Synthesis and cytotoxic activities of semisynthetic zearalenone analogues

Article abstract of DOI:10.1016/j.bmcl.2016.06.007

Zearalenone is a β-resorcylic acid macrolide with various biological activities. Herein we report the synthesis and cytotoxic activities of 34 zearalenone analogues against human oral epidermoid carcinoma (KB) and human breast adenocarcinoma (MCF-7) cells as well as noncancerous Vero cells. Some zearalenone analogues showed moderately enhanced cytotoxic activities against the two cancer cell lines. We have discovered the potential lead compounds with diminished or no cytotoxicity to Vero cells. Preliminary structure–activity relationship studies revealed that the double bond at the 1′ and 2′ positions of zearalenone core was crucial for cytotoxic activities on both cell lines. In addition, for zearalenol analogues, the unprotected hydroxyl group at C-2 and an alkoxy substituent at C-4 played key roles on cytotoxic effects of both cell lines.

Full text of DOI:10.1016/j.bmcl.2016.06.007

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and cytotoxic activities of semisynthetic zearalenone
analogues
a
a
a
Kwanruthai Tadpetch a, , Benyapa Kaewmee , Kittisak Chantakaew , Kawalee Kantee ,
⇑
Vatcharin Rukachaisirikul a, Souwalak Phongpaichit b
a Department of Chemistry and Center of Excellence for Innnovation in Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
b Department of Microbiology and Natural Products Research Center of Excellence, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Zearalenone is a b-resorcylic acid macrolide with various biological activities. Herein we report the syn-
thesis and cytotoxic activities of 34 zearalenone analogues against human oral epidermoid carcinoma
(KB) and human breast adenocarcinoma (MCF-7) cells as well as noncancerous Vero cells. Some zear-
alenone analogues showed moderately enhanced cytotoxic activities against the two cancer cell lines.
We have discovered the potential lead compounds with diminished or no cytotoxicity to Vero cells.
Preliminary structure–activity relationship studies revealed that the double bond at the 10 and 20 posi-
tions of zearalenone core was crucial for cytotoxic activities on both cell lines. In addition, for zearalenol
analogues, the unprotected hydroxyl group at C-2 and an alkoxy substituent at C-4 played key roles on
cytotoxic effects of both cell lines.
Received 9 April 2016
Revised 26 May 2016
Accepted 3 June 2016
Available online xxxx
Keywords:
Zearalenone
Structure modification
Cytotoxicity
Structure–activity relationship
Ó 2016 Elsevier Ltd. All rights reserved.
Zearalenone (1) is a b-resorcylic acid macrolactone originally
isolated from the fungus Gibberella zeae (Fusarium graminearum)
by Baldwin et al. in 1962 (Fig. 1).1 Compound 1 has been shown
to exhibit various biological activities2 particulary estrogen agonis-
tic properties3 and anabolic activities.4 Several members of this
class of metabolites are potent protein kinase inhibitors, which
could potentially be developed as anticancer drugs5.
There have been a number of literature precedents for biological
activity studies of zearalenone analogues obtained either from
commercial sources or simple semisyntheses; however, there are
only a few reports on cytotoxic activities of zearalenone deriva-
tives. In 2010, Banjerdpongchai and co-workers reported that zear-
alenone exhibited weak cytotoxic activities against human
exhibited very weak cytotoxicities against the three cancer cell
lines. Only b-OH analogues (b-zearalenol, 2 and b-zearalanol, 3)
displayed moderate cytotoxicity against H460 cell line
(IC50 = 15.4 and 9.5 lM, respectively) (Fig. 2). Several structure–
activity relationship (SAR) studies of related resorcylic acid
lactones for protein kinase inhibition have been disclosed. These
studies suggested that the Z-enone moiety at the 70–80 positions
was important for highly potent kinase inhibitory activity. In addi-
tion, reduction of the enone functionality to allylic alcohol led to
reduction in potency of kinase inhibition.8 In 2011, Murphy and
co-workers found that isosteric replacement of the Z-enone in
RALS with the E-enone (4) resulted in more potent kinase inhibi-
tors of a subset of kinases containing a conserved cysteine
(Fig. 2). Chai et al. also explored SAR for the inhibition of protein
kinases related to cancer pathways by aigialomycin D (5) and a ser-
ies of its analogues, which led to discovery that an unprotected
resorcinol motif and a double bond at the 10 and 20 positions are
crucial for such activity (Fig. 2).9
As part of ongoing search for biologically active compounds
from fungi, our group has found that zearalenone is a major
secondary metabolite produced by the seagrass-derived fungus
Fusarium sp. PSU-ES123 and the para rubber-derived fungus
Fusarium sp. PSU-H266. Due to therapeutic potentials and avail-
ability in a large quantity of zearalenone, we pursued the chemical
structure modification of zearalenone obtained from these fungi
and evaluated cytotoxic activities of zearalenone analogues against
leukemia HL-60 cells with an IC50 of 138.21 lM and discovered
that 1 induced leukemic cell apoptosis by endoplasmic stress and
mitochondrial pathway.6 In 2011, Oberlies et al. disclosed studies
on cytotoxic and NF-
lactones including zearalenone analogues.7 In their studies, zear-
alenone (1) and analogues: -zearalenol, b-zearalenol, -zear-
jB inhibitory activities of 12 resorcylic acid
a
a
alanol and b-zearalanol were assayed against three cancer cell
lines: MCF-7 human breast carcinoma, NCI-H460 human large cell
lung carcinoma and SF-268 human astrocytoma. These compounds
⇑
Corresponding author. Tel.: +66 74 288437; fax: +66 74 558841.
