Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-H1299 cells

Article abstract of DOI:10.1016/j.tetlet.2020.151873

Eight novel moxifloxacin (MXF) derivatives 4a-h were synthesized by functional modification of the N-5-Aza ring. Their growth inhibitory activities on human non-small lung cancer cell NCI-H1299 and A549 were evaluated by the MTT colorimetric assay. Based on the half inhibitory concentration (IC₅₀) values, we determined that compounds 4b was the most efficacious derivative (IC₅₀ = 2.56 ± 0.07 μM for NCI-H1299 and IC₅₀ = 13.69 ± 0.70 μM for A549, respectively) that inhibited the proliferation of NCI-H1299 cells. Of these, Compound 4b (1 – cyclopropyl – 6 – fluoro – 8 – methoxy – 4 – oxo – 7 – ((4aS,7aS) – 1 – (2 – oxo – 2 – (p – tolylamino) ethyl) hexahydro – 1H – pyrrolo [3,4-b] pyridine – 6(2H)-yl) – 1,4 – dihydroquinoline – 3-carboxylic acid) showed good potency against the growth of NCI-H1299 cells and also selectivity on HUVEC cells (IC₅₀ > 500 μM). The dose-response relationship of the characteristic morphological changes of NCI-H1299 cells induced by Compound 4b was confirmed by AO/EB fluorescent staining. Furthermore, Compound 4b triggered apoptosis of NCI-H1299 in a concentration-dependent manner and arrested cells in the G0/G1 phase. These data indicate that the N-(p-tolyl)propanamide functionalized N-5-Aza ring of moxifloxacin may be a promising lead compound and candidate for the development of new agents against non-small-cell lung cancer.

Full text of DOI:10.1016/j.tetlet.2020.151873

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and evaluation of moxifloxacin derivatives for effects on
proliferation and apoptosis of NCI-H1299 cells
c
c
c
b
a,
Fangmiao Yu a,b,c, , Zhuangwei Zhang , Wei Li , Hengqun Tian , Jun Xu , Yongzhong Bao
⇑
⇑
a College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
b Zhejiang Casnovo Materials Co., Ltd., Zhoushan 316022, China
c Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Eight novel moxifloxacin (MXF) derivatives 4a-h were synthesized by functional modification of the N-5-
Aza ring. Their growth inhibitory activities on human non-small lung cancer cell NCI-H1299 and A549
were evaluated by the MTT colorimetric assay. Based on the half inhibitory concentration (IC50) values,
Received 19 February 2020
Revised 21 March 2020
Accepted 24 March 2020
Available online xxxx
we determined that compounds 4b was the most efficacious derivative (IC50 = 2.56 0.07
lM for NCI-
H1299 and IC50 = 13.69 0.70 M for A549, respectively) that inhibited the proliferation of NCI-
l
H1299 cells. Of these, Compound 4b (1 – cyclopropyl – 6 – fluoro – 8 – methoxy – 4 – oxo – 7 –
((4aS,7aS) – 1 – (2 – oxo – 2 – (p – tolylamino) ethyl) hexahydro – 1H – pyrrolo [3,4-b] pyridine – 6
(2H)-yl) – 1,4 – dihydroquinoline – 3-carboxylic acid) showed good potency against the growth of
Keywords:
Moxifloxacin
Antiproliferative
Apoptosis
NCI-H1299 cells and also selectivity on HUVEC cells (IC50 > 500 lM). The dose-response relationship of
the characteristic morphological changes of NCI-H1299 cells induced by Compound 4b was confirmed
by AO/EB fluorescent staining. Furthermore, Compound 4b triggered apoptosis of NCI-H1299 in a concen-
tration-dependent manner and arrested cells in the G0/G1 phase. These data indicate that the N-(p-tolyl)
propanamide functionalized N-5-Aza ring of moxifloxacin may be a promising lead compound and can-
didate for the development of new agents against non-small-cell lung cancer.
Cytotoxicity
Ó 2020 Elsevier Ltd. All rights reserved.
