Synthesis and structure-activity relationships study of α-aminophosphonate derivatives containing a quinoline moiety

Article abstract of DOI:10.1016/j.cclet.2017.02.012

Two series of α-aminophosphonate derivatives containing a quinoline moiety have been designed and synthesized by introducing bioactive quinoline scaffold to α-aminophosphonate. The in vitro cytotoxic activities of target compounds were first investigated against two human cancer cell lines including Eca109 and Huh7 by MTT assay. Results revealed that most of target compounds exhibited moderate to high antitumor activities against the tested cancer cell lines and some demonstrated more potent inhibitory activities compared with Sunitinib. Among them, compounds 4b2 and 4b4 containing methyl-substituted aniline group were found to be more active than Sunitinib against both of two cancer cell lines, with IC₅₀ in the range of 2.26?μmol/L–7.46?μmol/L.

Full text of DOI:10.1016/j.cclet.2017.02.012

Accepted Manuscript
Title: Synthesis and structure-activity relationships study of
α-aminophosphonate derivatives containing a quinoline
moiety
Authors: Xi-Feng Zhu, Jing Zhang, Shuo Sun, Yan-Chun Guo,
Shu-Xia Cao, Yu-Fen Zhao
PII:
S1001-8417(17)30068-2
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2017.02.012
CCLET 3985
To appear in:
Chinese Chemical Letters
Received date:
Accepted date:
17-2-2017
17-2-2017
Please cite this article as: Xi-Feng Zhu, Jing Zhang, Shuo Sun, Yan-Chun Guo, Shu-
Xia Cao, Yu-Fen Zhao, Synthesis and structure-activity relationships study of ␣-
aminophosphonate derivatives containing a quinoline moiety, Chinese Chemical Letters
http://dx.doi.org/10.1016/j.cclet.2017.02.012
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Original article
Synthesis and structure-activity relationships study of α-aminophosphonate
derivatives containing a quinoline moiety
a
a
b
a, *
a,*
a,c
Xi-Feng Zhu , Jing Zhang , Shuo Sun , Yan-Chun Guo , Shu-Xia Cao , Yu-Fen Zhao
a
The College of Chemistry and Molecular Engineering, the Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou
University, Zhengzhou 450001, China
Department of Chemistry, International College of Zhengzhou University, Zhengzhou University, Zhengzhou 450001, China
b
c
Department of Chemistry, College of Chemistry and Chemical Engineering, the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University,
Xiamen 361005, China

Corresponding authors.
E-mail addresses: ycguo@zzu.edu.cn (Y.-C. Guo); csx@zzu.edu.cn (S.-X. Cao)
Graphical absrtract
Two series of α-aminophosphonate derivatives containing a quinoline moiety have been designed, synthesized and evaluated for
cytotoxic activity against Eca109 and Huh7 cancer cell lines in vitro. Among them, compounds 4b2 and 4b4 were found to be more
active than Sunitinib against both of two cancer cell lines.
ABSTRACT
Two series of α-aminophosphonate derivatives containing a quinoline moiety have been designed and synthesized by introducing bioactive quinoline
scaffold to α-aminophosphonate. The in vitro cytotoxic activities of target compounds were first investigated against two human cancer cell lines
including Eca109 and Huh7 by MTT assay. Results revealed that most of target compounds exhibited moderate to high antitumor activities against
the tested cancer cell lines and some demonstrated more potent inhibitory activities compared with Sunitinib. Among them, compounds 4b2 and 4b4
containing methyl-substituted aniline group were found to be more active than Sunitinib against both of two cancer cell lines, with IC50 in the range of
2
.26 μmol/L-7.46 μmol/L.
Keywords: Quinoline, α-Aminophosphonate , Synthesis, Antitumor activity, In vitro.
1
. Introduction
Cancer has become an important public health concern and a significant cause of death in the human population [1]. Cancer
incidence and mortality have been increasing in China, making cancer the leading cause of death since 2010 and a major public health
problem in the country [2]. Lung cancer was the leading cause of death in China followed by liver cancer, stomach cancer, esophageal
cancer and colorectal cancer [3]. Despite many efforts to fight against cancer, the successful treatment of certain tumor types continues
to be a challenge owing to their aggressiveness, the mechanisms of malignant cell metastasis, chemoresistance, and the lack of
selectivity of some drugs [4]. Therefore, the development of novel anticancer agents with high efficacy and minimal side effects by
synthesizing small and simple molecules is indispensable.
N-heterocyclic compounds are very crucial in drug design [5-7]. Compounds containing quinoline rings are extensively found in
several classes of natural and synthetic biologically active compounds [8-10]. Quinoline-bearing structures are well-known due to their
broad biological activities [11], such as anticancer [12], antifungal [13], antibacterial [14], antitubercular [15] and antimalarial [16] that
have been used in traditional medicine as a remedy. Recently, quinoline-based azolyalkylquinolines bearing different azole groups,
such as benzothiazole (SRA-HX-1), tetrazole (SRA-HX-2), and 1,2,4-triazole (SRAHX-3), have been synthesized and reported as
potent antitumor agents for breast cancer cells in vitro [17]. 8-Hydroxyquinoline derivative (8-hydroxy-2-quinolinecarbaldehyde) has
been reported to possess strong antitumor activities against human cancer cell lines and hepatocellular carcinoma Hep3B [18].
Moreover, a novel quinoline derivative 83b1 (8-(4-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydro-2-methylquin-oline, has shown to
inhibit cancer growth in human esophageal squamous cell carcinoma.[19].The structure of the quinoline derivative is depicted in Fig. 1.
α-Aminophosphonic acids and their corresponding α-amino phosphonates have received much attention in organic and medicinal
chemistry because of their pharmacological properties and clinical applications [20-22]. Some of them have been used as potent
enzyme inhibitors, antimicrobial, antitumor, antioxidant and antiviral agents [23-28]. It was reported that introduction of

