Synthesis and cytotoxicity of (3β)-3-acetyloxy-5(6)-androsten-7-one oxime and 3,5(6)-androstadien-7-one oxime

Article abstract of DOI:10.1007/s00044-013-0788-9

(3β)-3-Acetyloxy-5(6)-androsten-7-one oxime and 3,5(6)-androstadien-7- one oxime were synthesized and their in vitro cytotoxic activities against human epidermoid carcinoma cell line KB, human cervical carcinoma cell line HeLa, human gastric carcinoma cell line MKN-28, and human breast carcinoma cell line MCF-7 were evaluated. The compound (3b)-3-acetyloxy-5(6)-androsten-7-one oxime exhibited significant growth inhibitory properties against cell lines tested and afforded IC 50 value 26.0 ± 1.6, 12.8 ± 1.0, 18.1 ± 0.2, 10.2 ± 1.2 lM for KB, HeLa, MKN-28, and MCF-7, respectively. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0788-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1839–1843
DOI 10.1007/s00044-013-0788-9
ORIGINAL RESEARCH
Synthesis and cytotoxicity of (3b)-3-acetyloxy-5(6)-androsten-7-one
oxime and 3,5(6)-androstadien-7-one oxime
•
Juan Yao Weijian Ye Jinliang Liu
•
•
•
Juanjuan Liu Cunde Wang
Received: 13 July 2013 / Accepted: 10 September 2013 / Published online: 21 September 2013
Ó Springer Science+Business Media New York 2013
Abstract (3b)-3-Acetyloxy-5(6)-androsten-7-one oxime
and 3,5(6)-androstadien-7-one oxime were synthesized and
their in vitro cytotoxic activities against human epidermoid
carcinoma cell line KB, human cervical carcinoma cell line
HeLa, human gastric carcinoma cell line MKN-28, and
human breast carcinoma cell line MCF-7 were evaluated.
The compound (3b)-3-acetyloxy-5(6)-androsten-7-one
oxime exhibited significant growth inhibitory properties
against cell lines tested and afforded IC50 value 26.0 1.6,
12.8 1.0, 18.1 0.2, 10.2 1.2 lM for KB, HeLa,
MKN-28, and MCF-7, respectively.
modified compounds, or analogs, developed from the lead
compound and prepared by connecting special functional
groups to the core structure of the steroid. The steroidal
oximes, (6E)-hydroximino-24-ethylcholest-4-en-3-one and
(6E)-hydroximinocholest-4-en-3-one, were isolated from
Cinachyrella alloclada and C. apion (Jaime et al., 1997) in
1997, and (3E)-hydroximinocholest-4-en-6-one was iso-
lated from marine sponge Cinachyrella australiensis of
South China Sea (Xiao et al., 2005) in 2005. These com-
pounds display antiviral function to hepatitis virus (Hep
G2) in vitro (Xiao et al., 2005) and exert cytotoxic activ-
ities against several types of cancer cells such as P-388
(murine leukemia), A-549 (human lung carcinoma), HT-29
(human colorectal adenocarcinoma), and MEL-28 (human
myeloma) tumor cells (Deive et al., 2001). The synthesis
and biological activities of some steroidal oximes pos-
sessing unusual and interesting structures have been
described recently (Cui et al., 2008, 2009a, b; Jindal et al.,
2003; Krstica et al., 2007; Poza et al., 2007). These pre-
vious studies indicated that the cytotoxicity of these ste-
roidal oximes against cancer cells is dependent on the
location of the hydroximino group on the steroidal nucleus.
The parental steroids with a hydroximino group located at a
different position display a remarkable difference in their
cytotoxicities (Dubey et al., 2008; Huang et al., 2011).