Introduction
of all lung cancer cases [3]. Most patients receive a combination
of chemotherapy and/or radiation therapy rather than lobectomy
New cancer cases and mortality rates around the world are
growing rapidly, irrespective of the Human Development Index
(HDI) score of a country or region. The data visualization tool ‘‘Can-
cer Tomorrow” provided by International Agency for Research on
Cancer (IARC), part of the World Health Organization (WHO), esti-
mates that there will be 29.5 million new cases and 16.5 million
cancer deaths worldwide by 2040 [1]. Lung cancer cases dominate
the number of new cases of all cancers (up to 2,093,876, account-
ing for 11.6% of total new cases) and are the leading cause of cancer
deaths among men in 93 countries/regions and women in 28 coun-
tries/regions (accounting for 18.4% of total cancer deaths) [2]. In
general, lung cancer can be divided into two categories by its
pathological morphology: small cell lung cancer (SCLC) and non-
small cell lung cancer (NSCLC). Of these, NSCLC accounts for 83%
or lung resection. Chemotherapy remains one of the most effective
means of treating lung cancer. However, the lack of selectivity and
serious systemic toxicity of chemotherapy poses huge challenges
for cancer treatments [4,5]. In view of this, there is a need to find
novel selective pharmacological agents that increase the clinical
effectiveness of chemotherapy drugs.
Quinolones are a family of potent broad-spectrum antibacterial
agents that disrupt the supercoiling activity of prokaryotic type II
topoisomerases (DNA gyrase and topoisomerase IV) and perma-
nently break the double-stranded DNA structure to exert antibac-
terial activity [6]. Due to the high degree of amino acid sequence
homology and the similar catalytic mechanism between prokary-
otic type II topoisomerase and eukaryotic type II topoisomerase,
the latter is a target for chemotherapeutic quinolone interventions,
leading to successful synthesis of novel anti-tumor quinolones by
functional modification [7–13]. Voreloxin (SNS-595), Quarfloxin
(CX-3543), AT-3639 and Delafloxacin (ABT-492) are in the clinical
development stage as effective anticancer drugs, and they are
expected to advance to the clinical stage as cancer treatments
⇑
Corresponding authors at: College of Chemical and Biological Engineering,
Zhejiang University, Hangzhou 310027, China (F. Yu).
E-mail addresses: fmyu@zjou.edu.cn (F. Yu), all_zzw@163.com (Z. Zhang),
liweizjou@163.com (W. Li), thq_22326@163.com (H. Tian), casnovo_xj@126.com
(J. Xu), yongzhongbao@zju.edu.cn (Y. Bao).
[14–16].
Moxifloxacin
(1-cyclopropyl-6-fluoro-8-methoxy-7-
https://doi.org/10.1016/j.tetlet.2020.151873
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: F. Yu, Z. Zhang, W. Li et al., Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-
H1299 cells, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151873

2
F. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
((4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid) is a fourth-generation quino-
lone antibacterial agent in which a methyl group is substituted
with an 8-methoxy moiety. Moxifloxacin has been reported to
have a strong inhibitory effect on topoisomerase II activity, which
supports the design of moxifloxacin-based drugs for the search for
novel antitumor drugs [17]. Yadav et al. [18] claimed that moxi-
floxacin directly exerted cytotoxic effects on pancreatic cancer cell
lines MIA PaCa-2 and Panc-1, and also enhanced cisplatin-induced
apoptosis in human pancreatic cancer cells. Moxifloxacin is a
potential candidate for melanoma treatment due to its toxic effects
on human amelanotic C32 and melanotic COLO829 melanoma cells
in vitro. It was also found that moxifloxacin can lead to the loss of
mitochondrial membrane potential, activated caspase-3/7, G2-M
stagnation, and damaged DNA structural induced apoptosis [19].
Chen et al. [20] synthesized 9 kinds of moxifloxacin/gatifloxacin-
1,2,3-triazole-isatin hybrids, and found that they are all exerts
anti-proliferation activity on A549 and HepG2 cancer cells. In addi-
tion, hybrid 8i has more potential to inhibit the proliferation of
cancer cells A549, HepG2 and MCF-7 than positive control
Vorinostat.
