Abstract
Both symmetrical (1a-f) and asymmetrical (2a-f) analogues of dicoumarol were synthesized in 20 – 86% yield by using microwave assisted one-pot protocol. Their ability to inhibit NAD (P)H:oxidorectase quinone 1 (NQO1) and cytotoxicity towards A549 small lung cancer cell line were evaluated. Interestingly, (E)-3-(2-hydroxynaphthalen-1-y)chroman-2,4-dione (2d) showed not only moderate inhibitory potency (IC50 = 20 ± 6 nM) towards NQO1 but also was toxic (IC50 = 9.2 ± 0.2 µM) towards the A549 small lung cancer cell line.
Highlights
NAD (P)H:oxidorectase quinone 1 (NQO1) is a ubiquitous flavoprotein, which functions in a catalytic manner and can be called flavoenzyme
There are evidences in support for a role of NQO1 in the detoxification of quinones (3a). This is provided by the observation that dicoumarol (Figure 1), an inhibitor of NQO1 with IC50 value = 2.6 nM (Ernester, (1967), enables the toxicity of quinones to hypatocytes (Miller, Rogers, & Cohen, 1986; Thor et al, 1982) and this can only be possible by blocking 2 electron reduction to non-toxic hydroquinone (3c) and allowing large amount of quinones to be available for one electron reduction to toxic semi-quinone radicals (3b) by cytochrome p450 reductases as depicted in Scheme 1
The IC50 value, in terms of an enzyme assay, represents the concentration of a drug that is required for 50% inhibition in vitro, whereas, in terms of cytotoxicity, it represents the concentration of a drug required to inhibit the growth of cells by 50%
Summary
NQO1 is a ubiquitous flavoprotein, which functions in a catalytic manner and can be called flavoenzyme. Vol 10, No 3; 2018 causing agents They are highly reactive as electrophiles and generate unstable semi-quinone radicals via one electron reduction by cytochrome p450 reductases. The semi-quinone radicals subsequently undergo redox cycling in the presence of molecular oxygen forming highly reactive oxygen species (ROS) as depicted in Scheme 2. One electron reduction of quinone to a semi-quinone radical caused by cytochrome p450 reductases and redox cycling in the presence of molecular oxygen forming superoxide (O2-) a reactive oxygen species (ROS). This can lead to oxidative stress and tissue degeneration, apoptosis, premature aging, cellular transformation and neoplasia according to a research carried out by Schuetzie et al, (1994). The aim of this research was to prepare some new inhibitors of NQO1 using the biologically active 4-hydroxycoumarin and its derivatives as precursors (Overmunn et al, 1994; Silvia, 2012)
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