Recent Progress in the Development of Quinoline Derivatives for the Exploitation of Anti-Cancer Agents

Abstract

Background
Along with the progress in medicine and therapies, the exploitation of anti-cancer agents focused more on the vital signaling pathways and key biological macromolecules. With rational design and advanced synthesis, quinoline derivatives have been utilized frequently in medicinal chemistry, especially in developing anti-cancer drugs or candidates.

Methods
Using DOI searching, articles published before 2020 all over the world have been reviewed as comprehensively as possible.

Results
In this review, we selected the representative quinoline derivate drugs in market or clinical trials, classified them into five major categories with detailed targets according to their main mechanisms, discussed the relationship within the same mechanism, and generated a summative discussion with prospective expectations. For each mechanism, the introduction of the target was presented, with the typical examples of quinoline derivate drugs.

Conclusion
This review has highlighted the quinoline drugs or candidates, suited them into corresponding targets in their pathways, summarized and discussed. We hope that this review may help the researchers who are interested in discovering quinoline derivate anticancer agents obtain considerable understanding in this specific topic. Through the flourishing period and the vigorous strategies in clinical trials, quinoline drugs would be potential but facing new challenges in future.

Full text

Anti-Cancer Agents in Medicinal Chemistry
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Anti-Cancer Agents in Medicinal Chemistry, 2021, 21, 825-838
825
REVIEW ARTICLE
Recent Progress in the Development of Quinoline Derivatives for the Exploitation of
Anti-Cancer Agents
Ruo-Jun Man1,‡, Nasreen Jeelani2,‡, Chongchen Zhou3,* and Yu-Shun Yang2,*
1College of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning, China; 2Institute of Chemistry and
BioMedical Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China; 3Henan Provincial Key Laboratory of
Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University,
Zhengzhou, 450018, China
A R T I C L E H I S T O R Y
Received: December 31 , 2019
Revised: January 23, 2020
Accepted: February 10 , 2020
DOI:
10.2174/1871520620666200516150345
Abstract: Background: Along with the progress in medicine and therapies, the exploitation of anti-cancer agents
focused more on the vital signaling pathways and key biological macromolecules. With rational design and ad-
vanced synthesis, quinoline derivatives have been utilized frequently in medicinal chemistry, especially in develop-
ing anti-cancer drugs or candidates.
Methods: Using DOI searching, articles published before 2020 all over the world have been reviewed as compre-
hensively as possible.
Results: In this review, we selected the representative quinoline derivate drugs in market or clinical trials, classified
them into five major categories with detailed targets according to their main mechanisms, discussed the relationship
within the same mechanism, and generated a summative discussion with prospective expectations. For each mecha-
nism, the introduction of the target was presented, with the typical examples of quinoline derivate drugs.
Conclusion: This review has highlighted the quinoline drugs or candidates, suited them into corresponding targets
in their pathways, summarized and discussed. We hope that this review may help the researchers who are interested
in discovering quinoline derivate anti-cancer agents obtain considerable understanding of this specific topic.
Through the flourishing period and the vigorous strategies in clinical trials, quinoline drugs would be potential but
facing new challenges in the future.
Keywords: Anti-cancer agents, quinoline derivatives, marketed drugs, clinical trials, molecular targets, major mechanisms.
1. INTRODUCTION
Risking the health of people worldwide, cancer is the second
highest cause of death all over the world [1]. For quite a long pe-
riod, there has been a lack of available preventative measures, accu-
rate diagnose approaches and potent therapeutic schedules for most
of the cancers [2-4]. The major impediments are the complex
mechanisms and contributing factors in specific tumor types, and
what could be worse, the fast-paced life and environmental pollu-
tion nowadays might make the situations more sophisticated [5, 6].
Fortunately, along with the progress in medicine and therapies,
researchers have gradually comprehended the tumor pathogenesis
in the cellular and molecular scale, thus have revealed more and
more vital signaling pathways and key biological macromolecules
including membrane receptors and kinases [7-9]. As the consequent
assistance, the key nodes have been studied as specific targets,
which has enlarged the possibility of developing high efficiency,
low toxic and unique anti-cancer agents [10, 11]. Accordingly, in
the rational design procedures of anti-cancer agents, in considera-
tion of the relationship between targets and ligands, there are two
major strategies. One is analyzing the inner requirements of the
targets to polish a rough hit-compound, thus to obtain a well-crafted
*Address correspondence to these authors at the Institute of Chemistry and
BioMedical Sciences, School of Life Sciences, Nanjing University, Nanjing
210023, China; E-mail: ys_yang@nju.edu.cn and Henan Provincial Key
Laboratory of Children's Genetics and Metabolic Diseases, Children's
Hospital Affiliated to Zhengzhou University, Zhengzhou University,
Zhengzhou, 450018, China; E-mail: zhouchongchen@163.com
prodrug step-by-step [12]. The other is evaluating the actual po-
tency of the hit-compounds to deduce the modification demands
and rationally dispose the functional groups, thus to form a well-
organized candidate after screening [13]. Both strategies are actu-
ally based on structural factors, which infer the significance of dis-
cussing the exploitation of anti-cancer agents with certain backbone
structures [14, 15].