Based on the evidence above, a series of novel moxifloxacin-
acetyl-aniline derivatives were designed, synthesized and evalu-
ated for their in vitro antiproliferative activity against NCI-H1299
and A549 cells. Preliminary screening showed that most of the
novel benzene series functionalizing N-5-Aza rings of moxifloxacin
4a-h changed the biological properties of the parent moxifloxacin
from an antibacterial to a cytotoxic agents (Fig. 1). Furthermore,
we retained the N-(p-tolyl)propanamide functional N-5-Aza ring
of a moxifloxacin analog (4b) as a potential cytotoxic agent to fur-
ther investigate the effects of 4b on apoptosis and selectivity for
the cell cycle in NCI-H1299 cells.
Results and discussion
Chemistry
The synthetic route of moxifloxacin derivatives is outlined in
Scheme 1 [4,21–23]. Chloroacetamide derivatives were synthe-
sized by reaction of aniline derivatives with chloroacetyl chloride
using triethylamine (TEA) as an organic base in dichloromethane
(DCM). The nucleophilic substitution reaction with potassium
iodide (KI) in acetone (ACE) allows access to the Compounds 2a-
h. With the 2-iodoacetamide intermediates 2a-h in hand, the mox-
ifloxacin derivatives 4a-h were then synthesized via a nucleophilic
substitution reaction in a single-step process with good yields. The
representative chemical features of moxifloxacin derivatives are
the (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b] pyridine substituted
the
1-cyclopropyl-6,7-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-
quinoline carboxylic moiety. The characteristic structural pattern
for the parent moxifloxacin was confirmed with 1H NMR data. Fur-
thermore, the characteristic singlet of –N–CH2– moiety of the
amino linker appeared at d 3.21 ppm. On the basis of that scaffold,
we designed the different structures depicted in Scheme 1 and
confirmed them by FT-IR, 1H NMR, 13C NMR and HR-MS (Supple-
mentary Materials).
Fig. 1. The structural formula of Moxifloxacin.
Scheme 1. The synthetic route of moxifloxacin derivatives 4a-h. Reagents and conditions: (i) Chloroacetyl chloride, TEA and DCM, r.t., 12 h; (ii) KI and ACTN, reflux, 6 h; (iii)
TEA, acetone, reflux, 24 h.
Please cite this article as: F. Yu, Z. Zhang, W. Li et al., Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-
H1299 cells, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151873

F. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Biological investigations
liferative activity and selectivity between cancer and normal cell
lines, the anti-proliferative activity of Compound 4b was almost
195-fold greater when used against cancer cells than against
HUVEC cells. Therefore, Compound 4b was selected for further
mechanistic studies.
Cytotoxicity of moxifloxacin derivatives on NCI-H1299 cells
To evaluate the antiproliferative activity of eight newly syn-
thetic moxifloxacin derivatives, 4a-h, a 3-(4,5-dimethylthiazole)-
2,5-diphenyltetrazolium bromide (MTT) assay was performed to
measure the payoff cytotoxicity of derivatives against NCI-
H1299, A549 cells and Human Umbilical Vein Endothelial (HUVEC)
Cells. All cells were incubated with different concentrations of
moxifloxacin derivatives 4a-h for 24 h. The parent moxifloxacin
and cisplatin, were used as reference compounds. The anticancer
activity of the moxifloxacin derivative is described as the concen-
tration of active compound that killed 50% of the cells (IC50);
results are summarized in Table 1. Synthetic moxifloxacin deriva-
tives generally have low cytotoxicity towards normal cells, which
is a desirable attribute for new anticancer drugs. The moxifloxacin
derivatives of the N-5-Aza ring with N-(aryl)propionamide sub-
stituent exhibited promising activity against NCI-H1299 and
A549 cells, which was higher than the parent moxifloxacin and
the chemotherapeutic drug DPP (IC50 values for NCI-H1299 and
A549 cells were was >100, 50.78 mM and >100, 53.33 mM, respec-
tively). Of these derivatives, Compound 4b exhibited high efficacy
AO/EB staining
Characteristic morphological changes of cells during apoptosis
can be further confirmed by AO/EB fluorescence staining [24]. With
the observation of fluorescence microscope, AO dye makes the
nucleus of normal cells show green uniform fluorescence, and
the nucleus of apoptotic cells are stained with dense yellow green
fluorescence. EB only stained necrotic cells, which were orange red.