aminophosphonate group to pharmacy core is able to improve the antitumor activity and many aminophosphonate derivatives have
demonstrated potent inhibitory activities against human tumors [29,30].
Existing thieno[2,3-d]pyrimidine in one α-amino phosphonate molecule can exhibit valuable anti-tumor activity [31]. These special
scaffold compounds strongly provoked our interest to continuously explore this kind of compounds. Based on this strategy, we lead to
the proposal to incorporate quinoline scaffold into the α-aminophosphonate. Then two series of α-aminophosphonate derivatives
containing a quinoline moiety were synthesized (Scheme 1). The in vitro cytotoxic activities of target compounds were tested against
esophageal cancer (Eca109) and hepatocellular carcinoma (Huh7) by MTT method. This represents the first report about the synthesis
and in vitro antitumor activity evaluation of α-aminophosphonate derivatives containing a quinoline moiety.
2
. Results and discussion
As shown in Table 1, the results of preliminary bioassay reveal that most of target compounds exhibited moderate to strong
antitumor activity against human cancer cell lines Eca109 and Huh7 cells. Some of them demonstrated more potent antitumor activities
than the reference drug. Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity.
Recently, Sunitinib has been used to treat solid cancers, such as renal cell carcinoma, gastrointestinal stromal tumors, neuroendocrine
tumors in several Phase II/III trials, lung cancer, pancreatic cancer, chondrosarcoma, esophageal cancer, bladder cancer, glioma,
aggressive fbromatosis, and also showed potential efficacy in progression-free survival and overall survival [32]. Furthermore, research
shows that Sunitinib has same antitumor activity in hepatocellular carcinoma [33]. So Sunitinib was selected as the positive control.
In Eca109 assay, compounds 4a1, 4a2, 4a5, 4a7, 4a12, 4a13, 4b1 and 4b8 exhibited preferable cytotoxic activity than the Sunitinib
(
4
IC50 = 16.54 μmol/L), implying favorable inhibition activities of these compounds on Eca109 cell. Besides, compounds 4a3, 4a4, 4b2,
b3, 4b4 and 4b7 were approximately 2-3 times potent than Sunitinib. Interestingly, compound 4a11, the most promising compound,
showed significant inhibitory preference to Eca109 with IC50 value of 3.41 μmol/L, about 5 times more potent than Sunitinib. In Huh7
assay, compounds 4a3, 4a4, 4a7, 4b2, 4b3, 4b4 and 4b8 showed potent antitumor activity. Especially, compounds 4b2 and 4b4 (IC50
.26 μmol/L -4.00 μmol/L) showed more potent activity against Huh7 than Sunitinib (IC50 = 5.27 μmol/L). Among all the target
=
2
compounds, it is worth noting that compounds 4b2 and 4b4 which possess methyl-substituted aniline group were found to be more
active than Sunitinib against both of two cancer cell lines, with IC50 in the range of 2.26 μmol/L-7.46 μmol/L.
The antitumor data also indicate that the substituents of phosphonate have no apparent influence on antitumor activity to Eca109
and Huh7 cells. For example, when R was Ph and R´ was Et, compound 4a2 exhibited good antitumor activities against Eca109 and
Huh7 cells, with IC50 values of 11.18, 10.78 μmol/L, respectively. The inhibitory activity of compound 4b2, where the phosphonate
was substituted by i-Pr, was litter higher than that of 4a2 against Eca109 and Huh7 with IC50 values of 6.67, 4.00 μmol/L, respectively.
The same trend was observed for compounds 4a3/4b3, 4a4/4b4 and 4a8/4b8 against Eca109 and Huh7 cells. While compound 4a5
with 3-F (R) and Et (R´) showed antitumor activity against Huh7 with IC50 values of 11.94 μmol/L. Compound 4b5 with 3-F (R) and i-
Pr (R´) had a lower activity (IC50 = 14.4 μmol/L) than that of 4a5. This also applied to compounds 4a11/4b11, 4a12/4b12 against Eca
1
09 and Huh7 cells.
Different substituents on the phenyl ring had a great influence in antitumor activity. Compound 4a1 and 4b1 with unsubstituted
aryl ring exhibited good antitumor activities against Eca109 and Huh7 cells, with IC50 values of 12.68, 17.93 and 14.38, 10.18 μmol/L,
respectively. Compounds 4a2-4a4 and 4b2-4b4 containing methyl-substituted aniline group showed more potent antitumor activities
against the tested cancer cell lines with IC50 in the range of 2.26-11.18 μmol/L. Compounds 4a7, 4b7 and 4b8 with 3-chlorophenyl and
4
4
-chlorophenyl moiety showed enhanced inhibitory activity against Eca109 and Huh7 cells, as well as compounds 4a11, 4b11 and
a12 with 3-nitrophenyl and 4-nitrophenyl moiety. Besides, meta-substituted derivatives showed more potent activity than para-
substituted derivatives (4a7 vs. 4a8, 4a11 vs. 4a12, 4b11 vs. 4b12). These results indicated that methyl-, chloro- and nitro-substituent
at the phenyl ring is favorable for activity. However, compounds 4a6, 4b5 and 4b6 with 3-fluoro phenyl and 4-fluoro phenyl moiety
had less cytotoxic activity against Eca109 and Huh7 cells. The antitumor activities of compounds 4a9, 4a10, 4b9 and 4b10 with 3-
methoxyl phenyl and 4-methoxyl phenyl moiety were decreased dramatically. These results indicated that methoxyl at the phenyl ring
are unfavorable. When aromatic amine group was substituted by benzylamine or 2-aminopyridine, the target compounds 4a13, 4a14,
4
b13 and 4b14 had less or inconspicuous cytotoxic activity. The bioactive assay implied that the substitutions on the phenyl ring
significantly affect the antitumor activity of the target compounds.
3
. Conclusion
In summary, two series of α-aminophosphonate derivatives containing a quinoline moiety were synthesized efficiently and their
cytotoxic activities against two human cancer cell lines including Eca109 and Huh7 were evaluated for the first time. Moreover, based
on experimental results, the structure-activity relationship was analyzed. Biological assays revealed that the substitutions on the phenyl
ring influenced the antitumor activity remarkably, while the substitutes of phosphonate had no apparent influence on the antitumor
activity. Among them, compound 4a11 showed excellent inhibitory activity to Eca109, approximately 5-fold more active than
Sunitinib. Additionally, compounds 4b2 and 4b4 containing methyl-substituted aniline group were the most efficient against both of