Moreover some steroidal compounds with a,b-unsaturated
ketone core gave the potency against human cancer cell
lines (Cui et al., 2008, 2009a, b; Jiang et al., 2010; Li et al.,
2010; Wang et al., 2011). In an effort to find the new
analogs of this type of novel steroidal oximes that exhibit
higher activity along with simpler chemical reactions and
moreover are easily prepared, we synthesized some ste-
roidal compounds with a,b-double bond and oxime group
at the C-7 position using dehydroepiandrosterone as a
starting material. In order to evaluate the antitumor activity
Keywords Steroidal oxime Á Dehydroepiandrosterone Á
Antiproliferative activity Á Cytotoxicity
Introduction
The modifications of the natural steroids and the studies on
the biological activity of these steroidal derivatives have
attracted considerable attentions from synthetic organic
chemists and pharmaceuticals researchers (Geall et al.,
2002; Gupta et al., 2010; Kim et al., 2000; Willemen et al.,
2002; Zeelen, 1990). The modified steroidal derivatives
have been a rich source of candidates with potential
pharmaceutical applications. Researches showed that ste-
roids elicit different biological action via various functional
groups located around the periphery of their rigid tetra-
cyclic skeleton. Most steroid based pharmaceuticals are
J. Yao Á W. Ye Á J. Liu Á J. Liu Á C. Wang (&)
School of Chemistry and Chemical Engineering, Yangzhou
University, 180 Siwangting Street, Yangzhou 225002, Jiangsu,
People’s Republic of China
e-mail: wangcd@yzu.edu.cn
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Med Chem Res (2014) 23:1839–1843
of steroidal derivatives, the cytotoxicity of synthesized
compounds was tested in vitro against human epidermoid
carcinoma cell line KB, human cervical carcinoma cell line
HeLa, human gastric carcinoma cell line MKN-28, and
human breast carcinoma cell line MCF-7.
stirred at room temperature for 4 h. Ice-water (120 mL) was
poured into the reaction mixture. The white precipitate was
filtered and the white solid was washed with water. Re-crys-
tallization of the crude product using ethyl acetate and hexane
as solvents gave white tabular crystals: 3b-acetoxyandrost-5-
ene (3.0 g, 95 %); mp: 97–98 °C (PE/AcOEt); IR (KBr,
cm-1): 2964, 2936, 2905, 2824, 1730, 1437, 1370, 1246, 1035;
1H NMR (600 MHz, CDCl3) d (ppm): 0.74 (s, 3H), 1.02 (s,
3H), 2.02 (s, 3H), 4.60–4.62 (m, 1H, 3a-H), 5.38 (d,
J = 4.9 Hz, 1H);13C NMR (150 MHz, CDCl3)d(ppm):17.27
(H3C–CO), 19.32 (C-11), 20.58 (C-18), 21.08 (C-19), 21.45
(C-16), 25.67 (C-2), 27.80 (C-15), 32.02 (C-7), 32.24 (C-1),
36.74 (C-8), 37.16 (C-10), 37.96 (C-4), 38.53 (C-12), 40.22 (C-
17), 40.98 (C-13), 50.28 (C-9), 54.80 (C-14), 73.86 (CH–O),
122.62 (C=CH), 139.52 (C=CH), 170.58 (C=O); EI-MS: m/
z (%): 316 (12) [M?], 256 (100).
Experimental
All melting points were determined in a Yanaco melting
point apparatus and are uncorrected. IR spectra were
1
recorded in a Nicolet FT-IR 5DX spectrometer. The H
NMR (600 MHz) and 13C NMR (150 MHz) spectra were
recorded in a Bruker AV-600 spectrometer with TMS as
internal reference in CDCl3 solutions. The J values are
given in Hertz. Only discrete or characteristic signals for
1
the H NMR are reported. The MS spectra were obtained
on a ZAB-HS mass spectrometer with 70 eV. The ele-
mental analyses were performed in a Perkin-Elmer 240C
instrument. Flash chromatography was performed on silica
gel (230–400 mesh) eluting with ethyl acetate–hexane
mixture.
Preparation of 3b-acetoxyandrost-5-en-7-one (4)
The mixture of acetic acid (32 mL), acetic anhydride
(32 mL), and chromium trioxide (2.0 g, 20 mmol) was
added rapidly to a solution of 3b-acetoxyandrost-5-ene (3)
(3.8 g, 12 mmol) in methylene chloride (40 mL) under
stirring at room temperature. The resulting mixture was
stirred under reflux for 10 min, and the reaction was
monitored on TLC. After completion of the reaction, the
majority of solvent was evaporated under reduced pressure.