Intact cell structures were presented by the control group, nuclear
chromatin was stained with AO dye which displayed uniform
green fluorescence with clear cell boundaries (Fig. 2). The cells
treated with moxifloxacin derivative 4b showed clear apoptosis
characteristics, such as cell membrane shrinkage, condensed
nuclear chromatin, and an increased number of apoptotic bodies.
With the increase in Compound 4b concentration, the intercellular
gap expanded, and the number of apoptotic cells with yellow green
and orange red fluorescent nuclei increased, which suggested that
Compound 4b has a dose-response relationship with the pro-apop-
totic effect on NCI-H1299 cells.
against NCI-H1299 cells (IC50
(IC50 = 13.69 mM), which was 19.8 and 3.9 times the value of DPP
(IC50 = 50.78 mM). Compound 4b displayed relatively high anti-pro-
= 2.56 mM) and A549 cells
Table 1
The IC50 value of the synthesized compounds obtained for anti-proliferative activity.
Compound
R
Absolute IC50 (lM)
NCI-H1299 cells
A549 cells
HUVEC cells
4a
4b
4c
4d
4e
4f
4g
4h
C6H5
63.05 4.02
2.56 0.07
52.12 1.85
4.33 0.09
5.55 0.37
13.07 1.17
30.46 1.23
31.46 2.25
>100
42.59 1.11
13.69 0.70
62.97 2.57
50.84 4.63
65.78 2.73
63.91 5.26
>100
>100
>100
53.33 3.76
No inhibitory
>500
>500
>300, <500
<300
>500
>300, <500
>500
No inhibitory
7.05 0.61
4-CH3-C6H4
2-OCH3-C6H4
3-OCH3-C6H4
4-OCH3-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
Moxifloxacin (MXF)
Cisplatin (DPP)
50.78 1.20
1MTT colorimetry was used to determine cell viability and IC50
(lM) values which were calculated using GraphPad Prism 8 (GraphPad Software Co., Ltd, San Diego, CA, USA).
Fig. 2. Representative images of AO/EB double stained NCI-H1299 cells after treatment with Compound 4b (drug concentrations were 5, 10, 15 and 25
(100 M) or DPP (25 M) for 24 h. Control group (CG) cells received 1% DMSO (v/v). Each experiment was performed three times. Representative morphological features were
present.
lM) and MXF
l
l
Please cite this article as: F. Yu, Z. Zhang, W. Li et al., Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-
H1299 cells, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151873

4
F. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 3. Cell-cycle analysis of NCI-H1299 cells after treatment by flow cytometry. (A) Patterns of cell cycle distribution in NCI-H1299 cells treated with Compound 4b (drug
concentrations were 5, 10, 15 and 25
l
M) and MXF (100
lM) or DPP (25
lM) for 24 h; (B) Cell cycle profile of Compound 4b-treated NCI-H1299 cells. * Significant difference
compared to the Control group at P < 0.05.
Compound 4b induced G0/G1 phase arrest in NCI-H1299 cells
Compound 4b altered the cell cycle distribution in NCI-H1299
The genetic control of cell division in cancer is different to that
of normal cells, causing uncontrolled cell cycles to maintain unre-
stricted cell proliferation [25,26]. Therefore, induction of the cell
cycles is an effective means of inhibiting cancer cell division and
suppressing tumor growth. To test the effect of Compound 4b on
cell cycle arrest, we examined the cell cycle distribution of NCI-
H1299 cells by flow cytometry. As shown in Fig. 3, both MXF and
cells. After treatment with 5–25 lM of Compound 4b for 24 h,
the percentage of NCI-H1299 cells arrested in the G0/G1 phase
was markedly up-regulated. In the positive control group, only
41.48 3.09% of the cells were in the G0/G1 phase. According to
the results, the moxifloxacin derivative 4b caused dose-dependent
accumulation of NCI-H1299 cells in the G0/G1 phase, which is con-
sistent with the cell viability assay results.
Fig. 4. Detection of the apoptosis ratio associated with Compound 4b by Annexin V-FITC/PI assay. (A). After treatment with Compound 4b at different concentrations (5, 10,
15, 25 M) for 24 h, apoptotic analysis was performed. The second quadrant representative dead cell, the third quadrant normal active cell, the first quadrant representative
late death cell, the fourth quadrant representative early death cell; (B). The percentage of apoptotic cells (cells at early and late apoptosis stages). The results of three
l
*
**
independent experiments are expressed as mean SD; Significant difference from Control group at P < 0.05, Significant difference from Control group at P < 0.01.