the tested cancer cell lines. All the above results demonstrated that these compounds could be promising lead compounds of novel
antitumor drugs. Further studies will focus on structural optimization and precise mechanism of action of these compounds.
4
. Experimental
Commercial reagents and solvents were used as received without further purification unless otherwise specified. Toluene was
freshly distilled over sodium with the use of diphenyl ketone as an indicator under nitrogen. High resolution mass spectra (HRMS)
were obtained with a Q-Tof mass spectrometer using the ESI technique. NMR spectra were recorded on a Bruker Avance 400 MHz
1
13
31
spectrometer. H and C chemical shifts were quoted in DMSO-d
chemical shifts were acquired in DMSO-d with H PO as the internal standard. Column chromatography was performed on silica gel
00-300 mesh.
The target compounds 4a1-4a14 and 4b1-4b14 were prepared as shown in Scheme 1. Compound 1 was synthesized according to
well-established literature procedures [34]. Commercially available 4-bromo-2-methoxyaniline treated with glycerin in the presence of
-nitrobenzenesulfonic acid with concentrated sulfuric acid to afford 6-bromo-8-methoxy-quinoline (1). Compound 1 then underwent
Suzuki cross-coupling reaction with 4-formylphenylboronic acid in toluene, using Pd(PPh as a catalyst to give intermediate 2 with
6
with tetramethylsilane (TMS) as the internal standard, and
P
6
3
4
2
3
3 4
)
excellent yield. Various methods for the synthesis of α-aminophosphonates were reported. To our best knowledge, one pot Mannich-
type process of carbonyl compounds, amines, and dialkyl phosphonate in the presence of a Lewis acid remains the most efficient,
simple, general and high yielding method. Therefore, the reaction of intermediate 2 with diethyl or diisopropyl phosphonate and
3
various substituted amines in the presence of FeCl in absolute ethanol generated target compounds (4a1~4a10 and 4b1~4b10) with
good yields (Pathway 1). Unfortunately, the scope of this reaction was limited and the target compounds (4a11~4a14 and 4b11~4b14)
were obtained by the reaction of intermediate 2, various amine with dialkyl phosphonate in anhydrous toluene by one pot synthesis
1
13
31
without any catalyst (Pathway 2). All the newly synthesized compounds were characterized by H NMR, C NMR, P NMR, IR and
high resolution mass spectrometry, respectively (see Supporting information for structure characterization).
For preliminary screening of antitumor candidates, the cytotoxic activities of target compounds were evaluated against two human
cancer cell lines Eca109 and Huh7 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cancer cell
o
lines seeded into the 96-well plate (100 μL each well) were incubated at 37 C in a 5% CO
2
incubator. After 24 h, the target compounds
at different concentrations were added to the culture medium and the cell cultures were continued for 72 h. The cultured cells were
o
mixed with 10 μL 5 mg/mL of MTT solution and incubated for 4 h at 37 C. The formazan crystals were dissolved in 100 mL DMSO
each well, and the absorbency at 570 nm and 630 nm (for the reference wavelength) was measured with microplate reader. Each
experiment was performed at least three times. The results expressed as IC50 (inhibitory concentration 50%) were the averages of three
determinations and calculated by using the GraphPad Prism 6.0 software. The results were illustrated in Table 1 with Sunitinib as the
positive control.
Acknowledgment
We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (Nos. 21105091,
2
1172201).
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7

