of OA, and the reduction of compound 4 afforded compound 5 as a known product. In addition, we synthesized compounds 6-8 from compound 3 using MsCl, MeI and p-nitrobenzoyl chloride, respectively, in good yields. Compounds 6 and 8 are new analogues of OA. The new compounds 12 and 13 were also synthesized starting from OA using with MOMBr and TBDMSiCl as the reagents. The all synthesized compounds were purified by using column chromatography and/or crystallization. RESULTS: In the present study, thirteen OA derivatives linked at C-28 and (or) C-3 were synthesized and evaluated for their cytotoxic activity on 3T3 cell lines which are the standard fibroblast cell lines, derived from Swiss albino mouse embryo tissue. 3T3 cell viability was observed at low concentrations of the tested triterpenoids while they displayed anti-proliferative effect at higher concentrations. CONCLUSION: Oleanolic acid 28-methyl ester (2) showed fairly different behavior from all the other compounds tested and found to be the least cytotoxic compound. However, at 200 µM concentration, it exhibited the same cytotoxicity with compounds 3, 9 and 10 around 58-59%. Among the tested 13 compounds, 7 exhibited the most drastic decline for the viability from 12,5 µM to 25 µM concentration. Compound 6 displayed the most cytotoxic effect, almost in all concentrations, particularly at 6.25 and 25 µM concentrations while the highest cytotoxic effect at 50 µM was observed for compound 11 among all the tested triterpenoids. As a result, all the tested OA derivatives showed proliferative effect at 1,56 µM although no proliferative effect was observed for OA. Moreover, OA exhibited higher cytotoxic effect than its derivatives, particularly at higher concentrations (50, 100, 200 µM) with an exception for compound 11. Because, the latter showed highest proliferative effect at lowest concentration, and highest anti-proliferative effect at highest concentration which surpassed all the OA derivatives.