Please cite this article as: F. Yu, Z. Zhang, W. Li et al., Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-
H1299 cells, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151873

F. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
5
Compound 4b induced cell apoptosis in NCI-H1299 cells
Zhoushan Science and Technology project, China (grant no.
2019C21018) and the Postdoctoral Research Projects of Zhejiang
Province, China (grant no. zj20180096).
Apoptosis is a basic and ubiquitous biological process. Apopto-
sis maintains the integrity and balance of growth and development
through gene-controlled autonomic cell death. However, cancer
cells can avoid apoptosis and grow uncontrollably. Therefore, the
induction of apoptosis of cancer cells is an effective method for
treating cancer [27]. Compound 4b induced apoptosis of NCI-
H1299 cells was confirmed by Annexin V-FITC/PI double staining
flow cytometry (Fig. 4). Treatment of NCI-H1299 cells with DPP
Appendix A. Supplementary data
All the copies of FT-IR, 1H-NMR, 13C-NMR and HR-MS for the
title compounds are available online. Supplementary data to this
article can be found online at https://doi.org/10.1016/j.tetlet.
2020.151873.
(25
the percentages of 8.05 0.18% and 10.34 0.14%, respectively.
Compound 4b at the concentrations of 5, 10, 15 and 25 M led
lM) or MXF (100 lM) for 24 h resulted in cell apoptosis at
l
to an increase in the proportion of early and late apoptotic cells
compared to normal cells. Specifically, the percentage of late apop-
totic cells increased from 7.40 0.58% to 12.27 1.73%, and the
percentage of early apoptotic cells increased from 4.50 1.08% to
References
[1] Cancer Tomorrow. Available online: http://gco.iarc.fr/tomorrow/home
(accessed on 22 October, 2019).
[2] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide
for 36 cancers in 185 countries, CA Cancer J. Clin. 68 (2018) 394–424.
[3] Miller, K.D., Nogueira, L., Mariotto, A.B., Rowland, J.H., Yabroff, K.R., Alfano, C.
M., Jemal, A., Kramer, J.L., Siegel, R.L., Cancer treatment and survivorship
statistics, 2019. CA: A Cancer J. Clin., 2019, 69, 363–385.
17.47
2.49%. These results indicate that Compound 4b could
induce both early and late apoptosis of NCI-H1299 cells in a
dose-dependent manner and that it produces a killing effect at
micromolar concentrations.
[4] H.H.H. Mohammed, A.A. Abd El-Hafeez, S.H. Abbas, E.-S.M.N. Abdelhafez, G.E.-
D.A.
Abuo-Rahma,
New
antiproliferative
7-(4-(N-substituted
Conclusions
carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell
cycle arrest at G2/M phase, Bioorg. Med. Chem. 24 (2016) 4636–4646.
[5] S. Jiang, Y. Jia, Y. Tang, D. Zheng, X. Han, F. Yu, Y. Chen, F. Huang, Z. Yang, G.
Ding, Anti-proliferation activity of a decapeptide from perinereies aibuhitensis
toward human lung cancer H1299 cells, Mar. Drugs 17 (2019) 122.
[6] G.A.R.Y. Suaifan, A.A.M. Mohammed, Fluoroquinolones structural and
medicinal developments (2013–2018): where are we now?, Bioorg. Med.
Chem. 27 (2019) 3005–3060.
[7] O. Aranha, L. Zhu, S. Alhasan, D.P. Wood, T.H. Kuo, F.H. Sarkar, Role of
mitochondria in ciprofloxacin induced apoptosis in bladder cancer cells, J. Urol.
167 (2002) 1288–1294.
[8] M. Abdel-Aziz, S.-E. Park, G.E.-D.A.A. Abuo-Rahma, M.A. Sayed, Y. Kwon, Novel
N-4-piperazinyl-ciprofloxacin-chalcone hybrids: synthesis, physicochemical
properties, anticancer and topoisomerase I and II inhibitory activity, Eur. J.