The cold water (20 mL) was poured into the residues. The
resultant mixture was extracted with methylene chloride
(3 9 15 mL). The combined extracts were washed with
5 % sodium hydroxide, water, and saturated brine, dried
over Na2SO4, and evaporated under reduced pressure to get
a crude product. The product was purified by preparative
TLC (EtOAc:hexane = 1:15) to furnish 3b-acetoxyan-
drost-5-en-7-one (2.1 g, 53 %) as white needles solid; mp:
177–178 °C (PE/AcOEt); IR (KBr, cm-1): 2963, 2862,
1729, 1667, 1411, 1261, 1020, 799; 1H NMR (CDCl3,
600 MHz) d (ppm): 0.65 (s, 3H), 1.14 (s, 3H), 1.98 (s, 3H,
CH3CO), 2.12 (t, J = 10.8 Hz, 1H), 2.41 (t, J = 12.6 Hz,
2H), 2.90 (d, J = 12.0 Hz, 1H), 4.69–4.62 (m, 1H, 3a-H),
5.65 (s, 1H, 6-H); 13C NMR (CDCl3, 150 MHz) d (ppm):
16.20 (H3C-CO), 19.62 (C-11), 20.22 (C-18), 22.06 (C-19),
22.45 (C-16), 26.34 (C-2), 26.53 (C-15), 35.02 (C-1), 36.76
(C-6), 37.34 (C-4), 38.16 (C-12), 40.33 (C-17), 44.76 (C-
9), 44.86 (C-8), 47.02 (C-13), 49.16 (C-14), 71.18 (CH-O),
125.52 (C=CH), 163.18 (C=CH), 169.22 (CH3C=O),
200.84 (C-7=O); EI-MS: m/z (%): 330 (8) [M?], 270
(100).
Preparation of (3b)-androst-5(6)-en-3-ol (2)
The mixture of 3b-hydroxyandrost-5(6)-en-17-one (1)
(2.9 g, 10 mmol), 85 % hydrazine hydrate (2.4 g,
60 mmol), sodium hydroxide (2.6 g, 46 mmol), and eth-
ylene glycol (40 mL) was stirred under reflux for 6 h. After
some low boiling-point compounds were removed by dis-
tillation from the reaction system, the residues were cooled
to room temperature. Then, to the resulting mixture was
added ice-water (100 mL), the precipitate was filtered and
the white solid were washed with water. Re-crystallization
of the crude product using ethyl acetate and hexane as
solvents gave white needles solid: (3b)-androst-5(6)-en-3-
ol (1.92 g, 70 %); mp: 133–135 °C (AcOEt/PE); IR (KBr):
3263, 2942, 2899, 2964, 1455, 1375, 1316, 1056 cm-1; 1H
NMR (600 MHz, CDCl3) d (ppm): 0.73 (s, 3H, 18-Me),
1.04 (s, 3H, 19-Me), 3.54–3.57 (m, 1H, 3a-H), 5.40 (d,
J = 6.6 Hz, 1H, 6-H); 13C NMR (150 MHz, CDCl3): d
(ppm): 17.28 (C-11), 19.36 (C-18), 20.88 (C-19), 21.24 (C-
16), 25.67 (C-15), 31.59 (C-7), 32.02 (C-1), 32.22 (C-8),
36.58 (C-2), 37.28 (C-10), 38.77 (C-12), 40.28 (C-17),
40.55 (C-4), 42.24 (C-13), 50.38 (C-9), 54.78 (C-14), 71.92
(CH–OH), 121.35 (C=CH), 140.80 (C=CH); EI-MS: m/
z (%): 274 (100) [M?].
Preparation of 3b-acetoxyandrost-5-ene (3)
Preparation of 3b-acetoxyandrost-5-en-7-one oxime (5)
The mixture of (3b)-androst-5(6)-en-3-ol (2)(2.8 g, 10 mmol),
acetic anhydride (10 mL), catalytic amount 4-dimethylami-
nopyridine (61 mg, 0.5 mmol) and dried pyridine (20 mL) was
The mixture of 3b-acetoxyandrost-5-en-7-one (4) (0.45 g,
1.35 mmol), hydroxylamine hydrochloride (0.57 g, 8.1 mmol),
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Med Chem Res (2014) 23:1839–1843
1841
and sodium acetate (0.55 g, 0.68 mmol) in ethanol (30 mL)
was stirred under reflux for 6 h. The reaction was monitored on
TLC. After completion of the reaction, the mixture was cooled
to room temperature and was poured to ice-water (50 mL).
