Identification of novel ureido benzothiophenes as dual VEGFR-2/EGFR anticancer agents.

Presently, dual-targeting by a single small molecule stands out as a fruitful cancer-fighting strategy. Joining the global effort to fight cancer, a leading cause of death worldwide, we report in this study a novel set for benzothiophene-based aryl urea derivatives as potential anti-proliferative candidates endowed with dual VEGFR-2/EGFR inhibitory activities. The prepared ureido benzothiophenes 6a-r have been evaluated for their anticancer action on a panel of tumor cell lines, namely PanC-1, MCF-7, and HepG2 cells. Most newly synthesized benzo[b]thiophene ureas disclosed effective cytotoxic activities against the examined cancer cell lines. In particular, compound 6q, with an appended 4-trifluoromethoxy group on the terminal phenyl ring, exhibited the most significant cytotoxic activity in MCF-7 with IC50 3.86 ± 0.72 ug/mL; IC50 of 3.65 ± 0.18 ug/ml in PanC-1 cell line and an IC50 of 4.78 ± 0.06 ug/ml in HepG2. After that, derivatives that exhibited the most potent cytotoxic activities (6g, 6j, 6q, and 6r) were further evaluated as VEGFR-2 and EGFR inhibitors. Fortunately, they displayed low nanomolar IC50 values against both enzymes, where compound 6q emerged to possess superior inhibitory effects towards both EGFR and VEGFR-2 with IC50 46.6 nM and 11.3 nM simultaneously compared to the reference medications Erlotinib and Sorafenib, respectively. The docked structure of 6q within the catalytic region of VEGFR-2 and EGFR kinases was acquired and studied so that we could investigate potential binding mechanisms for the target ureido benzothiophenes. Hence, the benzothiophene-based aryl urea scaffold has great potential for advancing the development of highly effective dual inhibitors targeting both EGFR and VEGFR-2, which can serve as effective candidates for anticancer therapy.

Structure-function relationship of oat flour fractions when blended with wheat flour: Instrumental and nutritional quality characterization of resulting breads.

The present work investigated the structure-function relationship of dry fractionated oat flour (DFOF) as a techno-functional ingredient using bread as a model system. Mechanically, DFOF fractions (F), that is, F1: <224 µm, F2: 250-280 µm, F3: 280-500 µm, F4: 500-600 µm, and whole oat flour (F5) were blended with white wheat flour at 10%, 30%, and 50% substitution levels for bread making. The blended flours, doughs, and bread samples were assessed for their techno-functional, nutritional, and structural characteristics. The results of Mixolab and the Rapid Visco Analyzer show that the 50% substituted F3 fraction exhibits the highest water absorption properties (69.53%), whereas the 50% F1 fraction exhibits the highest peak viscosity of the past slurry. Analysis of bread samples revealed a lower particle size of DFOF fractions and higher supplementation levels, increased ß-glucan levels (0.13-1.29 g/100 bread (db), reduced fermentable monosaccharides, that is, glucose (1.44-0.33 g/100 g), and fructose (1.06-0.28 g/100 g). The effect of particle size surpassed the substitution level effect on bread volume reduction. The lowest hardness value for F1 is 10%, and the highest value for F2 is 50%. The total number of cells in the bread slice decreased from the control to the F4 fraction (50%). Multi-criteria analysis indicated that DFOF fractions produced breads with similar structure and higher nutritional value developed from white wheat flour. PRACTICAL APPLICATION: The use of mechanically fractionated oat flours fractions in white wheat flour breads can improve the nutritional profile without affecting the physical properties of the bread product. Based on the oat flour fractions, bakers and food processing companies can tailor the bread formulations for high ß-glucan, high fiber, and low reduced sugar claims.

Discovery of new thiazolidine-2,4-dione derivatives as potential VEGFR-2 inhibitors: In vitro and in silico studies.

In this study, a series of seven novel 2,4-dioxothiazolidine derivatives with potential anticancer and VEGFR-2 inhibiting abilities were designed and synthesized as VEGFR-2 inhibitors. The synthesized compounds were tested in vitro for their potential to inhibit VEGFR-2 and the growth of HepG2 and MCF-7 cancer cell lines. Among the compounds tested, compound 22 (IC50 = 0.079 µM) demonstrated the highest anti-VEGFR-2 efficacy. Furthermore, it demonstrated significant anti-proliferative activities against HepG2 (IC50 = 2.04 ± 0.06 µM) and MCF-7 (IC50 = 1.21 ± 0.04 M). Additionally, compound 22 also increased the total apoptotic rate of the MCF-7 cancer cell lines with cell cycle arrest at S phase. As well, computational methods were applied to study the VEGFR-2-22 complex at the molecular level. Molecular docking and molecular dynamics (MD) simulations were used to investigate the complex's structural and kinetic characteristics. The DFT calculations further revealed the structural and electronic properties of compound 22. Finally, computational ADMET and toxicity tests were performed indicating the likeness of the proposed compounds to be drugs. The results suggest that compound 22 displays promise as an effective anticancer treatment and can serve as a model for future structural modifications and biological investigations in this field.