Med. Chem. 69 (2013) 427–438.
A series of moxifloxacin derivatives of the N-5-Aza ring with
different substituents were synthesized, and their structural for-
mulas were identified by different spectroscopic techniques,
including FT-IR, 1H NMR, 13C NMR and HR-MS. Based on our phar-
macological mechanism studies, various derivatives were associ-
ated with high induction of cytotoxicity or apoptosis of NCI-
H1299 cells but not of HUVEC cells. The cytotoxic activity of the
active derivatives 4a-h was in the range of 2.56
0.07–
0.70–
63.05
65.78
4.02 lM on NCI-H1299 cells and 13.69
27.29 on A549 cells, these derivatives exhibited more
[9] J. Azéma, B. Guidetti, J. Dewelle, B. Le Calve, T. Mijatovic, A. Korolyov, J. Vaysse,
M. Malet-Martino, R. Martino, R. Kiss, 7-((4-Substituted)piperazin-1-yl)
derivatives of ciprofloxacin: synthesis and in vitro biological evaluation as
potential antitumor agents, Bioorg. Med. Chem. 17 (2009) 5396–5407.
[10] G.G. Rajulu, H.S. Bhojya Naik, A. Viswanadhan, J. Thiruvengadam, K. Rajesh, S.
Ganesh, H. Jagadheshan, P.K. Kesavan, New hydroxamic acid derivatives of
fluoroquinolones: synthesis and evaluation of antibacterial and anticancer
properties, Chem. Pharm. Bull. 62 (2014) 168–175.
potent cytotoxicity than the parent moxifloxacin, which was used
as a reference (IC50 > 100 M). The potency of the active Compound
4b was 2.56 0.07 M and 13.69 0.70 M, and was associated
with 19.8 and 3.9 times greater inhibition of NCI-H1299 cells and
A549 cells growth than DPP (50.78 1.20 M, 53.33 3.76 M).
Furthermore, the dose dependent apoptosis-inducing activity of
Compound 4b in NCI-H1299 cells was examined by AO/EB staining
and an Annexin V-FITC/PI double staining cell apoptosis assay. Cell
cycle analysis indicated that Compound 4b arrested NCI-H1299
cells at the G0/G1 phase. Thus, the novel moxifloxacin derivative
Compound 4b, created via a N-(p-tolyl)propanamide substitution
of the N-5-Aza ring, could be a promising candidate for the treat-
ment of non-small cell lung cancer.
l
l
l
l
l
[11] G.G. Rajulu, H.S.B. Naik, G.C. Kumar, S. Ramaraj, G. Sambasivam, K.P. Koppolu,
New
azetidine-3-carbonyl-N-methyl-hydrazino
derivatives
of
fluoroquinolones: synthesis and evaluation of antibacterial and anticancer
properties, Med. Chem. Res. 23 (2014) 2856–2868.
[12] A.E. Kassab, E.M. Gedawy, Novel ciprofloxacin hybrids using biology oriented
drug synthesis (BIODS) approach: anticancer activity, effects on cell cycle
profile, caspase-3 mediated apoptosis, topoisomerase II inhibition, and
antibacterial activity, Eur. J. Med. Chem. 150 (2018) 403–418.
ˇ
ˇ
[13] S. Jantová, E. Paulovicová, L. Paulovicová, M. Janošková, M. Pánik, V. Milata,
Immunobiological efficacy and immunotoxicity of novel synthetically
prepared fluoroquinolone ethyl 6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-
3-carboxylate, Immunobiology 223 (2018) 81–93.
Declaration of Competing Interest
[14] F. Gao, X. Zhang, T. Wang, J. Xiao, Quinolone hybrids and their anti-cancer
activities: an overview, Eur. J. Med. Chem. 165 (2019) 59–79.
[15] P. Dhiman, N. Arora, P.V. Thanikachalam, V. Monga, Recent advances in the
synthetic and medicinal perspective of quinolones: a review, Bioorg. Chem. 92
(2019) 103291.
[16] K. Tomita, Y. Tsuzuki, K.-I. Shibamori, M. Tashima, F. Kajikawa, Y. Sato, S.