The white precipitate was filtered and was purified by pre-
parative TLC (EtOAc:hexane = 1:10) to give the target
compound: 3b-acetoxyandrost-5-en-7-one oxime (0.38 g,
81 %); mp: 200–203 °C (PE/AcOEt); IR (KBr, cm-1): 3437,
2936, 2855, 1733, 1641, 1547, 1428, 1368, 1235, 1029, 959,
907; 1H NMR (CDCl3, 600 MHz) d (ppm): 0.66 (s, 3H), 1.06
(s, 3H), 1.97 (s, 3H, CH3CO), 4.60–4.64 (m, 1H, 3a-H), 6.52
(s, 1H, 6-H), 7.95 (s, 1H, N–OH); 13C NMR (CDCl3,
150 MHz) d (ppm): 17.30 (H3C–CO), 17.92 (C-18), 20.04 (C-
19), 20.82 (C-11), 21.33 (C-16), 27.43 (C-2), 28.52 (C-1),
36.28 (C-15), 37.78 (C-8), 38.01 (C-10), 38.12 (C-12), 38.56
(C-4), 39.32 (C-17), 41.02 (C-9), 48.24 (C-13), 49.92 (C-14),
72.94 (CH–O), 113.60 (C=CH), 152.42 (C=NOH), 157.76
(C=CH), 170.32 (CH3C=O); MS m/z: 368 ([M? Na]?,
100 %); Anal. Calcd. for C21H31NO3: C, 73.01; H, 9.04; N,
4.05; Found: C, 73.18; H, 9.22; N, 3.89.
(0.68 g, 88 %) as
a
light yellow solid; mp
:
183–185 °C(PE/AcOEt); IR (KBr, cm-1): 3430, 2932,
2855, 1645, 1540, 1427, 1370, 950, 902; 1H NMR (CDCl3,
600 MHz) d (ppm): 0.70 (s, 3H), 0.95(s, 3H), 5.90–5.92
(m, 1H, 3-H), 6.03 (d, J = 10 Hz, 4-H), 6.48 (s, 1H, 6-H),
8.00 (s, 1H, N–OH); 13C NMR (CDCl3, 150 MHz) d
(ppm): 17.1 (C-18), 17.6 (C-19), 20.4 (C-11), 21.0 (C-2),
23.2 (C-16), 28.9 (C-15), 33.2 (C-8), 36.3 (C-10), 38.0 (C-
12), 38.4 (C-17), 39.5 (C-1), 41.5 (C-9), 49.5 (C-13), 49.7
(C-14), 111.7 (C-6), 128.5(C-4), 132.4 (C-3), 151.5(C-5),
157.9 (C-7); EI-MS m/z: 286 ([M? 1]?, 100); Anal. Calcd.
for C19H27NO: C, 79.95; H, 9.53; N, 4.91; Found: C, 79.79;
H, 9.50; N, 4.72.
Cytotoxic activity against human epidermoid carcinoma
cell line KB, human cervical carcinoma cell line HeLa,
human gastric carcinoma cell line MKN-28, and human
breast carcinoma cell line MCF-7 (Li et al., 2010)
All tumor cell lines tested were purchased from Shanghai
Institute of Cell Biology, Chinese Academy of Science.
The cell lines were cultured in RPMI 1640 medium with
10 % newborn calf serum. It was maintained in a
humidified incubator with an atmosphere of 95 % air and
5 % CO2 at 37 °C. The cells were continuously passaged
once every 3–4 days. Growing cells were collected on
experiments.
Preparation of 3,5(6)-androstadien-7-one (6)
The mixture of 3b-acetoxyandrost-5-en-7-one (4) (1.3 g,
3.8 mmol) and 10 % sodium hydroxide (10 mL) in ethanol
(30 mL) was stirred under reflux for 4 h. The reaction was
monitored on TLC. After completion of the reaction, the
solvent was evaporated under reduced pressure. Next, water
(25 mL) was added to the residue, and the resultant mixture
was extracted with methylene chloride (3 9 10 mL). The
combined extracts were washed with 5 % HCl, water and
saturated brine, dried over Na2SO4, and evaporated under
reduced pressure to get a crude product. The product was
purified by preparative TLC (EtOAc:hexane = 1:10) to
yield a white solid: 3,5(6)-androstadien-7-one (0.96 g,
84 %); mp: 182–183 °C (PE/AcOEt); IR (KBr, cm-1): 3025,
DMSO was used as latent solvent with the highest
concentration \0.1 % in solution of the drug. The control
groups of Doxorubicin, blank (1640), and DMSO solvent
were set up at the same time. Proliferative activity was
evaluated by colorimetric sulforhodamine B (SRB) assay.