E-mail address: kwanruthai.t@psu.ac.th (K. Tadpetch).
http://dx.doi.org/10.1016/j.bmcl.2016.06.007
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tadpetch, K.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.007

2
K. Tadpetch et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
11'
3'
derivatives of 15 (16 and 17) were also prepared using the same
reaction conditions for preparation of 6 and 7.
OH
O
1
9'
3
7'
O
12'
The second series of zearalenone analogues were the corre-
sponding alcohols (Scheme 2). Reduction of the ketone functional-
ity of 1 with NaBH4 in methanol at 0 °C led to the formation of a
mixture of alcohol diastereomers which could be separated by
reverse phase column chromatography (70% MeOH/H2O as an elu-
5'
HO
O
5
1'
zearalenone (1)
Figure 1. Structure of zearalenone (1).
ent) to afford b- (2) and
a-zearalenol (18) in 58% and 29% yield,
respectively. Alkylation of the 4-hydroxy group of 2 and 18 was
achieved using iodomethane, iodoethane or iodopropane in the
presence of K2CO3 in acetone at room temperature or 1-bromooc-
tane and K2CO3 in refluxing acetone to provide derivatives 19–23
and 26–30, respectively. Acetylation and propionylation of the
hydroxyl group at the 4-position of 2 and 18 were accomplished
utilizing the same procedure for preparation of compounds 8 and
10 to give compounds 24–25 and 31–32. In order to identify the
importance of the double bond at 10 and 20 positions of zearalenol
two cancer cell lines in comparison with noncancerous Vero cells
(African green monkey kidney fibroblasts).
The first series of zearalenone analogues were synthesized by
methylation and acylation as shown in Scheme 1. Monomethyla-
tion of the hydroxyl group at the 4-position and bismethylation
of the 2- and 4-hydroxyl groups of 1 were performed by treatment
with 4 equiv and 10 equiv of iodomethane in the presence of K2CO3
in acetone at room temperature to deliver 4-methoxyzearalenone
(6) and 2,4-dimethoxyzearalenone (7), respectively. Acetylation
of the hydroxyl group at the 4-position or both hydroxyl groups
was achieved by reacting 1 with 1 and 3 equiv of acetic anhydride
in pyridine in CH2Cl2 to give acetylated analogues 8 and 9. Simi-
larly, propionylated derivatives 10 and 11 were prepared by a sim-
ilar procedure using 1 and 2 equiv of propionyl chloride in the
presence of Et3N in THF, respectively. The 5-chlorinated analogues
12–14 were also synthesized by treatment of compounds 1, 6 and
7 with N-chlorosuccinimide in DMF at room temperature10 in
order to evaluate the effect of a Cl atom which has been previously
shown to enhance cytotoxicity of some RALs against MCF-7 breast
cancer cells.11 In addition, zearalanone (15) could be obtained by
catalytic hydrogenation of 1. Methylated and bismethylated
derivatives, both b- (3) and
a-zearalanols (35) and their methy-
lated analogues 33–34 and 36–37 were prepared via catalytic
hydrogenation and methylation of the corresponding parent com-
pounds (Scheme 3). With the aforementioned chemical transfor-
mations, 34 zearalenone analogues were obtained.