Fig 1 Quinoline derivatives
Scheme 1 The synthetic route for target compounds.

Table 1
The cytotoxic activity of target compounds against human cancer cell lines
a
a
a
Compd.
IC50 (μmol/L)
Compd.
IC50 (μmol/L)
Compd.
IC50 (μmol/L)
b
c
b
c
b
c
Eca109
Huh7
Eca109
Huh7
Eca109
Huh7
4
4
4
4
4
4
4
4
4
4
a1
a2
a3
a4
a5
a6
a7
a8
a9
a10
12.68 ± 1.28
11.18 ± 1.25
7.13± 1.23
9.03 ± 1.24
11.44 ± 1.18
27.72 ± 1.25
10.12 ± 1.23
57.79 ± 1.70
17.93 ± 1.08
10.78 ± 1.10
8.28 ± 1.07
9.40± 1.09
4b1
4b2
4b3
4b4
4b5
4b6
4b7
4b8
4b9
4b10
14.38 ± 1.13
6.67± 1.24
4.84 ± 1.28
7.46 ± 1.11
24.16 ± 1.15
27.56 ± 1.29
5.97 ± 1.19
11.37 ± 1.20
>50.00
10.18 ± 1.06
4.00 ± 1.14
6.65 ± 1.07
2.26 ± 1.20
14.40 ± 1.04
10.76 ± 1.04
10.31 ± 1.07
9.00 ± 1.05
27.12
4a11
3.41 ± 1.50
10.60 ± 1.18
11.49 ± 1.34
75.38 ± 1.21
18.10 ± 1.13
62.92 ± 1.79
>50.00
11.86 ±1.06
11.70 ± 1.08
12.43 ±1.10
39.11
4a12
4a13
4a14
11.94 ± 1.07
10.16 ± 1.17
5.46 ± 1.10
37.01 ± 1.21
4b11
4b12
4b13
4b14
Sunitinib
12.43 ±1.07
46.12
82.77
91.58 ± 1.43
16.54 ± 1.17
72.53
d
127.30 ± 1.94 77.79
5.27
125.40 ± 2.07 21.89 ± 1.10
>50.00
72.00
a
b
c
d
IC50: Concentration which produces 50% inhibition of proliferation.
Eca109: Esophageal cancer
Huh7: Hepatocellular carcinoma
Positive control, a small-molecule multi-targeted receptor tyrosine kinase inhibitor with activity against many human cancer cell lines.