Briefly, cells were plated in 96-well plates. After cell
adhering, they were treated with different compounds in a
dose-dependent way for 44 h. Then the cells were fixed by
10 % TDA for 1 h and stained by SRB for 10 min. After
washed with acetic acid to remove the excess dye, protein
bounding dye were dissolved in 10 mM Tris and detected
by a Model Elx 800 Autoplate reader (Bio-Tek Instru-
ments, USA).
1
2938, 2862, 1655, 1602, 1456, 1379, 1295, 1192, 881; H
NMR (CDCl3, 600 MHz) d (ppm): 0.68 (s, 3H), 1.05 (s, 3H),
5.54 (s, 1H, 6-H), 6.03 (d, J = 10 Hz, 1H), 6.09–6.14 (m,
1H, 3-H); 13C NMR (CDCl3, 150 MHz) d (ppm): 15.60 (C-
18), 16.32 (C-11), 19.61 (C-19), 20.20 (C-2), 22.28 (C-16),
26.62 (C-15), 31.83 (C-10), 35.32 (C-12), 36.90 (C-17),
38.28 (C-1), 40.72 (C-9), 45.34 (C-8), 47.86 (C-13), 48.90
(C-14), 123.02 (C-6), 126.72 (C-4), 135.60 (C-3), 160.22 (C-
5), 201.34 (C-7=O); MS m/z: 293 ([M? Na]?, 100 %); Anal.
Calcd. for C19H26O: C, 84.39; H, 9.69; Found: 84.20; H,
9.76.
Results and discussion
Condition and Reagent: (a) N2H4ÁH2O, diglycol, reflux, 6 h,
70 %; (b) (CH3CO)2O, Py, DMAP, r t, 4 h, 95 %;
(c) (CH3CO)2O, CH3COOH, CrO3, CH2Cl2, reflux, 10 min,
53 %; (d) NH2OHÁHCl, CH3COONa, C2H5OH, reflux, 6 h,
81 %; (e) 10 % NaOH, C2H5OH, reflux, 4 h, 84 %;
(f) NH2OHÁHCl, CH3COONa, C2H5OH, reflux, 6 h, 88 %.
For the synthesis of target compounds 4–7, a synthetic
route was worked out starting from dehydroisoandroster-
one (1) (see Scheme 1).
Preparation of 3,5(6)-androstadien-7-one oxime (7)
Using the same method described for compound 5, com-
pound 3,5(6)-androstadien-7-one (6) (0.78 g, 2.7 mmol)
was converted to 3,5(6)-androstadien-7-one oxime (7)
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Med Chem Res (2014) 23:1839–1843
Scheme 1 Preparation of (3b)-
3-acetyloxy-5(6)-androsten-7-
one oxime and 3,5(6)-
O
a
b
androstadien-7-one oxime
HO
HO
AcO
2
3
1
c
d
AcO
O
AcO
NOH
5
4
f
e
4
NOH
O
7
6
Compound 1 was first converted to androst-5-en-3b-ol (2)
in 70 % yield via the Wolf-Kishner reduction. Then com-
pound 2 was esterified with acetic anhydride and pyridine in
the presence of a catalytic amount DMAP to give androst-5-
en-3b-yl acetate (3) in 95 % yield. The compound 3 was
oxidized using chromium trioxide in the presence of acetic
anhydride and acetic acid to generate rapidly the keto steroid
derivative 4 in 53 % yield. The keto steroid derivative 4 was
treated with hydroxylamine hydrochloride in the presence of
sodium acetate in ethanol under reflux to afford the desired
target product 5 in 81 % yield. Then compound 4 was
hydrolyzed with 10 % sodium hydroxide in ethanol to yield
the corresponding 3,5(6)-androstadien-7-one (6). Finally,
compound 6 was reacted with hydroxylamine hydrochloride
to result in the desired conjugated diene oxime product 7 in
88 % yield. According to the experimental results, the
mechanism for the formation of compound 6 from com-
pound 4 can be explained for the first formation of inter-
mediate negative ion from compound 4 with an active a-
methylene group attached bya strong base hydroxide radical,
and the subsequent keto-enol tautomerism of the interme-
diate negative ion gives a steroid 4,5(6)-dienol as an anion,
then the enol-keto tautomerism of the enol forms the ketone
form, followed by loss of acetate radical affords the corre-
sponding product 6.