As one kind of widely used chemicals, quinoline derivatives
have been involved in fields such as medicinal chemistry [16], pes-
ticides [17], dyestuffs [18], analytical solvent [19], preservatives
[20] and rubber accelerators [21]. Although the flat conjugate struc-
ture with the capability of transferring electrons has brought them
applicable potential in solvability and photo-electric sensitivity, the
most attractive point is that it has appeared in the core position or
synthetic routes of quite a few drugs [22]. As the synthesis interme-
diates, the typical examples include the preparation of nicotinic acid
and hydroxyquinoline drugs [23]. As the structural component, we
would like to review this topic here with the classification based on
their molecular targets. In medicinal chemistry, although quinoline
derivatives have indicated broad activities including anti-bacterial
[24], anti-inflammatory [25], anti-malarial [26] and cardiotonic
effect [27], one of their most important roles is acting as anti-cancer
agents. Quinoline derivatives can exhibit fine results in treating
cancer via several different mechanisms, such as blocking the cell
cycle, inducing the cell apoptosis, inhibiting the vascular growth,
stopping the cell migration and activating the immune responses
[28-31]. Accordingly, along with the reported mechanisms, certain
target nodes through the involved pathways have been successfully
investigated to exploit hit-compounds, candidates, prodrugs and
1875-5992/21 $65.00+.00 © 2021 Bentham Science Publishers

826 Anti-Cancer Ag ents in Medicinal C hemistry, 2021, Vol. 21, No. 7 Man et al.
even listed drugs. In this review, we selected the representative
quinoline derivate drugs in market or clinical trials, classified them
into five major categories with detailed targets according to their
main mechanisms, discussed the relationship within the same
mechanism, and generated a summative discussion with prospective
expectations. We hope that this review may help the researchers
who are interested in discovering quinoline derivate anti-cancer
agents obtain considerable understanding of this specific topic.
2. QUINOLINE DERIVATE DRUGS IN VARIOUS
MECHANISMS
2.1. Through Receptor Tyrosine Kinases Mediated Pathways
The Receptor Tyrosine Kinases (RTKs) are a tremendous su-
perfamily of receptors [32]. They are not only receptors but also
enzymes. Their major biological function is acting as the receptors
for a large range of growth factors such as Epidermal Growth Fac-
tor (EGF), Platelet-Derived Growth Factor (PDGF), Vascular Endo-
thelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF),
Nerve Growth Factor (NGF), insulin and the Insulin-lik e Growth
Factors (IGF), and the ephrins and angiopoietins [33-40]. Usually,
they can bind with the ligands, therefore, induce the phosphoryla-
tion of the tyrosine on the target protein. They commonly consist of
three sections, the ligand binding site outside the cell, the single
transmembrane hydrophobic helix and the tyrosine protein kinase
part in the cell [41]. RTKs have been reported to play vital roles in
the development and deterioration of cancers [42-44]. The mutation
of RTKs activates a series of signaling cascade and impacts the
expression or activation of downstream proteins. Focusing on the
quinoline derivate anti-cancer agents, we have illustrated a simpli-
fied pathway map with the involved targets in this review (Fig. 1).
The colored nodes are the targets of quinoline derivatives. The de-
tailed interactions with the ligands have been discussed for each
target in the following paragraphs, accompanied by the structures of
selected quinoline derivate drugs (Figs. 2-5).
2.1.1. Quinoline Derivatives as EGFR/HER2 Inhibitors
Epidermal Growth Factor Receptor (EGFR, ErbB1) and Human
Epidermal growth Factor Receptor-2 (HER2, ErbB2) both belong to
the ErbB family [45, 46]. The ErbB family includes four members,
EGFR, HER2, ErbB3 and ErbB4. They transport the signals to
major signal pathways such as Mitogen-Activated Protein Kinase
(MAPK) [47] or Phosphoinositide 3-Kinase/Protein KinaseB
(PI3K/Akt) [48] pathways, thus to regulate cell proliferation, migra-
tion, differentiation, apoptosis and movement [49-51]. The overex-
pression and amplification of the ErbB family and their ligands are
often observed in many forms of malignant tumors, which make the
ErbB family an important therapeutic target [52, 53]. Among them,
EGFR has been associated with Non-Small Cell Lung Cancer
(NSCLC) [54] and neuroglioma [55], while HER2 amplification is
found in breast, ovarian, bladder, NSCLC and several other tumor
types [56-58]. After being activated , the formation of EGFR
changes into dimer from monomer. The homologous dimer is
formed by two EGFR, while the heterologous dimer is usually
formed by EGFR and HER2 [59, 60]. Both preclinical and clinical
studies have convinced that bi-targeting ErbB inhibition is more
effective than single-targeting therapies [61].
The quinoline derivatives listed here are exactly the bi-targeting
inhibitors for EGFR and HER2. Though Trastuzumab (Herceptin®)
is still the most popular drug in curing HER2-positive breast can-
cers [62], the unavoidable drug resistance has pushed the research-
ers to find better solutions such as bi-targeting inhibition. As shown
in Fig. (2a), all three selected drugs have a similar core structure to
typical EGFR inhibitors (e.g., Erlotinib and Gefitinib) [63, 64]
whereas have replaced the quinazoline moiety by the quinoline.
