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.

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.

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.