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Page 2 of 12 Goyal et al. J Cancer Metastasis Treat 2021;7:18 https://dx.doi.org/10.20517/2394-4722.2020.143

Results: The design and synthesis of two series of novel pyridine-based compounds, with varying substituents and
substitution locations on the pyridine ring, as well as their inhibitory activities on cytochrome P450 2A6 and their
interactions with its active site are discussed here. Substitutions at position 3 of the pyridine ring with an imidazole
or propargyl ether containing group showed the most optimal interactions with the P4502A6 active site.

Conclusion: The pyridine compounds with an imidazole or propargyl ether containing substituent on position 3
were found to be promising lead compounds for further development. Hydrogen-bonding interactions were
determined to be crucial for effective binding of these molecules within the P450 2A6 active site.

Keywords: Phytochemicals, cytochrome P450 enzymes, tobacco smoking, nicotine

INTRODUCTION
Phytochemicals are plant-produced natural products, and are commonly found in human and animal diets
[1-3]
as well as in plant-based medications and natural remedies . While most of these chemicals have basic
nutritional value, some have preventive, therapeutic or toxic effects. Phytochemicals can play a preventive
role in carcinogenesis in multiple ways; as primary preventive agents that can be used to prevent the advent
of cancer; as secondary agents that can prevent progression of cancer as in the case of premalignant lesions;
[4,5]
and as tertiary agents that can prevent the recurrence of cancer . Some examples of such phytochemicals
are capsaicin from chili pepper , polyphenols from green tea, fruits, and vegetables , carotenoids such as
[8,9]
[6,7]
lycopene found in fruits [10,11] , cucurbitacin B from Chinese medicinal plants [12-14] , isoflavones from
legumes [15,16] , etc. Phytochemicals have also been shown to modulate multiple mechanisms in cancer,
resulting in their anti-cancer activities [5,17-21] . Phytochemicals are known to have similar preventive and/or
therapeutic effects on many other diseases [10,11,16,19,22] .

Phytochemicals are often toxins produced by plants as a defense mechanism against disease-causing
organisms or herbivorous animals. Certain herbs and plants routinely used by humans, contain phytotoxins
with carcinogenic, teratogenic and/or endocrine influencing activities . While some of these
[1]
phytochemicals are direct-acting toxins, others, such as procarcinogenic agents, need metabolic activation.
Certain procarcinogenic alkenylbenzenes, pyrrolizidine alkaloids, ptaquiloside, aristolochic acids, and
furanocoumarins are known DNA-alkylating agents [3,22-25] . Metabolic activation of phytochemical
procarcinogens into their ultimate carcinogenic forms by phase I and phase II enzymes has been well
established [26,27] . Cytochrome P450 enzymes, a superfamily of Phase I enzymes, metabolize endogenous and
xenobiotic compounds including phytochemicals, through monooxygenation reactions [26-29] .

Nicotine, a phytotoxin present in many plants and vegetables, including tobacco, and in much smaller
concentrations in potatoes, tomatoes, eggplants, and green peppers, is primarily metabolized by human liver
P450 2A6, and to a smaller extent by human lung P450 2A13. The metabolism of nicotine to cotinine takes
place in two steps - initial oxidation to the intermediate nicotine-△ -iminium ion by either of the two
1’(5’)
P450 enzymes [29-31] , and further oxidation to cotinine by cytosolic aldehyde oxidase [29,32] . Nicotine plays a
critical role in tobacco-dependence, and is the main cause of lung cancer deaths in men and women. It is
estimated that more than 16 million Americans are affected by cigarette smoking, and more than 480,000
deaths per year are attributed to tobacco use . Several strategies have been developed and implemented for
[33]
cessation of cigarette smoking, such as nicotine replacement therapies alone or in combination with
varenicline, a nicotinic acetylcholine receptor partial agonist . However, only about 6% of smokers are able
[34]
to overcome the addiction to nicotine . The addiction to nicotine in smokers modulating their smoking
[35]
behaviors has a direct correlation to the levels of nicotine in the blood and brain [36-38] . Drop of the levels of
nicotine in the blood and brain due to the P450 2A6 metabolism, causes the smokers to adjust their tobacco