Zearalenone and its analogues 2, 3 and 6–37 were evaluated for
cytotoxic activities against two cancer cell lines: human oral epi-
dermoid carcinoma (KB) and human breast adenocarcinoma
(MCF-7) cells using the resazurin microplate assay (REMA)12 as
well as against noncancerous Vero cells (African green monkey
kidney fibroblasts) using the green fluorescent protein (GFP)-based
assay.13 Ellipticine, doxorubicin and tamoxifen were used as
Only β-OH analogues
shows cytotoxicity against
H460 cell line.
OH
O
OH
O
O
O
6'
6'
HO
OH
HO
OH
2
3
)
β-zearalenol (
)
β-zearalanol (
Unprotected
resorcinol motif
is essential for
protein kinase
inhibition.
Enone is essential for
OH
1
O
kinase inhibition. E-enone is
more active than Z-enone.
OH
O
3
O
1'
O
HO
7'
5
MeO
8'
Double bond
is required for
this activity.
OH
2'
O
OH
4
5
)
aigialomycin D (
Figure 2. Structural effects of zearalenone analogues on cytotoxicity against H460 cell line and on protein kinase inhibition.
OR1
Cl
O
OR1
O
OH
O
O
O
d
O
a, b or c
R2O
O
R2O
O
HO
O
: R1 = H, R2 = Me; 92%
1
6
: R1 = Me, R2 = Me; 98%
12
13
7
: R1 = H, R2 = H; 32%
: R1 = H, R2 = Me; 88%
8: R1 = H, R2 = Ac; 78%
9: R1 = Ac, R2 = Ac; 99%
14: R1 = Me, R2 = Me; 56%
e
: R1 = H, R2 = propionyl; 62%
10
11
: R1 = propionyl, R2 = propionyl; 70%
OR1
OH
O
O
O
O
a
HO
O
R2O
O
: R1 = H, R2 = Me; 85%
15
(96%)
16
17
: R1 = Me, R2 = Me; 94%
Scheme 1. Reagents and conditions: (a) iodomethane, K2CO3, acetone, rt; (b) Ac2O, pyridine, CH2Cl2, 0 °C to rt; (c) propionyl chloride, Et3N, THF, 0 °C to rt; (d)
N-chlorosuccinimide, DMF, rt; (e) H2, Pd/C (4 mol %), EtOH, rt.
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K. Tadpetch et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
OH
O
OH
O
OH
O
NaBH4
O
O
O
+
MeOH, 0 °C to rt
(reverse phase CC)
HO
O
HO
OH
HO
OH
OH
1
18
(29%)
a, b or c
2 (58%)
a, b or c
OR1
O
OR1
O
O
O
R2O
OH
R2O
19: R1 = H, R2 = Me; 68%
20: R1 = Me, R2 = Me; 64%
21: R1 = H, R2 = Et; 83%
26: R1 = H, R2 = Me; 88%
: R1 = Me, R2 = Me; 52%
: R1 = H, R2 = Et; 85%
: R1 = H, R2 = Pr; 61%
27
28
29
: R1 = H, R2 = Pr; 96%
: R1 = H, R2 = Oct; 57%
22
23
30: R1 = H, R2 = Oct; 60%
31: R1 = H, R2 = Ac; 61%
24: R1 = H, R2 = Ac; 71%
25: R1 = H; R2 = propionyl; 51%
: R1 = H; R2 = propionyl; 59%
32
Scheme 2. Reagents and conditions: (a) iodomethane or iodoethane or iodopropane, K2CO3, acetone, rt; (b) 1-bromooctane, K2CO3, acetone, reflux; (c) Ac2O, pyridine, CH2Cl2,
0 °C to rt or propionyl chloride, Et3N, THF, 0 °C to rt.
OR1
O
OH
O
OH
O
H2, Pd/C
a
O
O
O
EtOH, rt, 97%
R2O
OH
HO
OH
HO
OH
3
33: R1 = H, R2 = Me; 58%
2
34: R1 = Me, R2 = Me; 73%
OR1
O
OR1
O
H2, Pd/C
EtOH, rt
O
O
R2O
OH
R2O
OH
: R1 = H, R2 = H
26: R1 = H, R2 = Me
27: R1 = Me, R2 = Me
: R1 = H, R2 = H; 79%
35
18
36: R1 = H, R2 = Me; 99%
37: R1 = Me, R2 = Me; 93%
Scheme 3. Reagents and conditions: (a) iodomethane, K2CO3, acetone, rt.
positive controls. The cytotoxic activities of all compounds tested
were expressed as IC50 values in M as shown in Table 1.
