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Goyal et al. J Cancer Metastasis Treat 2021;7:18 https://dx.doi.org/10.20517/2394-4722.2020.143 Page 9 of 12

presence of other polymorphic variants of CYP2A6 that could be naturally found in liver microsomes.
Therefore, the Vivid CYP2A6 Kit used in this study does not account for any polymorphism of CYP2A6.
However, it is very important to understand the inhibitory effect of new compounds on CYP2A6
polymorphism as people with other allelic variants of CYP2A6 exhibit varied metabolic response. Our
future studies would aim to study this phenomenon, either by developing the cell systems expressing
various CYP2A6 allelic variants using baculovirus and insect cell lines by genetic engineering tools [59-61] , or
by deploying the “molecular lego” approach developed by Castrignano et al. , using a chimeric CYP2A6-
[50]
flavodoxin/CYP2A6 and determining the kinetic parameters of coumarin electrocatalysis by electrochemical
detection.

DISCUSSION
Based on the pyridine scaffold of nicotine, two series of compounds were designed and synthesized for this
study. The compounds containing an imidazole or propargyl ether substituents at position 3 of the pyridine
ring were found to be promising lead compounds for further development. Our studies clearly illustrated
that H-bonding interactions were very important for effective binding of these molecules within the P450
2A6 active site. Many of the pyridine derivatives developed by the Cashman and Lazarus Research Groups
have a primary or secondary amine functional group that interacts with the heme iron [51-54] . The compounds
developed by our group do not contain any amine functional groups, resulting in the aromatic heterocyclic
rings facing the heme-Fe and also showing low P450 2A6 inhibition IC values (micromolar). Using these
50
lead compounds, additional potential inhibitors with increased number of interactions with the amino acid
residues of the P450 2A6 active site will be designed and synthesized.

DECLARATIONS
Acknowledgement
Research reported in this publication was supported by the Louisiana Cancer Research Center, its Tobacco
Free Living Program, the National Institute of General Medical Sciences of the National Institutes of Health
under Award Number 5RL5GM118966, and the NIMHD-RCMI grant number 5G12MD007595. The
content is solely the responsibility of the authors and does not necessarily represent the official views of the
National Institutes of Health or the Louisiana Cancer Research Center.

Authors’ contributions
Design, synthesis, purification, and structural analysis of the compounds: Goyal N
Design and performance of the docking studies: Sridhar J
Synthesis and purification of the compounds: Do C
Design and performance of the inhibition assays: Bratton M, Shaik S, Jiang Q
Overall project conception and direction: Foroozesh M
Contributed significantly and equally to the manuscript: Goyal N, Sridhar J, Foroozesh M

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflict of interest
All authors declared that there are no conflicts of interest.