2 research outputs found
Novel synthetic biscoumarins target tumor necrosis factor-α in hepatocellular carcinoma in vitro and in vivo
No full textTNF is a pleotropic cytokine known to be involved in the progression of several pro-inflammatory disorders. Many therapeutic agents have been designed to counteract the effect of TNF in rheumatoid arthritis as well as a number of cancers. In the present study we have synthesized and evaluated the anti-cancer activity of novel biscoumarins in vitro and in vivo. Among new compounds, BIHC was found to be the most cytotoxic agent against the HepG2 cell line while exhibiting less toxicity toward normal hepatocytes. Furthermore, BIHC inhibited the proliferation of various hepatocellular carcinoma (HCC) cells in a doseand time-dependent manner. Subsequently, using in silico target prediction, BIHC was predicted as a TNF blocker. Experimental validation was able to confirm this hypothesis, where BIHC could significantly inhibit the recombinant mouse TNF-binding to its antibody with an IC50 of 16.5 μM. Furthermore, in silico docking suggested a binding mode of BIHC similar to a ligand known to disrupt the native, trimeric structure of TNF, and also validated with molecular dynamics simulations. Moreover, we have demonstrated the down-regulation of p65 phos-phorylation and other NF-KB-regulated gene products upon BIHC treatment, and on the phenotypic level the compound shows inhibition of CXCLF2-induced invasion of HepG2 cells. Also, we demonstrate that BIHC inhibits infiltration of macrophages to the peritoneal cavity and suppresses the activity of TNF-α in vivo in mice primed with thioglycollate broth and lipopolysaccharide. We comprehensively validated the TNF-α inhibitory efficacy of BIHC in an inflammatory bowel disease mice model. © 2014 by I he American bociety tor Biochemistry and Molecular Biology, Inc
Nano-MoO3-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching
No full textThe efficacy of thiazolidin-4-ones as synthons for diverse biological small molecules has given impetus to anti-bacterial studies. Our work aims to synthesize novel bioactive thiazolidin-4-ones using nano-MoO3 for the first time. The compelling advantage of using nano-MoO3 is that the recovered nano-MoO3 can be reused thrice without considerable loss of its catalytic activity. The synthesized thiazolidin-4-ones were tested for anti-bacterial activity against two strains of pathogenic bacteria, namely, Salmonella typhi and Klebsiella pneumoniae. Our results indicated that 3-(benzodisoxazol-3-yl)-2-(3-methoxyphenyl)thiazolidine-4-one (compound 3b) showed significant inhibitory activity towards Salmonella typhi{,} in comparison with gentamicin. Furthermore{,} in silico target prediction presented the target of compound 3b as the FtsK motor domain of DNA translocase of Salmonella typhi. Hence{,} our hypothesis is that compound 3b may disrupt chromosomal segregation and thereby inhibit the division of Salmonella typhi. In addition{,} similarity searching showed that 34 compounds with a chemical similarity of 70% or higher to compound 3b{,} which were retrieved from ChEMBL{,} bound to targets associated with biological processes related to cell development in 36% of the cases. In summary{,} our work details novel usage of nano-MoO3 for the synthesis of novel thiazolidin-4-ones possessing anti-bacterial activity{,} and presents a mode-of-action hypothesis