Fig. (1). The simplified pathway map with the RTKs-mediated target proteins of quinoline derivate anti-cancer agents. The colored nodes are the targets of
quinoline derivatives. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Recent Progress in the Development of Quinoline Derivatives Anti-Cancer Agents in Medicinal Chemistry, 2021, Vol. 21, No. 7 827
NO
H
N
O
NCN
HN
Cl
O
N
Neratinib
Listed in 2017
HER2, ErbB4, EGFR
NO
H
N
O
CN
HN
O
N
Cl
N
Pyrotinib
Applying NDA
HER2, EGFR
NO
H
N
O
NCN
NH
F
Cl
Pelitinib
Phase II (Terminated)
EGFR, HER2
NO
O
NH2
O
H
N
F
Anlotinib
Listed in 2018
VEGFR3, PDGFR
β
, FGFRs,
VEGFR2, KIT
NO
H2N
OCl
H
N
O
H
N
O
Lenvatinib
Listed in 2015
PDGFR
α
, VEGFR3, FGFR2, VEGFR2,
KIT, FGFR3, RET, FGFR4, VEGFR1, FGFR1
NO
O
O
H
N
O O
H
N
F
Cabozantinib
Listed in 2012
VEGFR3, TYRO3, ROS, UFO, VEGFR2,
TIE2, c-Met/HGFR, KIT, NTRK2, RET, VEGFR1
NO
O
O
H
N
O O
H
N
F
F
N
O
Foretinib
Phase II
VEGFR2, c-Met/HGFR
NO
O
O
H2N
H
N
O
Lucitanib
Phase II
PDGFR
α
, VEGFR3, PDGFB,
VEGFR2, VEGFR1
NO
O
N
O
OH
N
O
PF-337210
Phase II
VEGFR2
NO
O
HO
FH
N
O
N
N
O
Ningetinib
Phase I
UFO, VEGFR2, c-Met/HGFR
NO
O
FH
N
S
N
H
O
H
N
O
TAS-115
Phase I
VEGFR2, c-Met/HGFR
N
NH
S
O
H
N
O
F3C
Thiophenib
Phase I
PDGFR
β
, VEGFR2, KIT
a) EGFR/HER2
Inhibitors
b) VEGFR/PDGFR/RET
Inhibitors
c) c-Met
Inhibitors
NO
O
NN
N
N
AMG-208
Phase II (Terminated)
c-Met/HGFR
N
NN
N
N
F
ONH
Capmatinib
Phase III
c-Met/HGFR
NN
N
N
N
F F
N
N
JNJ-38877605
Phase I
c-Met/HGFR
NN
N
N
N
F F
N
JNJ-38877618
Phase I
c-Met/HGFR
N
NN
N
N
N
N
NOH
PF-04217903
Phase I (Terminated)
c-Met/HGFR
S
NN
N
N
N
N
N
SGX-523
Phase I (Terminated)
c-Met/HGFR
Fig. (2). The structures of quinoline derivatives as anti-cancer agents for RTKs. (a) EGFR/HER2 inhibitors; (b) VEGFR/PDGFR/RET inhibitors; (c) c-Met
inhibitors.

828 Anti-Cancer Agents in Medicinal C hemistry, 2021, Vol. 21, No. 7 Man et al.
Neratinib Maleate was approved in July 2017 for the use as an ex-
tended adjuvant treatment in adult patients with early-stage HER2-
overexpressed/amplified breast cancer, to follow adjuvant trastu-
zumab-based therapy [65]. Its approval was granted to Puma Bio-
technology Inc. for the trade name Nerlynx. It exhibited antitumor
action against EGFR, HER2 and ErbB4 positive carcinomas [66].
With the modification in the pharmacokinetic group, Pyrotinib
Maleate was applying New Drug Application (NDA) by Jiangsu
Hengrui Medicine Co. [67]. Pelitinib (EKB-569; WAY-EKB 569),
who lost the pyridine moiety, indicated better potency for EGFR
(IC50=38.5nM) instead of HER2 (IC50=1255nM) [68]. It could also
exhibit inhibitory activity against Src and MEK/ERK. Exploited by
Pfizer, it was utilized in NSCLC and colorectal cancer but termi-
nated in phase II clinical trials. In general, for inhibiting the ErbB
family, the backbone was usually a 3-cyanoquinoline. Moreover,
quinoline derivatives could supply a good fit for the updated pursuit
of bi-targeting ErbB inhibition, thus might be potential for further
optimization of existing listed drugs.
2.1.2. Quinoline Derivatives as VEGFR/PDGFR/RET Inhibitors
Besides the ErbB family, other major RTKs, including Vascular
Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived
Growth Factor Receptors (PDGFR) and RET, can also be inhibited
by quinoline derivatives. VEGF is a signal protein that stimulates
angiogenesis in cells with the function of promoting angiogenesis
and regeneration [69]. VEGF binds to VEGFR on the surface of the
cell membrane, and produces biological effects through a series of
signaling pathways, leading to angiogenesis [70]. In 1971, Folkman
first proposed the theory of tumor angiogenesis [71]. Accordingly,
tumor growth should depend on tumor angiogenesis. Moreover,
VEGFR can cause drug resistance by regulating the downstream
pathways to motivate endothelial and tumor cells to proliferate and
spread. Now VEGFR is one of the hottest targets for monoclonal
antibody in spite of PD-1 and TNF-α, while actually, there have
been several listed chemical drugs for VEGFR [72]. Among them,
there are also quinoline derivates.
