Interestingly, 2′-hydroxy-4,4′,6′-trimethoxychalcone (also known as flavokawain A) (4) appeared to be the most potent compound in cytotoxic screening against both HL-60 and MCF-7 cell lines.
Cardiac glycosides such as ouabain and proscillaridin were among the most potent compounds in the screen.
The most potent hit from that screen, compound 2, had a structure unlike existing hDAAO inhibitors.
We evaluated the pharmacokinetic properties of the two most potent and selective profens screened to date, 3a and 7a, in C57BL/6 mice.
We found that only expression of MAP3K14, the most potent hit in our screen, and TNFSF10 were cytotoxic relative to the empty vector control.
In vivo anti-inflammatory and analgesic activity, and in vitro 5-LO Xenzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods.
These in vitro assays act as important filters removing in-active compounds to progress only the most potent ones to in vivo screening.
Surprisingly the most potent antagonist from the biochemical screening, the free carboxylic acid compound YH239, showed no significant effect on the cells with wt p53, but the corresponding ethyl ester precursor YH239-EE showed potent inhibition of cell proliferation on OCI-AML-3 cells in the same range as Nutlin-3.
In the scPTZ screen the most potent were compound 6 with an ED50 = 40.87 mg/kg, and 4-benzylpiperidine derivative 22 – ED50 = 60.00 mg/kg.
Through the anti-proliferation assay, the most potent anti-cancer agent was screened out, namely Q9 (IC50 = 0.88 ± 0.18 μM against MCF-7 cell line), and it showed lower cytotoxicity against non-cancer cells, human embryonic kidney cells (293T) (IC50 = 54.38 ± 3.78 μM).
