Oya Unsal Tan

Molecular Docking Studies and Biological Evaluation of Chalcone Based Pyrazolines as Tyrosinase Inhibitors and Potential Anticancer Agents

Studies on the discovery of tyrosinase enzyme inhibitors and exploration for better cytotoxic agents remain an important line in drug discovery and development. A series of synthetic chalcones and pyrazoline derivatives was evaluated for their inhibitory effects on the diphenolase activity of mushroom tyrosinase. The effects of these compounds on proliferation and microtubule assembly were also evaluated in seven different cancer cell lines. The results revealed that some of the synthetic compounds showed significant inhibitory activity, with four compounds being more potent tyrosinase inhibitors than the reference standard inhibitor kojic acid. Several compounds were toxic to cancer cell lines. Compound 1a was found to possess the highest anticancer activity towards all cell lines with an IC50 in the range of 0.9–2.2 μM. Seven of the compounds showed considerable tubulin polymerization activity at a concentration of 25 μM. Molecular modeling studies of these synthetic compounds were performed to investigate their interactions with the tyrosinase enzyme. The structure–activity relationship (SAR) study using in-silico analysis matched well with the in vitro tumour cell inhibitory activity.

Biological Activity and Molecular Docking Studies of Curcumin-Related α,β-Unsaturated Carbonyl-Based Synthetic Compounds as Anticancer Agents and Mushroom Tyrosinase Inhibitors

Hyperpigmentation in human skin and enzymatic browning in fruits, which are caused by tyrosinase enzyme, are not desirable. Investigations in the discovery of tyrosinase enzyme inhibitors and search for improved cytotoxic agents continue to be an important line in drug discovery and development. In present work, a new series of 30 compounds bearing α,β-unsaturated carbonyl moiety was designed and synthesized following curcumin as model. All compounds were evaluated for their effects on human cancer cell lines and mushroom tyrosinase enzyme. Moreover, the structure-activity relationships of these compounds are also explained. Molecular modeling studies of these new compounds were carried out to explore interactions with tyrosinase enzyme. Synthetic curcumin-like compounds (2a-b) were identified as potent anticancer agents with 81-82% cytotoxicity. Five of these newly synthesized compounds (1a, 8a-b, 10a-b) emerged to be the potent inhibitors of mushroom tyrosinase, providing further insight into designing compounds useful in fields of food, health, and agriculture.

Synthesis and antimycobacterial activities of some new thiazolylhydrazone derivatives.

This Letter reports the synthesis and evaluation of some thiazolylhydrazone derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. The cytotoxic activities of all compounds were also evaluated. The compounds exhibited promising antimycobacterial activity with MICs of 1.03-72.46 μM and weak cytotoxicity (8.9-36.8% at 50 μg/mL). Among them, 1-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine 10 was found to be the most active compound (MIC of 1.03 μM) with a good safety profile (16.4% at 50 μg/mL). Molecular modeling studies were done to have an idea for the mechanism of the action of the target compounds. According the docking results it can be claimed that these compounds may bind most likely to TMPK than InhA or CYP121.

Design, Synthesis and In Vitro Study of 5,6-Diaryl-1,2,4-triazine-3-ylthioacetate Derivatives as COX-2 and β-Amyloid Aggregation Inhibitors

In order to find novel cyclooxygenase (COX)‐2 inhibitors for treating inflammatory‐based diseases such as Alzheimers disease (AD), an ethyl carboxylate side chain was added to 5‐(4‐chlorophenyl)‐6‐(4‐(methylsulfonyl)phenyl)‐3‐(methylthio)‐1,2,4‐triazine (lead compound II) to maintain residual inhibition of COX‐1 through interacting with Arg120. A preliminary molecular docking study on both the COX‐1/COX‐2 active sites truly confirmed our hypothesis. Accordingly, a series of ethyl 5,6‐diaryl‐1,2,4‐triazine‐3‐ylthioacetate derivatives were synthesized and their chemical structures were confirmed by NMR, IR and MS spectra. Further in vitro COX‐1/COX‐2 evaluations revealed that compound 6c (COX‐2 IC50 = 10.1 μM, COX‐1 IC50 = 88.8 μM) is the most selective COX‐2 inhibitor while maintaining residual inhibition of COX‐1. In order to evaluate their potential use against AD, an in vitro evaluation of β‐amyloid fibril formation was performed. The results indicated that the prototype compounds 6 are effective β‐amyloid destabilizing agents while compound 6c could inhibit 94% of the β‐amyloid fibril formation after 48 h. Finally, the in silico assessment results of their blood–brain barrier permeability were satisfactory.