PDGFR system mainly affects the development of the embryo,
especially the angiogenesis and organ formation in the process of
development, while in the adult stage, under physiological state, it
is related to the repair of tissue and wound healing [73]. However,
the overexpression of PDGFR will lead to the occurrence and de-
velopment of tumors [74]. As a kind of transmembrane glycopro-
tein, PDGFR is composed of α and β protein tyrosine kinase
subunits. Furthermore, the α subunit can trigger the downstream
enzyme effectors (PI3K, MAPK, Src, SHP2, etc) and non-enzyme
effectors (Crk, Sch, Grbs, etc) [75], thus affect the cell growth,
survival, proliferation and differentiation.
RET protein, encoded by the corresponding proto oncogene, is
a transmembrane tyrosine kinase receptor that can activate a series
of downstream pathways after itself being activated [76]. Despite
PI3K, MAPK, Src, it can also activate the Focal Adhesion Kinase
(FAK) pathway [77].
Here we listed the VEGFR/PDGFR/RET multi-target tyrosinase
inhibitors with quinoline as the pharmacodynamic group (Fig. 2b).
Anlotinib Dihydrochloride, launched by CTTQ Pharmaceutical Co.,
Ltd. and listed in 2018, was a high-profile drug for NSCLC [78]. It
could inhibit a wide range of RTKs, including VEGFRs, PDGFRs,
FGFRs and KIT, whereas RET was not involved. Recently, based
on the clinical trial, Anlotinib was also approved for soft tissue
sarcoma [79]. Previously marketed drugs raised well-known exam-
ples, such as Lenvatinib Mesylate (listed in 2015) [80] and Cabo-
zantinib S-malate (listed in 2012) [81]. Both of them are different
from specific inhibitors for one or two unique targets, instead, they
are both available for almost ten targets, of course, with
VEGFR/PDGFR/RET. Especially for Cabozantinib, its targets can
even include TYRO3, ROS, UFO, TIE2, c-Met/HGFR and NTRK2.
Lenvatinib seemed particularly effective in the treatment of liver
cancer induced by hepatitis B, which provided new therapeutic
options for patients with liver cancer in a later period [82]. Mean-
while, Cabozantinib was approved by the FDA for refractory or
relapsed medullary thyroid carcinoma, and later renal cancer that
could not be treated by Sutent (Sunitinib) [83]. Other candidates in
Phase II clinical trials include Foretinib [84], Lucitanib [85] and
PF-337210 [86], while the ones in Phase II clinical trials contain
Ningetinib Tosylate [87], TAS-115 [88] and Thiophenib Tosylate
[89]. All of them indicated fewer targets than Lenvatinib or Cabo-
zantinib. The similar target of these candidates was VEGFR2, as we
demonstrated above, the hottest target for monoclonal antibody as
well. With a glance at all the mentioned drugs and candidates, we
can find that these compounds often have the quinoline core modi-
fied with cyclopropyl or urea-like groups.
2.1.3. Quinoline Derivatives as c-Met Inhibito rs
Although the multi-targeted drug Cabozantinib also inferred the
inhibitory effect against c-Met, quinoline moiety could be em-
ployed in specific c-Met inhibitors. In RTKs, c-Met is the only
receptor protein which can highly be affined with Hepatocyte
Growth Factor (HGF) [90]. The interactions between HGF and c-
Met can cause the phosphorylation and a series of biochemical
procedures to activate the signal pathway.
It is a pity that till now, there has been none listed drug for c-
Met inhibition. Crtzotinib might be one potential choice but should
not be emphasized here due to the lack of quinoline [91]. Within
quinoline derivatives, the most potential one is Capmatinib (Fig.
2c), which was developed by Incyte, obtained by Novartis, and is in
Phase III clinical trials now [92]. In ASCO 2019 conference, the
announced data of Capmatinib in treating NSCLC suggested the
curing potential in Metexon14-skipping locally later period or me-
tastatic situations. As shown, Capmatinib links the quinoline group
to the nitrogen heterocyclic ring with a methylene bridge. With a
similar structural feature, there are other candidates in Phase I clini-
cal trials, such as JNJ-38877605 [93], JNJ-38877618 [94], PF-
04217903 [95] and SGX-523 [96]. They were all developed for
treating solid tumors. As a unique case, AMG-208 [97], terminated
in Phase II clinical trials, has a methoxyl group on the quinoline and
a longer linker. On the whole, all the quinoline derivatives designed
for c-Met inhibition bear the highly conservative backbone, and are
all specifically targeted at the c-Met/HGFR pair.
