136116-18-2Relevant academic research and scientific papers
5,6-Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies
Singh, Jatinder V.,Kaur, Anumeet,Bhagat, Kavita,Gupta, Manish K.,Singh, Manwinder,Singh, Harbinder,Bedi, Preet Mohinder S.
, p. 490 - 502 (2018/03/28)
In a continued effort to develop potent cholesterol esterase (CEase) inhibitors, a series of 5,6-benzoflavone derivatives was rationally designed and synthesized by changing the position of the benzene ring attached to the flavone skeleton in previously reported 7,8-benzoflavones. All the synthesized compounds were checked for their inhibitory potential against cholesterol esterase (CEase) using a spectrophotometric assay. Among the series of forty compounds, seven derivatives (B-10 to B-16) exhibited above 90 percent inhibition against CEase in an in vitro enzymatic assay. Compound B-16 showed the most promising activity with an IC50 value of 0.73 nM against cholesterol esterase. To determine the type of inhibition, enzyme kinetic studies were carried out for B-16, which revealed its mixed-type inhibition approach. Moreover, to figure out the key binding interactions of B-16 with the amino acid residues of the enzyme's active site, molecular protein-ligand docking studies were also performed. B-16 completely blocks the catalytic assembly of CEase and prevents it from participating in the ester hydrolysis mechanism. The favorable binding conformation of B-16 suggests its prevailing role as a CEase inhibitor. Overall, the study showed that the cisorientation of ring A with respect to the carbonyl group of ring C is responsible for the potent CEase inhibitory activity of the newly synthesized compounds.
Synthesis and biological evaluation of flavones and benzoflavones as inhibitors of BCRP/ABCG2
Juvale, Kapil,Stefan, Katja,Wiese, Michael
, p. 115 - 126 (2013/10/01)
Multidrug resistance (MDR) often leads to a failure of cancer chemotherapy. Breast Cancer Resistance Protein (BCRP/ABCG2), a member of the superfamily of ATP binding cassette proteins has been found to confer MDR in cancer cells by transporting molecules with amphiphilic character out of the cells using energy from ATP hydrolysis. Inhibiting BCRP can be a solution to overcome MDR.We synthesized a series of flavones, 7,8-benzofl avones and 5,6-benzo flavones with varying substituents at positions 3, 3′ and 4′ of the (benzo)fl avone structure. All synthesized compounds were tested for BCRP inhibition in Hoechst 33342 and pheophorbide A accumulation assays using MDCK cells expressing BCRP. All the compounds were further screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity by calcein AM accumulation assay to check the selectivity towards BCRP. In addition most active compounds were investigated for their cytotoxicity. It was observed that in most cases 7,8-benzoflavones are more potent in comparison to the 5,6-benzoflavones. In general it was found that presence of a 3-OCH3 substituent leads to increase in activity in comparison to presence of OH or no substitution at position 3. Also, it was found that presence of 3′,4′-OCH3 on phenyl ring lead to increase in activity as compared to other substituents. Compound 24, a 7,8-benzoflavone derivative was found to be most potent being 50 times selective for BCRP and showing very low cytotoxicity at higher concentrations.
