Epigenetic-based cancer therapeutics: new potential HDAC8 inhibitors.

Designing dual small molecule inhibitors against enzymes associated with cancer has turned into a new strategy in cancer chemotherapy. Targeting DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzymes, involved in epigenetic modifications, are considered as promising treatments for a wide range of cancers, due to their association with the initiation, proliferation, and survival of cancer cells. In this study, for the first time, the dual inhibitors of the histone deacetylases 8 (HDAC8) and DNA methyltransferase 1 (DNMT1) has introduced as novel potential candidates for epigenetic-based cancer therapeutics. This research has been facilitated by employing pharmacophore-based virtual screening of ZINC and Maybridge databases, as well as performing molecular docking, molecular dynamics simulations and free binding energy calculation on the top derived compound. Results have demonstrated that the suggested compounds not only adopt highly favorable conformations but also possess strong binding interaction with the HDAC8 enzyme. Additionally, the obtained results from the experimental assay confirmed the predicted behavior of inhibitors from virtual screening. These results can be used for further optimization to yield promising more effective candidates for the treatment of cancer.Communicated by Ramaswamy H. Sarma.

Targeting the microRNA binding domain of argonaute 2: rational inhibitor design and study of mutation effects on protein-ligand interaction.

Based on the accumulative evidences during recent decades, miRNAs have been found overexpressed in several human cancer types and also in Down syndrome patients, contributing to the neuropathology of Down syndrome. From this point of view, investigations on the structure and dynamic mechanisms related to the Argonaute 2 miRNAs binding in which silencing of the mRNA occurs, have inspired many clinical researchers to target this complex to inhibit the silencing process. In the current research, we have virtually screened the OTAVA_CNS_library to introduce new inhibitor compounds for the Ago2/miRNA complex. Ten hit compounds were obtained, with just one of them nominated as the best compound. Following the interaction analysis, by utilizing molecular dynamics (MD) simulations, effects of two mutations (Thr526 to isoleucine and Gln545 to alanine) on the dynamic properties of Ago2 in the complex with the best inhibitor compound were investigated. RMSD, RMSF and h-bond number beside other analyses, highlighted the importance of the Thr526 and Gln545 mutations for the stability and flexibility of the (Ago2)/ligand complex.[Formula: see text]Communicated by Ramaswamy H. Sarma.

Structure-based pharmacophore design and virtual screening for novel potential inhibitors of epidermal growth factor receptor as an approach to breast cancer chemotherapy.

Cancer cells are described with features of uncontrolled growth, invasion and metastasis. The epidermal growth factor receptor subfamily of tyrosine kinases (EGFR-TK) plays a crucial regulatory role in the control of cellular proliferation and progression of various cancers. Therefore, its inhibition might lead to the discovery of a new generation of anticancer drugs. In the present study, structure-based pharmacophore modeling, molecular docking and molecular dynamics simulations were applied to identify potential hits, which exhibited good inhibition on the proliferation of MCF-7 breast cancer cell line and favorable binding interactions on EGFR-TK. Selected compounds were examined for their anticancer activity against the Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line which overexpresses EGFR using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay. Compounds 1 and 2, with an isoindoline-1-one core, induced significant inhibition of breast cancer cells proliferation with IC[Formula: see text] values 327 and 370 nM, respectively.

Urease Inhibitory Activities of some Commonly Consumed Herbal Medicines.

Urease enzyme has a crucial role in the persistent habitation of Helicobacter pylori (H. pylori) that induces gastrointestinal diseases, in particular gastritis, duodenal, peptic ulcer, and gastric cancer. Plants have long been utilized as the biggest source of substances with medicinal properties from natural origin and therefore result in less toxicity and adverse side effects upon usage. 15 medicinal plant extracts were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 80% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined. Three plant extracts including Ginkgo biloba, Rhus coriaria, and Matricaria inodora were found to be the most effective ones with IC50 values of 36.17, 80.29, and 100.6 µg/mL, respectively.

Determination of hydrogen cyanide concentration in mainstream smoke of tobacco products by polarography.

BACKGROUND: There has been a worldwide concern for the health risks of cigarette smoking and hydrogen cyanide (HCN) considered as one of the hazardous tobacco compounds which is needed to be determined in order to reduce the dose related to smoke disease risk. In this study, we prepare the experimental procedure to entrap the HCN from mainstream smoke of different brands of Tehran cigarette, through simulating human inhalation and determine its concentration applying polarography. RESULTS: The HCN level of the 50 commonly consumed tobacco products (47 cigarettes and 3 cigars) obtained from local store is ranged between 17.56 ± 1.02 and 1553.98 ± 0.56 µg per stick, this acquired amount is more than FDA approval (10 µg per stick), so the harmful effects of smoking is indicative. CONCLUSIONS: The comparative study of the results shows that the price and the weight of each product do not indicate HCN level. As can be seen, R(2) value which is a statistical measure of how close the data are to the fitted regression line is low (R(2) < 0.2). So it should not be deceived by names such as ultra light or infinite gravity to suck, because this names or the price haven(')t effect on the amount of HCN and its destructive effects.

Breast cancer cells imaging by targeting methionine transporters with gadolinium-based nanoprobe.

PURPOSE: Early cancer diagnosis using MRI imaging is of high global interest as a non-invasive and powerful modality. In this study, methionine was conjugated on gadolinium-based mesoporous silica nanospheres to evaluate intra-cellular uptake and its accumulation in human breast cancer cells. PROCEDURES: The contrast agent was synthesized and characterized using different techniques including N2 physisorption, thermal gravimetric analysis, dynamic light scattering, and inductively coupled plasma atomic emission spectroscopy (ICP-AES). The intra-cellular uptake of Gd(3+) was measured by ICP-AES, fluorescent microscopy, and flow cytometry. Finally, cellular and tumor MR imaging were performed to determine in vitro and in vivo relaxometry. RESULTS: According to the results, the contrast agents accumulated in tumor cells both in vitro and in vivo. There was no significant cellular toxicity on either normal or cancer cells along with strong intense signal on T 1 compared to the unlabeled cells. CONCLUSIONS: The results showed that the novel contrast agent could become a useful tool in early detection of cancer.