2.1.4. Quinoline Derivatives as PI3K Inhibitors
Seeking the downstream of RTKs, MAPK and PI3K-Akt-
mTOR pathways are two major pathways. Some of the quinoline
derivatives can block them by inhibiting RTKs, while at the same
time, PI3K itself has been studied as the target of quinoline derivate
drugs (Fig. 3). PI3K-Akt-mTOR pathway plays an important role in
cell growth, differentiation, apoptosis and other aspects. Therefore,
many members of this signal transduction are key drug targets in
the process of cancer, immunity and thrombosis control [98, 99].
PI3K can act as both Ser/Thr kinase and phosphatidylinositol
kinase, and it can be divided into three categories with differed
structures and functions. The most widely investigated one is Class
I PI3K [100]. Among the four catalytic subunits (α, β, δ, γ), δ and γ
are limited within leukocytes, whereas the rest are widely distrib-
uted in various cells. The downstream signal pathway of PI3K is
complex due to some feedback loops. Each of the four catalytic
isomers of Class I PI3K preferentially regulates specific signal
transduction and tumor cell survival, which depends on the type of
malignant tumor and the genetic or epigenetic changes.
Most of the quinoline derivatives here are PI3K pan-blockers
(Fig. 3a). As a typical example, Dactolisib, launched by Novartis
and in Phase II clinical trials now [101], has been set into the trials
including bladder cancer, pancreatic cancer, breast cancer, renal cell

Recent Progress in the Development of Quinoline Derivatives Anti-Cancer Agents in Medicinal Chemistry, 2021, Vol. 21, No. 7 829
cancer, and prostate cancer [102]. Its structural backbone is an imi-
dazolone-combined quinoline, while it also has an extra quinoline
group linked with the backbone. Another candidate developed by
Novartis, BGT-226, was terminated in Phase II clinical trials [103].
It retained the backbone of imidazolone-combined quinoline but
lost the other quinoline moiety. Similar situations in structural fea-
tures happened in LY-3023414 (in Phase II clinical trials for
NSCLC by Eli Lilly) [104] and Panulisib (in Phase I clinical trials
for solid tumor by Piramal Phytocare) [105]. Besides, also for PI3K
pan-blocker, GlaxoSmithKline exploited a candidate with alterna-
tive backbone, and the so-named Omipalisib inferred good potency
in Phase I clinical trials for the treatment of idiopathic pulmonary
fibrosis, solid tumors and lymphoma [106]. Despite the quinoline
backbone, its sulfonamide group is somehow attractive. Meanwhile,
GlaxoSmithKline attempted to develop the specific inhibitor for
PI3Kα, however, as a result, GSK-615 seemed to suffer a failure in
Phase I clinical trials for solid tumors and lymphoma [107]. Gener-
ally, although most of the quinoline derivate candidates suggested
splendid efficiency, unfortunately, none of them achieved the status
of being marketed at present.
2.1.5. Quinoline Derivatives as Src/Abl Inhibitors
Src (Proto-oncogene Tyrosine-protein Kinase) is actually not
involved in the traditional sense of RTKs. Discovered by Peyton
Rous in 1910, the protooncogene c-src opened the researches on the
structure, regulation, localization and function of the corresponding
protein Src [108]. Src can act as the inserted step within the typical
RTKs mediated pathways. By responding to the growth factors
directly or transporting the signals from G protein coupled recep-
tors, Src then activates the typical pathways including MAPK,
PI3K, FAK and STAT3, thus regulates the subsequent survival,
proliferation and motility [109]. The RTK inhibitor Imatinib could
show potency for most of the chronic myeloid leukemia patients,
while the following Nilotinib and Dasatinib were used to overcome
the drug resistance [110-112]. However, the toxicity and further
drug resistance made the requirement for new agents urgent.
Bosutinib, launched by Pfizer, was marketed in 2012 to act as a
potent orally-taken Src/Abl dual inhibitor [113]. It was over 15-fold
more potent than Imatinib, and low-toxic. As shown in Fig. (3b), its
3-cyanoquinoline backbone is quite similar to the above mentioned
EGFR/HER2 inhibitors, but the other linked groups are obviously
different.
2.2. Through DNA Related Mechanisms
DNA related mechanisms have been utilized in treating cancer
for a long period [114]. Till now, the platinum containing drugs are
the most widely used chemotherapeutics [115]. After the first ex-
ample, Cisplatin, being marketed in 1978, over 40 years evolution of
these drugs has not only promoted the drugs into the therapies for a
variety of cancers, but also broadened the corresponding mechanisms
around DNA. Since binding to the DNA sequences is cell cycle
nonspecific, these agents usually indicated relatively strong nephro-
toxicity, hematotoxicity and neurotoxicity [116]. Quinoline deriva-
tives selected in this review were designed for other DNA related
mechanisms with specific protein targets (Fig. 4). They inhibit their
specific targets and subsequently cause the corresponding effect to
impact the morphology or sequences of DNA, therefore, finally
induce the apoptosis of cancer cells. Based on the concrete mecha-
nisms, the quinoline derivate drugs or candidates are detailed as
follows.