relationship was also consistent with Chai’s observation on SAR
of RALs on kinase inhibition activity.9
l
The parent compound 1 exhibited weak cytotoxic activities
against KB and MCF-7 cells with IC50 values of 46.30 and
For cytotoxicity against MCF-7 breast cancer cells, the impor-
tance of the double bond at the 10 and 20 positions on cytotoxic
activity against this cancer cell line was still realized. All ketone
analogues (6–17) were inactive toward this cell line. Only three
b-zearalenol analogues with alkoxy substituents at the 4-position,
4-ethoxy b-zearalenol (21), 4-propoxy b-zearalenol (22) and
4-octoxy b-zearalenol (23), were active against this cancer cell line
104.72
(IC50 = 40.58
l
M, respectively, while being more cytotoxic to Vero cells
M). To the best of our knowledge, this is the first Let-
l
ter on cytotoxic activity of zearalenone toward human oral carci-
noma cells. For cytotoxic activity against KB cells, three
zearalenol derivatives, 4-propionoxy b-zearalenol (25), 4-propoxy
a
-zearalenol (29) and 4-octoxy
enhanced cytotoxicity with the IC50 values of 33.42, 35.70 and
40.87 M, respectively (entries 21, 29 and 30); however, the cyto-
a
-zearalenol (30), showed
with IC50 values of 70.23, 81.88 and 93.64 lM, respectively (entries
17–19), which was 1.1- to 1.5-fold more potent than 1. Neverthe-
less, compounds 21–23 were still cytotoxic to Vero cells although
l
toxicity of these compounds to Vero cells also increased. It should
be noted that although 4-acetoxyzearalenone (8) and 4-acetoxy
not as strong as 1. Similar to b-zearalenol analogues, five
alenol derivatives with alkoxy or alkanoyloxy side chains at the
4-position including 4-methoxy -zearalenol (26) 4-ethoxy
-zearalenol (29) and 4-octoxy
-zearalenol (30) and 4-acetoxy -zearalenol (31) exhibited
a-zear-
a-zearalenol (31) displayed similar level of cytotoxicity to that of
a
1 (IC50 = 52.86 and 51.63 M, respectively, entries 4 and 31), they
l
a
a
-zearalenol (28), 4-propoxy a
were approximately 3.3-fold less cytotoxic to Vero cells compared
a
to 1. Interestingly, 4-methoxy b-zearalenol (19) exhibited 1.2-fold
enhanced cytotoxicity against MCF-7 cells with IC50 values of
weaker cytotoxic activity (IC50 = 55.98
lM, entry 15) compared to
93.33, 61.76, 43.78, 75.22 and 89.01 M, respectively (entries 26
l
that of 1 without cytotoxicity against Vero cells. The Cl atom at
the 5-position seemed to decrease cytotoxicity in all cell lines
including Vero cells (entries 8–10). In addition, it was clear from
these results that the double bond at the 10 and 20 positions was
required for cytotoxic activity as the saturated analogues, zear-
alanones 15–17 and zearalanols 3, 33–34 and 35–37, were all inac-
tive. These results also suggested that the unprotected hydroxyl
group at the 2-position was important for cytotoxicity since 2,4-
dimethoxy analogues 7, 14, 20 and 27 were inactive against this
cancer cell line (entries 3, 10, 16 and 27). This structure–activity
and 28–31). These analogues were 1.1- to 2.4-fold more potent
that the parent 1. It is worth noting that compound 28 was 1.7-fold
more cytotoxic to MCF-7 cells compared to
1 while being
non-cytotoxic to Vero cells and compound 31 was approximately
3.3-fold less cytotoxic to Vero cells compared to 1. These results
strongly suggested that an alkoxy group at the 4-position played
an important role on cytotoxic activity against MCF-7 breast cancer
cells of zearalenol analogues. Additionally, the effect of a free
hydroxyl group at the 2-position of zearalenol derivatives on
cytotoxicity against this cancer cell line was similarly observed.
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K. Tadpetch et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
Cytotoxic activities of compounds 1–3 and 6–37 against KB, MCF-7 and Vero cells
OR1
O
O
R2O
R
R3
Entry
Compound
Cytotoxicity, IC50 (lM)
R
C10AC20
C@C
R1
R2
R3
KB cells
MCF-7 cells
Vero cells
1
1
C@O
H
H
Me
H
Ac
H
Propionyl
H
H
Me
H
H
Me
Me
Ac
Ac
Propionyl
Propionyl
H
Me
Me
H
Me
Me
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
H
46.30
n.a.
n.a.