Synthesis and Evaluation of Human Monoamine Oxidase Inhibitory Activities of Some 3,5‐Diaryl‐N‐substituted‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide Derivatives

Sixteen 3‐aryl‐5‐(4‐fluorophenyl)‐N‐substituted‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide derivatives were synthesized and their structure were identified by UV, IR, 1H NMR, mass spectra, and microanalyses. The compounds were evaluated in vitro for their human monoamine oxidase (hMAO) inhibitory activities and their MAO‐A and ‐B selectivity. All the compounds were found to potently inhibit MAO‐A isoforms. 5‐(4‐Fluorophenyl)‐3‐(4‐methoxyphenyl)‐N‐methyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide (1.0 × 10−3 µM) was found to inhibit hMAO‐A most selectively and potently. The binding mode of 5‐(4‐fluorophenyl)‐3‐(4‐methoxyphenyl)‐N‐methyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide to hMAO‐A was also predicted using docking studies.

1,2-Diaryl-2-hydroxyiminoethanones as Dual COX-1 and β-Amyloid Aggregation Inhibitors: Biological Evaluation and In Silico Study

To find out new agents for treating inflammatory‐involved diseases such as Alzheimers disease, a series of 1,2‐diaryl‐2‐hydroxyiminoethanones containing vicinal diaryl pharmacophore of COX inhibitors were tested by a set of in vitro, in vivo, and computational studies. The in vivo study of compounds indicated their prominent anti‐inflammatory ability at the doses of 10 and 20 mg/kg comparable to celecoxib (10 mg/kg). Further in vitro COX‐1/COX‐2 evaluations revealed that 4‐methoxy derivative 3 had a high selective COX‐1 inhibitory activity (COX‐1, IC50 = 0.12 μm, SI > 833). To evaluate their potential use against Alzheimers disease, in vitro evaluation of β‐amyloid fibril formation using Aβ(1–40) and Aβ(1–42) peptides was performed. The evaluation of their antiaggregation ability gave impressive results and comparable to rifampicin and indomethacin. Conformational study of compound 3 and subsequent docking of its restrained analogs on both active sites of COX‐1 and COX‐2 could provide a proof of its COX‐1 selectivity as well as molecular dynamic simulation could elucidate and give more insight into the amyloid disaggregation mechanisms leading to rational design of inhibitors.

A comparative study on monomer elution and cytotoxicity of different adhesive restoration materials

Abstract This study evaluated monomer release and cytotoxicity of different adhesive restoration materials used for dental restorations. The extracts (1, 2, and 7 days) of three types of adhesive dental restoration materials, [Quixfill (QF), Silorane Restorative (SR), and Ketac N 100 Restorative (KR)], and the adhesive resins, [XP Bond (XP), Silorane Primer (SP), Ketac N 100 Primer (KP), and Silorane Bond (SB)] were analyzed using high performance liquid chromatography/mass spectrometry (HPLC-MS). The cytotoxicity levels were determined at different time points (24, 48, and 72 h) of cell culture using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. All adhesive resin materials showed monomer release at varying amounts with the highest release after 7 days. The lowest amount of release was observed in QF and the highest with KP. Bis-Phenol A (BPA) was not detected in SP and KR that contain bisphenol-A diglycidyl ether dimethacrylate (bis-GMA). Decamethylpenthasiloxane (D5) was not eluted from SR. Except for SR and QF, all other adhesive restoration materials showed different degrees of toxicity along with different monomer release kinetics. The correlation between the monomer release and cytotoxicity of the materials indicated that the cytotoxicity of the materials increased with the monomer release (Spearman’s rho correlation coefficient – r). The correlation after 48 h was statistically significant (r = −0.342, p = 0.017).