Design, synthesis and biological evaluation of a new series of imidazothiazole-hydrazone hybrids as dual EGFR and Akt inhibitors for NSCLC therapy.

In search of small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC), an efficient four-step synthetic route was followed for the synthesis of new imidazothiazole-hydrazone hybrids, which were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human lung fibroblast (CCD-19Lu) cells. Among them, compounds 4, 6, 13, 16, 17 and 21 exhibited selective cytotoxic activity against A549 cell line. In vitro mechanistic studies were performed to assess their effects on apoptosis, caspase-3, cell cycle, EGFR and Akt in A549 cells. Compounds 6, 16, 17 and 21 promoted apoptotic cell death more than erlotinib. According to the in vitro data, it is quite clear that compound 6 promotes apoptosis through caspase-3 activation and arrests the cell cycle at the G0/G1 phase in A549 cells. Compounds 16 and 17 arrested the cell cycle at the S phase, whereas compounds 4, 13 and 21 caused the cell cycle arrest at the G2/M phase. The most effective EGFR inhibitor in this series was found as compound 13, followed by compounds 17 and 16. Furthermore, Akt inhibitory effects of compounds 16 and 17 in A549 cells were close to that of GSK690693. In particular, it can be concluded that the cytotoxic and apoptotic effects of compounds 16 and 17 are associated with their inhibitory effects on both EGFR and Akt. Molecular docking studies suggest that compounds 16 and 17 interact with crucial amino acid residues in the binding sites of human EGFR (PDB ID: 1M17) and Akt2 (PDB ID: 3D0E). Based on the in silico data, both compounds are predicted to possess favorable oral bioavailability and drug-likeness. Further studies are required to benefit from these compounds as anticancer agents for targeted therapy of NSCLC.

Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action.

Targeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay to evaluate their cyclooxygenase (COX) inhibitory profiles. Compounds 3b and 4a were found to be the most selective COX-1 inhibitors in this series with IC50 values of 8.90 µM and 10.00 µM, respectively. In vitro and in vivo assays were performed to evaluate their anti-NSCLC and anti-inflammatory action, respectively. 2-(1H-Indol-3-yl)-N'-(4-morpholinobenzylidene)acetohydrazide (3b) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound 3b decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound 3b diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound 3b stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor.

A new series of thiosemicarbazone-based anti-inflammatory agents exerting their action through cyclooxygenase inhibition.

In an endeavor to identify potent anti-inflammatory agents, new thiosemicarbazones (TSCs) incorporated into a diaryl ether framework (2a-2l) were prepared and screened for their in vitro inhibitory effects on cyclooxygenases (COXs). 4-[4-(Piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-cyanophenoxy)benzylidene]thiosemicarbazide (2c) was the most potent and selective COX-1 inhibitor in this series, with an IC50 value of 1.89 ± 0.04 µM. On the other hand, 4-[4-(piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-nitrophenoxy)benzylidene]thiosemicarbazide (2b) was identified as a nonselective COX inhibitor (COX-1 IC50 = 13.44 ± 0.65 µM, COX-2 IC50 = 12.60 ± 0.78 µM). Based on molecular docking studies, the diaryl ether and the TSC groups serve as crucial moieties for interactions with pivotal amino acid residues in the active sites of COXs. According to MTT test, compounds 2b and 2c showed low cytotoxic activity toward NIH/3T3 cells. Their in vivo anti-inflammatory and antioxidant potencies were also assessed using the lipopolysaccharide-induced sepsis model. Compounds 2b and 2c diminished high-sensitivity C-reactive protein, myeloperoxidase, nitric oxide, and malondialdehyde levels. Both compounds also caused a significant decrease in aspartate aminotransferase levels as well as alanine aminotransferase levels. In silico pharmacokinetic studies suggest that compounds 2b and 2c possess favorable drug-likeness and oral bioavailability. It can be concluded that these compounds may act as orally bioavailable anti-inflammatory and antioxidant agents.

The effects of atorvastatin on antioxidant/antiinflammatory properties of HDLs in hypercholesterolemics.

BACKGROUND/AIM: Hypercholesterolemia is characterized by changes in lipid profile, nitric oxide pathway, and oxidative stress markers, but functions of high-density lipoprotein (HDL) were not well established in hypercholesterolemic subjects treated with atorvastatin. In this study, we aimed to evaluate effects of atorvastatin treatment on functionality of HDL, oxidative stress, and endothelial functions in hypercholesterolemic subjects. MATERIALS AND METHODS: Thirty patients (20 females, 10 males) aged from 40 to 60 years and diagnosed as hypercholesterolemic were included. Patients were treated with 10 mg/day atorvastatin for 3 months. Markers of endothelial functions, namely asymmetric dimethylarginine (ADMA), homocysteine, and nitric oxide (NO), and markers of oxidative status, namely malondialdehyde (MDA), antioxidant potential (AOP), paraoxonase 1 (PON1), and arylesterase, were measured. Before and after atorvastatin treatment, glucose, lipid parameters, and antioxidant/antiinflammatory HDL levels were also measured. RESULTS: ADMA and homocysteine levels were decreased whereas NO levels were increased with atorvastatin therapy. MDA levels were decreased but AOP, PON1, and arylesterase levels and antinflammatory characteristics of HDLs were increased. Furthermore, lipid profiles of the patients improved with atorvastatin therapy. CONCLUSION: Hypercholesterolemia is a cause of oxidative stress, endothelial dysfunction, and proinflammatory HDL levels. Atorvastatin is a beneficial pharmacological modulator of impaired antiinflammatory HDL-C levels, endothelial functions, and oxidative status against atherosclerosis indicating pleiotropic effects of statins.

Synthesis and evaluation of new indole-based chalcones as potential antiinflammatory agents.

In the present work, new indole-based chalcone derivatives were obtained via the reaction of 5-substituted-1H-indole-3-carboxaldehydes/1-methylindole-3-carboxaldehyde with appropriate acetophenones. The synthesized compounds were investigated for their in vitro COX-1 and COX-2 inhibitory activity. The most effective COX inhibitors were also evaluated for their in vivo antiinflammatory and antioxidant activities in LPS induced sepsis model. Furthermore, the CCK-8 assay was carried out to determine cytotoxic effects of all compounds against NIH/3T3 mouse embryonic fibroblast cells. 3-(5-Bromo-1H-indol-3-yl)-1-(4-cyanophenyl)prop-2-en-1-one (6) can be considered as a non-selective COX inhibitor (COX-1 IC50 = 8.1 ± 0.2 µg/mL, COX-2 IC50 = 9.5 ± 0.8 µg/mL), whereas 3-(5-methoxy-1H-indol-3-yl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (1) inhibited only COX-1 (IC50 = 8.6 ± 0.1 µg/mL). According to in vivo studies, these compounds also displayed antiinflammatory and antioxidant activities.