Bioorganic & Medicinal Chemistry Letters
Design, synthesis, and enzymatic characterization of quinazoline-based
CYP1A2 inhibitors
Pedro A. Corral⁎, Jordy F. Botello, Chengguo Xing⁎
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, United States
A R T I C L E I N F O
A B S T R A C T
Keywords:
Tobacco
Cytochrome P450 isozyme 1A2 (CYP1A2) is one main xenobiotic metabolizing enzyme in humans. It has been
associated with the bioactivation of procarcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK), a tobacco specific and potent pulmonary carcinogen. This work describes the computational design and
in-silico screening of potential CYP1A2 inhibitors, their chemical synthesis, and enzymatic characterization with
the ultimate aim of assessing their potential as cancer chemopreventive agents. To achieve this, a combined
classifiers model was used to screen a library of quinazoline-based molecules against known CYP1A2 inhibitors,
non-inhibitors, and substrates to predict which quinazoline candidates had a better probability as an inhibitor.
Compounds with high probability of CYP1A2 inhibition were further computationally evaluated via Glide
docking. Candidates predicted to have selectivity and high binding affinity for CYP1A2 were synthesized and
assayed for their enzymatic inhibition of CYP1A2, leading to the discovery of novel and potent quinazoline-
based CYP1A2 inhibitors.
NNK
CYP1A2
Quinazoline
Computational
Synthesis
Tobacco use is the leading cause of preventable diseases and deaths
in the United States.1,2 Therefore, it is imperative to expand our
knowledge about diseases caused by its consumption and develop novel
and effective methods for their management. Of particular interest is
the discovery of safe and low-cost therapies that have the ability to
abate the risk of lung cancer, since tobacco use contributes to 80–90%
of lung cancer incidence and more people die from lung cancer than any
other cancer in the United States.3
induced carcinogenesis is to inhibit its bioactivation. NNK bioactivation
is mainly catalyzed by cytochrome P450 (CYP) isozymes, including
CYP1A2. This enzyme has been shown to be one of the main CYPs in-
volved in the methyl and methylene hydroxylation of NNK in rats and
in human tissues,5 with studies in human lung and liver microsomes
indicating that this enzyme has the highest activity in converting NNK
to its keto alcohol metabolite.7 The development of an inhibitor of
CYP1A2 therefore is an attractive approach to potentially reduce NNK-
induced lung cancer risk. This work explores the design, synthesis and
evaluation of a set of quinazoline compounds as CYP1A2 inhibitors.
Substantial effort has gone into the characterization and systematic
evaluation of CYP inhibitors due to the risk of drug-drug interactions
that arise from undesired inhibition of the enzymes in this crucial xe-
nobiotic compound-metabolizing family.8 Given the role of some of its
members in the bioactivation of procarcinogens, selectively inhibiting
members of this family also has therapeutic potential.6,8 The quinazo-
line class of compounds has been shown to significantly inhibit CYP
activity, with particular affinity for CYP1A2.9 Because of this, the
quinazoline moiety was selected as the framework for our inhibitor
design.
Although tobacco smoke contains several compounds that can ad-
versely affect an individual’s risk for developing lung cancer, 4-(me-
thylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most
important and well characterized carcinogens contained in this mix-
ture.4,5 NNK has been shown to be a potent inducer of lung adeno-
carcinomas in rodents at doses that mirror those experienced by smo-
kers5 and there is ample human evidence indicating that it may
contribute to lung cancer incidence in smokers. Given quitting is
challenging,6 preventing NNK-mediated lung tumorigenesis is an im-
portant strategy to reduce lung cancer incidence and eventually its
associated deaths.
As a procarcinogen, NNK is enzymatically bioactivated to generate
reactive intermediates. This will result in DNA modifications, leading to
mutations if not repaired. NNK-induced DNA damage has been pro-
posed as the root cause of lung carcinogenesis. Based on the carcino-
genesis mechanism for NNK, a possible approach to prevent NNK-
An initial screening of 138 quinazoline compounds was performed
to identify molecules with potential to selectively inhibit CYP1A2. This
was performed using the combined classifiers algorithm10 and soft-
ware11 developed by Cheng et al. The output of this screening identified
⁎ Corresponding authors.
Pleasecitethisarticleas:PedroA.Corral,JordyF.BotelloandChengguoXing,Bioorganic&MedicinalChemistryLetters,
https://doi.org/10.1016/j.bmcl.2019.126719