Table 1 The in vitro cytotoxic activity (IC50, in lM) of compounds
against human carcinoma cell lines (KB, HeLa, MKN-28, and MCF-7)
Compound
Cancer cell lines
KB HeLa
IC50 (lM)
MKN-28
MCF-7
4
5
6
7
62.0 3.2 34.0 2.6 48.5 1.8 39.5 4.2
26.0 1.6 12.8 1.0 18.1 0.2 10.2 1.2
[80
28.5 1.5 22.2 1.4 36.1 1.6 19.8 2.6
0.30 0.22 0.19
62.4 2.2 64.3 1.4 52.2 1.8
Doxorubicin 0.028
The results are the average mean of eight replicate determinations
SD
KB human epidermoid carcinoma, HeLa human cervical carcinoma,
MKN-28 human gastric cancer, MCF-7 human breast cancer
aromatase inhibitory activity. Some studies demonstrated
that the cytotoxicity of these compounds against cancer
cells is dependent on the chemical structure of the parental
steroid and the location of the hydroximino group on the
steroidal nucleus (Cui et al., 2008, 2009a, b; Dubey et al.,
2008; Huang et al., 2011). Moreover, some steroidal
compounds with a,b-unsaturated ketone core also gave the
potency against human cancer cell lines (Jiang et al., 2010;
Li et al., 2010; Wang et al., 2011). Thus, compounds 4–7,
as described above, were subjected to in vitro cytotoxic
evaluation against KB (human epidermoid carcinoma),
The natural and synthetic steroidal oximes exhibited
valuable biological activities such as cytotoxicity and
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1843
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showed a measurable anti-cancer activity against KB,
HeLa, MKN-28, and MCF-7 cell lines tested. Although this
is a preliminary screening, the results showed compound 6
containing only 3,5(6)-diene-7-ketone group without hy-
droximino group was found inactive to KB cell tested (IC50
value [80 lM) and lower active to HeLa, MKN-28, and
MCF-7 cell lines tested. Similar results were found for the
compound 4 containing 3-acetoxyl group and 5(6)-en-7-
ketone group without hydroximino group for all cell lines.
However, the cytotoxicity data of compound 5 possessing
3-acetoxyl group and 5(6)-en-7-hydroximino group
showed significant cytotoxicity activity (IC50 value
26.0 1.6, 12.8 1.0, 18.1 0.2, 10.2 1.2 lM for
KB, HeLa, MKN-28, and MCF-7, respectively). Similar
results were also found for the compound 7 containing
3,5(6)-diene-7-ketone oxime group without 3-acetoxyl
group for all cell lines. The above results indicated that the
3-acetoxyl group and 7-hydroximino group must be present
to retain cytotoxic activity. This may indicate that the
anticancer properties depend not only on hydroximino
group but also on the moieties attached to 3-acetoxyl
group.
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Conclusions
In this study, (3b)-3-acetyloxy-5(6)-androsten-7-one oxime
and 3,5(6)-androstadien-7-one oxime were synthesized and
their in vitro cytotoxic activities against human epidermoid
carcinoma cell line KB, human cervical carcinoma cell line
HeLa, human gastric carcinoma cell line MKN-28, and
human breast carcinoma cell line MCF-7 were evaluated.
The compound (3b)-3-acetyloxy-5(6)-androsten-7-one
oxime exhibited significant growth inhibitory properties
against cell lines tested and afforded IC50 value
26.0 1.6, 12.8 1.0, 18.1 0.2, 10.2 1.2 lM for
KB, HeLa, MKN-28, and MCF-7, respectively. Further
research on the structure–activity relationship, their possi-
ble mechanism of inhibiting proliferation of cancer cell
lines is ongoing and the information obtained from the
studies may be useful for the design of promising anti-
cancer agents.
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Acknowledgments Financial support of this research by the National
Natural Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged by authors. A Project Funded by the Priority Academic
Program Development of Jiangsu Higher Education Institutions.
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