ABSTRACT
The increased expression of VEGFR-2 in a variety of cancer cells promotes a cascade of cellular responses that improve cell survival, growth, and proliferation. Heterocycles are common structural elements in medicinal chemistry and commercially available medications that target several biological pathways and induce cell death in cancer cells. Herein, the evaluation of indazolyl-acyl hydrazones as antioxidant and anticancer agents is reported. Compounds 4e and 4j showed inhibitory activity in free radical scavenging assays (DPPH and FRPA). The titled compounds were employed in cell viability studies using MCF-7 cells, and it was observed that compounds 4f and 4j exhibited IC50 values 15.83 µM and 5.72 µM, respectively. In silico docking revealed the favorable binding energies of -7.30 kcal/mol and -8.04 kcal/mol for these compounds towards Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2), respectively. In conclusion, compounds with antioxidant activity and that target VEGFR-2 in breast cancer cells are reported.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Humans , Female , Molecular Structure , Structure-Activity Relationship , Antioxidants/pharmacology , Vascular Endothelial Growth Factor Receptor-2 , Breast Neoplasms/drug therapy , Hydrazones/pharmacology , Vascular Endothelial Growth Factor A/pharmacology , Cell Proliferation , Drug Design , Molecular Docking Simulation , Antineoplastic Agents/chemistry , Drug Screening Assays, AntitumorABSTRACT
Nuclear factor kappa B (NF-κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine- and piperazine-linked pyrimidines was developed as inhibitors of NF-κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine-pyrimidine and piperazine-pyrimidine derivatives, compounds 3a and 5b inhibited breast cancer cell (MCF-7) viability with an IC50 value of 9.17 and 6.29 µM, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4-methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF-κB, with the binding energies -9.32 and -7.32 kcal mol-1. Furthermore, compounds 3a and 5b inhibited NF-κB in MCF-7 breast cancer cells. In conclusion, we herein report newer structures that target NF-κB in BC cells.
ABSTRACT
Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Humans , Female , Histone Deacetylases/metabolism , Triazoles/chemistry , Cell Line, Tumor , Isoxazoles/pharmacology , Breast Neoplasms/drug therapy , Histone Deacetylase Inhibitors/chemistry , Cell Proliferation , Antineoplastic Agents/chemistry , Structure-Activity RelationshipABSTRACT
The COVID-19 is an international public health emergency and threatens psychological resilience. Here we assess the general health status of the public in India during the COVID-19 outbreak. A population-based cross-sectional study conducted using a General Health Questionnaire and the relationship between mental health and sociodemographic factors were analyzed. The mean score for the general health of citizens was 24.18. About 40.63% of the elderly and 40.18% of the female population was under severe physiological distress. The prevalence of psychological stress among the general population was higher than expected. Hence, there is a need to intensify awareness about the pandemic and should provide mental health management programs.
