Oxysterol receptors LXRs (α and β) are recently reported to be one of the novel and potential therapeutic targets in reducing cell proliferation and tumor growth in different system model. Activation of LXRs is correlated with modification of PI3K/Akt pathway. LXRs are also found to play a critical role in maintaining lipid homeostatais by regulating ABCA1, IDOL, SREBP1, LDLR and also certain lipogenic genes such as FASN and SCD1. In the present study a potential furanocoumarin, Bergapten (BeG) has been evaluated for its anticancer property on Hepatocellular Carcinoma (HCC) on LXR axis. The molecular docking analysis was carried out for BeG on LXR (α & β) using Maestro tool and compared with reference ligands. This was followed by in vitro (HepG2 cell lines) and in vivo (on NDEA induced HCC in Wistar albino rats) anticancer evaluation of BeG. The docking results revealed polar and hydrophobic interactions of BeG with LXR (α,β). The in vitro studies revealed the potential of BeG in lowering the accumulation of lipid droplets in HepG2 cells which was correlated with increase in LXR (α,β) protein expressions. Furthermore, the in vivo studies demonstrated the potential of BeG in ameliorating the cancer induced alterations in body weight, liver weight and significant restoration of the changes in mRNA and protein expressions of LXR(α,β), ABCA1, IDOL, SREBP1 and LDLR. BeG also modulated the expressions of PI3K, Akt and certain lipogenic genes like FASN and SCD1 and reduced the lipid droplets level in liver cancer cells. These results provide evidence and validates the critical role of BeG in maintaining the lipid homeostasis and justifies its anticancer potential against NDEA-induced HCC.

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Highly selective CYP1B1 inhibitors have potential in the treatment of hormone-induced breast and prostate cancers. Mimicry of potent and selective CYP1B1 inhibitors, α-naphthoflavone and stilbenes, revealed that two sets of hydrophobic clusters suitably linked via a polar linker could be implanted into a new scaffold 'biphenyl ureas' to create potentially a new class of CYP1B1 inhibitors. A series of sixteen biphenyl ureas were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™, yeast-derived recombinant microsomal enzymes. The most active human CYP1B1 inhibitors were further studied for their selectivity against human CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. The meta-chloro-substituted biphenyl urea 5h was the most potent inhibitor of CYP1B1 with IC value of 5 nM. It displayed excellent selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 (IC >10 μM in the four CYP assays, indicating >2000-fold selectivity). Similarly, two methoxy-substituted biphenyl ureas 5d and 5e also displayed potent and selective inhibition of CYP1B1 with IC values of 69 and 58 nM, respectively, showing >62 and >98-fold selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. In order to probe if the relatively insoluble biphenyl ureas were cell permeable and if they could at all be used for future cellular studies, their CYP1B1 inhibition was investigated in live recombinant human and yeast cells. Compound 5d displayed the most potent inhibition with ICs of 20 nM and 235 nM, respectively, in the two cell-based assays. The most potent and selective CYP1B1 inhibitor (compound 5h) from Sacchrosomes, also displayed potent inhibition in live cell assays. Molecular modeling was performed to understand the trends in potency and selectivity observed in the panel of five CYP isoenzymes used for the in vitro studies.

A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1-pyrazol-3-yl)phenol (pyrazoline) derivatives () have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative () behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity ((hMAO-B)/(hMAO-A) > 1751). In addition, exhibited little to no cytotoxic effects up to a 25 μM concentration and provided the best blood-brain barrier permeability among the derivatives synthesized. Molecular dynamics simulations revealed that a chlorine substituent at the-position of the phenyl ring in enabled a π-π stacking interaction with Tyr407 and Tyr444 that resulted in the formation of an "aromatic sandwich" structure. Consequently, this tight-binding aromatic cage culminated in a dramatically reduced active site volume that is believed to be the origin of the observed selectivity between the hMAO-A and hMAO-B isozymes. Removal of the chlorine from disrupted the favorable intermolecular interactions and resulted in a selectivity change towards hMAO-B.