2.2.1. Quinoline Derivatives as DNA Topoisomerase Inhibitors
DNA Topoisomerase (TOP) is a general term of enzymes that
catalyze the mutual transformation of DNA topoisomers [117]. It is a
vital kind of biological enzymes in both eukaryotic and prokaryotic
N
N
N
N
O
NC
Dactolisib
Phase II
PI3K
β
, mTORC2, mTORC1,
PI3K
δ
, PI3K
α
, PI3K
γ
N
N
N
N
O
O
NCF
3
HN
BGT-226
Phase II (Terminated)
Class I PI3K, mTORC2, mTORC1
N
N
N
N
O
HO
O
LY-3023414
Phase II
Class I PI3K, mTOR
N
N
N
N
N
N
CN
NC
H
2
N
F
3
C
Panulisib
Phase I
Class I PI3K, mTORC2, mTORC1
N
N
HN
S
O
O
GSK-615
Phase I (Terminated)
PI3K
α
N
N
N
NO
HN
S OO
F
FOmipalis ib
Phase I
PI3K
β
, mTORC2, mTORC1,
PI3K
δ
, PI3K
α
, PI3K
γ
a) PI3K
Inhibitors
b) Src/Abl
Inhibitor
N
O
ON
N
CN
HN
Cl Cl
O
Bosutinib
Listed in 2012
LYN, TPK HCK, Src, Bcr-Abl
Fig. (3). The structures of quinoline derivatives as anti-cancer agents for other RTKs-mediated pathways: (a) PI3K inhibitors; (b) Src/Abl inhibitors.

830 Anti-Cancer Agents in Medicinal C hemistry, 2021, Vol. 21, No. 7 Man et al.
N
N
O
N
H
O
HO
O
Belotecan
Listed in 2003
TOP1
N
N
O
O
O
HO
O
O
N
N
Irinotecan
Listed in 2011
TOP1
N
HN
OH
NS
O
O
Amsacrine
Listed
TOP2
N
N
O
O
O
HO
Camptothecin
Listed
TOP1
N
N
O
O
O
HO
Rubitecan
Applying NDA
TOP1
NO
2
N
N
O
O
O
HO
NH
2
9-Aminocamptothecin
Phase III (Terminated)
TOP1
N
N
O
O
O
HO
HO
Si
N
N
O
O
O
HO
Si
Cositecan
Phase III
TOP1
AR-67
Phase II (Terminated)
TOP1
O
N
O
N
OH
N
O
O
O
O
N
O
2
N
O
2
NNO
2
O
2
N
TLC-388 HCl
Phase II
TOP1
N
N
O
O
HO O
F
F
Diflomotecan
Phase II (Terminated)
TOP1
N
N
O
O
OH
O
O
HO
DRF-1042
Phase II
TOP1
N
N
O
O
O
HO
O
O
N
N
Lurtotecan
Phase II (Terminated)
TOP1
N
HN
OH
NS
O
O
Asulacrine
Phase II (Terminated)
TOP2
ONH
N
HN O
N
Acridine
Phase II (Terminated)
TOP2, TOP1
N
N
O
O
O
HO
N
O
Gimatecan
Phase II (Terminated)
TOP1
N
N
O
O
O
HO
NN
TP-300
Phase II
TOP1
N
O
HO NH
N
BMS-247615
Phase II
TOP2, TOP1
N
H
O
NO
2
N
N
N
Pyrazoloacridine
Phase II (Terminated)
TOP2, TOP1
N
N
O
O
O
HO
N
ONH
2
Namitecan
Phase I
TOP1
N
N
O
O
O
HO
O
O
N
N
Simmitecan
Phase I
TOP1
N
N
O
O
O
O
O
CZ-48
Phase I
TOP1
N
N
O
O
O
HO
Cl
N
Elomotecan
Phase I
TOP2, TOP1
N
N
O
O
O
O
O
NO
2
CZ-112
Phase I (Terminated)
TOP1
N
N
O
O
O
O
O
H
N
Genz-644282
Phase I
TOP1
N
N
O
O
O
HO
O
OO
OO
Tenifatecan
Phase I (Terminated)
TOP1
N
N
O
O
O
O
O
H
N
O
N
H
N
N
H
N
H
S
OO
O
HO OH
Afeletecan
Phase I (Terminated)
TOP1
a) DNA TOP
Inhibitors
b) ATM
Inhibitors
N
N
N
NO
O
ON
AZD-0156
Phase I
ATM N
N
N
NO
ON
F
AZD-1390
Phase I
ATM
Fig. (4). The structures of quinoline derivatives as anti-cancer agents for DNA-related pathways: (a) DNA TOP inhibitors; (b) ATM inhibitors.

Recent Progress in the Development of Quinoline Derivatives Anti-Cancer Agents in Medicinal Chemistry, 2021, Vol. 21, No. 7 831
cells [118]. All through the processes of DNA transcription, replica-
tion, chromosome separation and gene expression, TOP participates
in the regulation. With the unaffected higher level of expression in
tumor cells than in normal ones, the TOP family has been regarded
as suitable targets in anti-cancer strategies [119].