52.86
59.66
52.35
n.a.
89.85
108.41
n.a.
104.72
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
40.58
n.a.
n.a.
133.77
47.96
44.12
n.a.
140.27
51.44
n.a.
2
6
3
7
4
8
5
9
6
7
8
9
10
11
12
13
10
11
12
13
14
15
16
17
CAC
C@C
n.a.
n.a.
n.a.
151.26
n.a.
n.a.
H
Me
14
15
16
17
18
19
20
21
22
23
24
2
b-OH
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
n.a.
55.98
n.a.
60.10
83.40
82.16
48.92
33.42
n.a.
n.a.
n.a.
n.a.
70.23
81.88
93.64
n.a.
n.a.
n.a.
25.38
n.a.
n.a.
19
20
21
22
23
24
25
3
Me
Me
Et
Pr
Oct
Ac
Propionyl
H
Me
Me
45.26
53.30
73.35
13.63
35.01
22.61
147.97
n.a.
CAC
C@C
33
34
H
Me
n.a.
n.a.
n.a.
n.a.
25
26
27
28
29
30
31
32
33
34
35
18
26
27
28
29
30
31
32
35
36
37
a
-OH
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
100.29
103.71
n.a.
66.93
35.70
40.87
51.63
85.72
n.a.
n.a.
93.33
n.a.
61.76
43.78
75.22
89.01
n.a.
60.33
53.14
n.a.
Me
Me
Et
Pr
Oct
Ac
Propionyl
H
Me
Me
n.a.
26.21
24.20
136.22
129.26
50.00
n.a.
CAC
n.a.
n.a.
n.a.
H
Me
n.a.
n.a.
n.a.
36
37
38
Ellipticinea
8.28
1.06
4.26
Doxorubicina
Tamoxifena
15.69
19.33
n.a. refers to ‘not active’ which is indicative of no inhibition at >50
lg/mL of a compound tested.
a
Positive controls for cytotoxicity assays.
In term of selectivity toward each cell line, it was observed that
all derivatives that possessed cytotoxicity against MCF-7 cells were
also cytotoxic against KB cells. However, all cytotoxic ketone ana-
logues specifically displayed cytotoxicity to KB cells, but not to
MCF-7 cells. Nevertheless, this observation did not apply to the alco-
hol series as only 5 zearalenol analogues, 4-methoxy b-zearalenol
(19), 4-acetoxy b-zearalenol (24), 4-propionoxy b-zearalenol (25),
substituents on enhancing cytotoxicity was particularly more pro-
nounced in MCF-7 cell line. Our investigation also indicated that
some analogues showed potential cytotoxic activities against the
two cancer cells with diminished or no cytotoxicity to Vero cells
even though all of these compounds were less potent than the
standard drugs, ellipticine, doxorubicin or tamoxifen. Analogues
8, 19 and 31 displayed comparable cytotoxic activity against KB
cells to that of the parent zearalenone, while compounds 28 and
31 exhibited improved cytotoxic activity against MCF-7 cell line
compared to that of 1 with low or no cytotoxicity to Vero cells.
a-zearalenol (18) and 4-propioxy a-zearalenol (32), were selec-
tively cytotoxic to the KB cell line (entries 15, 20, 21, 25 and 32).
In conclusion, we herein report the synthesis of 34 analogues of
zearalenone by simple chemical modification. These analogues
were evaluated for their cytotoxic activities against KB and MCF-
7 cancer cell lines along with noncancerous Vero cells. The prelim-
inary SAR studies revealed that the double bond at the 10 and 20
positions and the unprotected hydroxyl group at C-2 of zear-
alenone core were crucial for cytotoxic activities to both cell lines.
However, a Cl substituent at the 5-position seemed to decrease
cytotoxic activity toward KB cell. In addition, for zearalenol ana-
logues, alkoxy and alkanoyloxy substituents at C-4 played key roles
on cytotoxic effects of both cell lines. Effect of 4-alkoxy
Acknowledgements
This work was financially supported by The Thailand Research
Fund (Grant No. DBG5680001). V.R. thanks the NSTDA Chair Pro-
fessor grant (the Fourth Grant) of the Crown Property Bureau Foun-
dation and the National Science and Technology Development
Agency. Center of Excellence for Innovation in Chemistry
(PERCH-CIC) is acknowledged for partial support. Additional sup-
port was generously provided by the Development and Promotion
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K. Tadpetch et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
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