Kashimoto, K. Chiba, K. Hino, Synthesis and structure–activity relationships of
novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-
carboxylic acids as antitumor agents. Part 1, J. Med. Chem. 45 (2002) 5564–
5575.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
Special thanks to Shuoqi Jiang (Zhejiang Ocean University) for her
guidance and help in the use of flow cytometry. Special thanks to
Pan Xiao (ChiaTai Tianqing Pharmaceutical Group Co., Ltd.,
Lianyungang, China) for providing information about the develop-
ment of quinolones.
[17] T. Idowu, F. Schweizer, Ubiquitous nature of fluoroquinolones: the oscillation
between antibacterial and anticancer activities, Antibiotics 6 (2017) 26.
[18] V. Yadav, P. Varshney, S. Sultana, J. Yadav, N. Saini, Moxifloxacin and
ciprofloxacin induces S-phase arrest and augments apoptotic effects of
cisplatin in human pancreatic cancer cells via ERK activation, BMC Cancer 15
(2015) 581.
´
[19] A. Beberok, Z. Rzepka, M. Respondek, J. Rok, M. Stradowski, D. Wrzesniok,
Moxifloxacin as an inducer of apoptosis in melanoma cells: A study at the
cellular and molecular level, Toxicol. In Vitro 55 (2019) 75–92.
[20] R. Chen, H. Zhang, T. Ma, H. Xue, Z. Miao, L. Chen, X. Shi,
Moxifloxacin/gatifloxacin-1,2,3-triazole-isatin hybrids with hydrogen-bond
donor and their in vitro anticancer activity, J. Heterocycl. Chem. 56 (2019)
2691–2694.
Funding
This research was financially supported by the National Natural
Science Foundation of China, China (grant no. 21502170),
Please cite this article as: F. Yu, Z. Zhang, W. Li et al., Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-
H1299 cells, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151873

6
F. Yu et al. / Tetrahedron Letters xxx (xxxx) xxx
[21] X. Zhu, J. Fu, Y. Tang, Y. Gao, S. Zhang, Q. Guo, Design and synthesis of novel 40-
demethyl-4-deoxypodophyllotoxin derivatives as potential anticancer agents,
Bioorg. Med. Chem. Lett. 26 (2016) 1360–1364.
2 ratio and caspase-dependent apoptosis in colorectal cancer cell line, Bioorg.
Chem. 93 (2019) 103329.
[25] T. Wu, T. Li, Y.-N. Kang, L. Liu, X.-M. Wang, J.-S. Lan, Y. Ding, T. Zhang, Synthesis
and Biological Evaluation of Novel Alkyl Amine Substituted Icariside II
Derivatives as Potential Anticancer Agents, Molecules 23 (2018) 2146.
[26] K. Vermeulen, D.R. Van Bockstaele, Z.N. Berneman, The cell cycle: a review of
regulation, deregulation and therapeutic targets in cancer, Cell Prolif. 36
(2003) 131–149.
[27] S. Zhao, Y. Zhen, L. Fu, F. Gao, X. Zhou, S. Huang, L. Zhang, Design, synthesis and
biological evaluation of benzamide derivatives as novel NTCP inhibitors that
induce apoptosis in HepG2 cells, Bioorg. Med. Chem. Lett. 29 (2019) 126623.
[22] M.E. González-Rosende, T. Olivar, E. Castillo, J. Sepúlveda-Arques, 2-
Sulfonyliminodihydropyrimidines:
Arch. Pharm. 341 (2008) 690–695.
a novel class of analgesic compounds,
[23] M. Mano, T. Seo, T. Hattori, T. Kaneko, K. Imai, V. Anticoccidials, Synthesis and
anticoccidial activity Of 2(1h)-pyrazinone 4-oxide derivatives, Chem. Pharm.
Bull. 28 (1980) 2734–2747.
[24] M.H. Ahagh, G. Dehghan, M. Mehdipour, R. Teimuri-Mofrad, E. Payami, N.
Sheibani, M. Ghaffari, M. Asadi, Synthesis, characterization, anti-proliferative
properties and DNA binding of benzochromene derivatives: Increased Bax/Bcl-
Please cite this article as: F. Yu, Z. Zhang, W. Li et al., Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-
H1299 cells, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151873