Since the TOP family can be generally divided into TOP1 and
TOP2, quinoline derivate drugs for these two subtypes are quite
different in structures (Fig. 4a). Most of them are TOP1 inhibitors
with a typical backbone mimicking Camptothecin [120]. When we
look into the listed drugs, despite the original Camptothecin, Be-
lotecan Hydrochloride (listed in 2003) [121] and Irinotecan Hydro-
chloride (listed in 2011) [122] are all in the similar structural pat-
tern and targeted at TOP1. Amsacrine, also listed, is a TOP2 inhibi-
tor for treating leukemia [123]. Its backbone is acridine, being dis-
tinguished from the Camptothecin-mimicking core for TOP1. In
spite of the marketed drugs, there are a large number of candidates
in their clinical trials for inhibiting the TOP family. As typical
strategies of developing TOP1 inhibitory anti-cancer agents, the
modification on Camptothecin led to several practical choices such
as adding substitutes, enlarging the aliphatic ring and linking other
functional fragments. The examples which are close to achieving
marketed drugs include Rubitecan (applying NDA) [124], 9-
Aminocamptothecin (terminated in Phase III) [125] and Cositecan
(in Phase III) [126]. All of these three candidates followed the
choice of adding suitable substitutes. Focusing on TOP1, other
Camptothecin-like candidates can be organized as follows: AR-67
(terminated in Phase II) [127], DRF-1042 (in Phase II) [128], Lur-
totecan (in Phase II) [129], Gimatecan (terminated in Phase II)
[130], TP-300 (in Phase II) [131], Namitecan (in Phase I) [132],
Simmitecan (in Phase I) [133], CZ-48 (in Phase I) [134], CZ-112
(in Phase I) [135] and Genz-644282 (in Phase I) [136] for adding
substitutes; Diflomotecan (terminated in Phase II) [137] for enlarg-
ing the aliphatic ring; TLC-388 (in Phase II) [138], Tenifatecan
(terminated in Phase I) [139] and Afeletecan (terminated in Phase I)
[140] for linking other functional fragments. Especially, one unique
case is Elomotecan (in Phase I) [141], because it bears an aliphatic
ring-enlarged Camptothecin backbone but exhibited the activities
for inhibiting both TOP2 and TOP1. Besides, there are several
acridine derivate candidates, whose designed target should be TOP2.
Actually, however, only Asulacrine (terminated in Phase II) [142]
was reported to specifically inhibit TOP2. Both of the other two
examples, Acridine (terminated in Phase II) [143] and Pyrazoloac-
ridine (terminated in Phase II) [144], did not present enough selec-
tivity for TOP2 from TOP1. Additionally, as a unique case, BMS-
247615 (in Phase II) [145], now being developed by Bristol-Myers
Squibb, is a TOP2/TOP1 bi-targeting inhibitor with a backbone of
indenoquinoline, which is different from neither Camptothecin nor
acridine. As a whole, no matter applied for TOP1, TOP2 or both of
them, exploiting quinoline derivatives for inhibiting the TOP family
seems a practical orientation with a considerable fever.
2.2.2. Quinoline Derivatives as ATM Kinase Inhibitors
Ataxia Telangiectasia Mutant (ATM) kinase inhibitors have
potential chemical or radiation sensitization and antitumor activities
due to blocking the ATM-induced signal transduction [146]. This
kind of blocking can prevent the activation of DNA damage check-
points, therefore, impact the DNA damage repair and lead to cell
death of ATM overexpressed tumor cells [147]. Meanwhile, ATM
N
ON
NOH
H
H
F
F
Zosuquidar
Phase III (Terminated)
PGY1
ON
N
HO
O
N
Dofequidar
Phase III (Terminated)
PGY1
O
N
N
N
N
O
O
Laniquidar
Phase II
PGY1
N
NOH
H
Cinchonine
Phase I (Terminated)
PGY1
a) PGY1
Inhibitors
N
N
N
NH2
Imiquimod
Listed in 1997
TLR7
N
N
N
NH2
H
N
S
O
O
PF-4878691
Phase II (Terminated)
TLR7
N
N
N
NH2
O
N
H
O
16
MEDI-9197
Phase I
TLR7, TLR8
N
HN
O
Cl
H
F
BMS-986205
Phase III
IDO
N
N
NH2
N
N
O
O
Crenolanib
Phase III
PDGFRs, FLT3
N
H2N
O
NN N
Galunisertib
Phase III
TGFBR1
O
N
N
O
O
N
Cl
H
N
OOH
Meclinertant
Phase III (Terminated)
NTS
b) TLR
Agonists
c) Other
Targets
Fig. (5). The structures of quinoline derivatives as anti-cancer agents through glycoprotein transmembrane transport, immune enhancement and other mechanisms:
(a) PGY1 inhibitors; (b) TLR agonists; (c) agents for other targets.

832 Anti-Cancer Agents in Medicinal C hemistry, 2021, Vol. 21, No. 7 Man et al.
inhibitors can also make tumor cells sensitive to chemotherapy and
radiotherapy.
ATM is a relatively new anti-cancer target, so the exploitation
of its inhibitors is still preliminary at present. Of course, quinoline
derivatives for this target are also in the initial stage (Fig. 4b).
AZD-0156 [148] and AZD-1390 [149], the selected two examples,
were both developed by AstraZeneca, and are in their Phase I clini-
cal trials for treating solid tumors. Their structures are similar to the
above mentioned PI3K inhibitors, but the detailed parts have been
polished.
