Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032

Dimensionless analysis for investigating the quality characteristics of aluminium matrix composites prepared through fused deposition modelling assisted investment casting

The aluminium matrix composites (AMCs) have become a tough competitor for various categories of metallic alloys, especially ferrous materials, owing to their tremendous servicing in the diversified application. In this work, additional efforts have been made to formulate a mathematical model, by using dimensionless analysis, able to predict the mechanical characteristics of the AMCs that have already been optimized and characterized by the authors. Here, the experimental and statistical data obtained from the Taguchi L18 orthogonal array and analysis of variance (ANOVA) have been used. They permit collection of the output responses and allow the identification of significant process parameters, respectively, which thereafter were used to design the mathematical model. Second order polynomial equations have been obtained from the specific output response and the relevant input parameter were incorporated with the highest level of contribution. The obtained quadratic equations indicate the regression values (R2) equal to unity, hence, proving the performances of the fit. The results demonstrate that the developed mathematical models present very high accuracy for predicting the output responses