In vitro antitumor activity, ADME-Tox and 3D-QSAR of synthesized and selected natural styryl lactones.

Prostate cancer is a common cause of death in men and a novel treating methods should be developed. In order to find a new drug for prostate cancer, a series of novel conformationally constrained analogues of (+)-goniofufurone and 7-epi-(+)-goniofufurone, as well as the newly synthesized styryl lactones containing the cinnamic acid ester groups were evaluated for in vitro cytotoxicity against prostate cancer cell (PC-3). Furthermore, prediction of physicochemical characteristics and drugability as well as in silico ADME-Tox tests of investigated compounds were performed. The 3D-QSAR model was established using the comparative molecular field analysis method. According to obtained results, the tricyclic compounds 9 and 10 had the highest potency with IC50 < 20 µM. Evaluation of structural features through 3D-QSAR model identified steric field feature on the cinnamic acid ester groups at C-7 as a crucial for the cytotoxic activity. This research suggests that most of the analysed compounds have desirable properties for drug candidates and high potential in drug development, which recommend them for further research in treatment of prostate cancer. Furthermore, obtained 3D-QSAR model is able to successfully identify styryl lactones that have significant cytotoxic activity and provide information for screening and design of novel inhibitors against PC-3 cell line that could be used as drugs in treatment of the prostate cancer.

Toward steroidal anticancer drugs: Non-parametric and 3D-QSAR modeling of 17-picolyl and 17-picolinylidene androstanes with antiproliferative activity on breast adenocarcinoma cells.

The present study is aimed to analyze lipophilicity and ADMET profiles, and to develop field based 3D-QSAR and ligand-based pharmacophore hypothesis for a series of 17α-picolyl and 17(E)-picolinylidene androstane derivatives in order to give detailed structural insights and to highlight important binding features of novel androstane derivatives, as compounds with antiproliferative activity toward breast adenocarcinoma cells. This study can provide guidelines for the rational design of novel potent compounds. Sum of ranking differences (SRD), as a non-parametric method, was applied for compounds ranking. 3D-QSAR methods, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied to predict the antiproliferative effect on breast adenocarcinoma cells and provide the regions in space where interactive fields may influence the activity. The compounds are ranked so the compounds with the most favorable ADME and lipophilicity features together with significant anticancer activity can be distinguished. The established 3D-QSAR model could be used for design of new compounds with antiproliferative activity on the human ER- breast adenocarcinoma cells. The pharmacophore model is able to accurately predict antiproliferative activity. Generally, the present study provides significant guidelines for further selection, synthesis and rational design of new highly potential androstane derivatives as anticancer drugs.

Modeling of rheological characteristics of the fermented dairy products obtained by novel and traditional starter cultures.

Tree different fermented dairy products obtained by conventional and non-conventional starter cultures were investigated in this paper. Textural and rheological characteristics as well as chemical composition during 21 days of storage were analysed and subsequent data processing was performed by principal component analysis. The analysis of samples` flow behaviour was focused on their time dependent properties. Parameters of Power law model described flow behaviour of samples depended on used starter culture and days of storage. The Power law model was applied successfully to describe the flow of the fermented milk, which had characteristics of shear thinning and non-Newtonian fluid behaviour.

In silico identification of milk antihypertensive di- and tripeptides involved in angiotensin I-converting enzyme inhibitory activity.

Identification of bioactive milk peptides could improve food technology through improved selection of food supplements with a focus on antihypertensive properties. We hypothesized that angiotensin I-converting enzyme (ACE) inhibitory activities of milk di- and tripeptides could be predicted using 3-dimensional quantitative structure activity relationship methods and that these activities could be explained through evaluation of structural features (hydrogen bond donor/acceptor, hydrophobic, steric, and electrostatic) that are responsible for this bioactivity. We aimed to build comparative molecular field analysis (CoMFA) models combined with in silico digestion to predict the peptide sequences released from enzymatic digestion and to evaluate peptides without experimental data. Furthermore, molecular docking simulation was performed with the aim to evaluate structural features. Molecular docking simulations revealed that the most potent inhibitory peptides contain hydrophobic amino acids that enter deep into the hydrophobic pocket of the ACE active site and make interactions with its residues. CoMFA results point out favorable steric interactions and electronegativity at the C-terminus of the milk dipeptides. The CoMFA model appears to favor electropositive amino acids at the second place in tripeptides and electronegative interaction with Tyr520. Furthermore, predicted values of ACE inhibitory activity of dipeptides obtained by peptide cutter are relatively high, which recommend them for application as functional food supplements and natural alternatives to ACE inhibitory drugs. This research suggests that obtained 3-dimensional quantitative structure activity relationship models are able to successfully identify milk-derived di- and tripeptides that have significant antihypertensive activity and provide information for screening and design of novel ACE inhibitors that could be used as supplements in human nutrition.