2.3. Through Glycoprotein Transmembrane Transport
Mechanism
The glycoprotein here is P-glycoprotein (P-gp), a member of
the ATP-Binding Cassette (ABC) transmembrane transporter super-
family [150]. It can pump the chemotherapeutic drugs outside the
cells to reduce the intracellular drug concentration. P-gp inhibitors,
conversely, can directly bind to P-gp, block the pumping-out and
cause accumulation of the drugs, therefore, reverse the drug resis-
tance. As shown in Fig. (5a), quinoline derivatives usually act as
the inhibitors of PGY1, one kind of P-gp. Almost all of them are
facing difficulty on the road to marketed drugs. Both Zosuquidar
Trihydrochloride (developed by Kanisa for acute myeloid leuke-
mia) [151] and Dofequidar Fumarate (developed by Bayer for
NSCLC and breast cancer) [152] were terminated in their Phase III
clinical trials. Laniquidar (developed by Janssen for breast cancer)
[153] is in Phase II clinical trials with no progress. Cinchonine
[154], an alkaloid with special backbone, was also terminated in
Phase I for treating solid tumors.
2.4. Through the Immune Enhancement Mechanism
As the target of the quinoline derivatives, Toll-Like Receptors
(TLRs) are widely expressed in the natural immune system [155].
Recent researches connected their expression with the cancer
physiology, and indicated that TLR7/TLR8 agonists could activate
several immune pathways at the same time, leading to effective
anti-tumor immunity [156]. In Fig. (5b), the selected TLR agonists
are all Imidazoquinoline derivatives with alkyl chain modification.
Among them, Imiquimod was listed in 1997 for inhibiting TLR7 by
Minnesota Mining and Manufacturing (3M) Company [157]. How-
ever, another attempt, PF-4878691, also targeting at TLR7, was
terminated in Phase II [158]. Now, MEDI-9197, designed for both
TLR7 and TLR8, has been promoted in Phase I for treating solid
tumors [159].
2.5. Through Other Mechanisms
In Fig. (5c), quinoline derivatives as anti-cancer agents via
other mechanisms have been displayed. BMS-986205 (developed
by Bristol-Myers Squibb), inhibiting Indoleamine 2,3-Dioxygenase
(IDO), is in Phase III clinical trials for solid tumors, bladder cancer
and melanoma [160]. Crenolanib Besylate (developed by Pfizer), as
a pan-FLT3 (FMS-like tyrosine kinase 3) inhibitor, is in Phase III
for AML [161]. Galunisertib (developed by Eli Lilly and Com-
pany), targeting at TGF-β Receptor type-1 (TGFBR1), is in Phase
III for Myelodysplastic Syndromes and solid tumors [162]. As a
negative example, only Meclinertant (developed by Sanofi), affect-
ing Neurotensin (NTS), was terminated in Phase III for prostate
cancer and colorectal cancer [163].
CONCLUSION
In summary, along with the deeper understanding of the vital
nodes in pathways and the principle for structural modification,
various quinoline derivatives have been developed into anti-cancer
agents. According to specific structural features, they can be ap-
plied in treating can cer via several mechanisms. Two major mecha-
nisms are RTKs inhibition and DNA obstruction. Acting as RTK
inhibitors, quinoline derivate drugs indicated the preference for
relatively upstream proteins, which were the receptors themselves
(EGFR/HER2, VEGFR, PDGFR, RET, c-Met) or the ones closely
next to the receptors (Src, PI3K). Impacting DNA, quinoline de-
rivate drugs inhibited their specific targets and subsequently caused
the corresponding effect to impact the morphology or sequences of
DNA, thus overcame the disadvantage of lacking selectivity from
normal cells. Among the selected compounds, ten are marketed
drugs. Half of them are involved in the RTKs inhibition, while four
are DNA topoisomerase inhibitors. The rest one is TLR agonist. We
can generally demonstrate that VEGFR2 and DNA TOP1 are the
most discovered targets for quinoline derivatives, and new research
target such as ATM kinase has been promoted to clinical trials. In
these drugs and candidates, quinoline moiety not only works as the
core, but serves as the linked functional group. These hints inferred
the significance of quinoline in both structural extension and phar-
macophore mimicking.
Furthermore, if we broaden our eyesight, we would find that the
market of small molecule drugs is gradually eroded by macromo-
lecular drugs. Thus in the future, the advanced parameters to de-
velop quinoline derivate drugs should be considered at least on two
orientations. One is continuously seeking for candidates with high
potency and low toxicity. The other is addressing the relationship
between quinoline-derived compounds and macromolecular drugs.
Still, there is a need to find the equilibrium in potency and mor-
phology.
Indeed, quinoline drugs experienced the flourishing period and
the vigorous strategies in clinical trials, and their future would be
potential but facing new challenges.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
This study was sponsored by Guangxi University for Nationali-
ties Research Funded Project, China (No. 2018KJQD13), Guangxi
Minority Preparatory Education Base Research Project, China (No.
2017B002), and Guangxi Biological Polysaccharide Separation,
Purification and Modification Research Platform, China (No.
GKZY18076005).
CONFLICT OF INTEREST
The author declares no conflict of interest, financial or other-
wise.
ACKNOWLEDGEMENTS
Declared none.
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