Insecticidal activity of twin compounds from podophyllotoxin and cytisine

Article abstract of DOI:10.1016/j.bmcl.2021.128104

To explore natural-product-based insecticide candidates, and high value-added application of natural plants in agriculture, a series of twin compounds were prepared from two natural products podophyllotoxin and cytisine, which are isolated from the plants

Full text of DOI:10.1016/j.bmcl.2021.128104

Bioorg. Med. Chem. Lett. 43 (2021) 128104
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Insecticidal activity of twin compounds from podophyllotoxin and cytisine
*
*
Yuanyuan Zhang, Min Lv , Hui Xu
College of Plant Protection/Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
To explore natural-product-based insecticide candidates, and high value-added application of natural plants in
agriculture, a series of twin compounds were prepared from two natural products podophyllotoxin and cytisine,
which are isolated from the plants Podophyllum hexandrum and Thermopsis lanceolata, respectively. Compounds
Twin insecticides
Botanical bioactive product
Insecticidal activity
Podophyllum hexandrum
Thermopsis lanceolata
1
2
1
2
1
2
IIa (X = Cl, Y = R = R = H), IIIc (X = Y = R = R = Cl) and IVd (X = R = R = Br, Y = H) exhibited >2-fold
potent insecticidal activity of podophyllotoxin against armyworm with FMRs greater than 60%. SARs were also
observed. It is noteworthy that the idea of twin insecticides was addressed for the first time. We hope this idea
will be conducive to design new twin insecticidal agents, and lay the foundation for future high value-added
application of the plants P. hexandrum and T. lanceolata as potentially botanical pesticides in agriculture.
′
′
′
Podophyllotoxin (1, Fig. 1) is isolated as a naturally occurring aryl-
tetralin lignan from Podophyllum hexandrum. Compound 1 is used as a
lead compound for development of potent medicinal drugs and agro-
As depicted in Scheme 1, 2 (2 ,6 )-(di)halogenopodophyllotoxins
(2–4) were prepared in 81%–85% yields according to our previous
method.5 5(3,5)-(Di)halogenocytisines (9b–d) were halogenated from
chemical agents.1 Previously, we found that some esters of 2 (2 ,6 )-
–4
′
′
′
cytisine (9a). Then compounds 1–4 reacted with succinic anhydride in
8
1
9
(
di)halogenopodophyllotoxins (2–4, Fig. 1) exhibited more pronounced
the presence of Et
3
N and DMAP to give intermediates 5–8. Finally,
insecticidal activity than toosendanin (Fig. 1, a botanical insecticide
registered in China) isolated from Melia azedarach.5 Once C2 -halogen
atom is introduced into compound 1, free rotation of its E-ring around
compounds 5–8 reacting with different 9a–d afforded podophyllotoxin-
′
20
cytisine hydrids (I–IV) in 14%–60% yields. Their structures were well
1
characterized by melting points, optical rotation, IR, HRMS, and
H
′
6
21
C1-C1 bond will be restricted (Fig. 1). interestingly, it can result in no
NMR (see Supplementary data).
′
significant cytotoxicity of corresponding C2 -halogenopodophyllotoxins
The insecticidal activity of compounds 1–9 and I–IV at 1 mg/mL was
tested against the pre-third-instar larvae of M. separata by leaf-dipping
7
derivatives. Cytisine (Fig. 1) is isolated from Thermopsis lanceolata, and
method.2
2,23
The toxic symptoms of M. separata treated by compounds
some derivatives of 5 (3,5)-(di)halogenocytisines showed potent pesti-
cidal activities.8 On the other hand, products containing the succinic
acid fragment usually displayed promising activities such as inhibitors
,9
6,22,23
1–9 and I–IV were the same as our previous reports.
Among all
derivatives, compounds 3, 9c, 9d, Ib, Ic, IIa, IIIb, IIIc, IIId, IVa, IVb and
IVd exhibited more potent insecticidal activity than toosendanin. The
final mortality rates (FMRs) of compounds 3, 9c, 9d, Ib, Ic, IIa, IIIb, IIIc,
IIId, IVa, IVb and IVd against M. separata were 55.2%, 48.3%, 51.7%,
55.2%, 51.7%, 65.5%, 48.3%, 62.1%, 48.3%, 55.2%, 55.2%, 55.2%, and
62.1%, respectively; however, the FMRs of two lead compounds 1 and
9a, and toosendanin were 31.0%, 37.9%, and 44.8%, respectively.
1
0,11
of interleukin-1β converting enzyme and anti-tumor activity;
moreover, their characteristics such as the high-affinity binding and the
deliverable ability were improved.12,13
Additionally, because of their high diversity and inherent biological
activities, chemical structural optimization of natural products has been
a
fascinating approach to obtain pesticide candidates in recent
1
4–17
1
2
1
years.
In the present paper, in continuation of our program to
Especially compounds IIa (X = Cl, Y = R = R = H), IIIc (X = Y = R =
2 1 2
discover new potential pesticidal agents, therefore, twin compounds of
R = Cl) and IVd (X = R = R = Br, Y = H) showed the most pronounced
′
′
podophyllotoxin and cytisine (I–IV, Fig. 1) were designed by insertion of
insecticidal activity. 2 ,6 -Dichloropodophyllotoxins (3 and 7) displayed
′
′
′
′
the
succinic
acid
fragment
between
2 (2 ,6 )-(di)halogen-
more potent activity than that of podophyllotoxins (1 and 5), 2 -chlor-
′
opodophyllotoxins and 5(3,5)-(di)halogenocytisines. Their insecticidal
activity was tested against one threatening lepidopteran pest, Mythimna
separata Walker.18
opodophyllotoxins (2 and 6) and 2 -bromopodophyllotoxins (4 and 8). It
′
′
suggested that introduction of two chlorine atoms at the C-2 and C-6
positions of podophyllotoxin was necessary for the insecticidal activity
*
Corresponding authors.
E-mail addresses: lvmin@nwsuaf.edu.cn (M. Lv), orgxuhui@nwsuaf.edu.cn (H. Xu).
https://doi.org/10.1016/j.bmcl.2021.128104
Received 11 March 2021; Received in revised form 26 April 2021; Accepted 5 May 2021
Available online 10 May 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

Y. Zhang et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128104
Fig. 1. Design of twin compounds from podophyllotoxin and cytisine isolated from Podophyllum hexandrum and Thermopsis lanceolata.
2

Y. Zhang et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128104
Scheme 1. Preparation of podophyllotoxin-cytisine twin insecticides (I–IV).
3

Y. Zhang et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128104
Table 1
Insecticidal activity of compounds 1–9 and I–IV against the pre-third-
instar larvae of M. separata.
Compound
Final mortality rate (mean ± SE, %)
1
2
3
4
5
6
7
8
31.0 ± 3.3
44.8 ± 3.3
55.2 ± 3.3
37.9 ± 5.8
31.0 ± 3.3
34.5 ± 3.3
41.4 ± 3.3
31.0 ± 3.3
37.9 ± 5.8
41.4 ± 3.3
48.3 ± 0
9
9
9
9
a
b
c
d
51.7 ± 3.3
37.9 ± 0
Fig. 3. Lethal time for 50% mortality of M. separata treated with compounds
Ib, Ic, IIa, IIIc, IVa, IVb and IVd.
Ia
Ib
55.2 ± 3.3
51.7 ± 3.3
41.4 ± 3.3
65.5 ± 3.3
41.4 ± 6.7
41.4 ± 3.3
48.3 ± 0
Ic
atoms on the cytisine was adverse to the insecticidal activity (e.g., IVc
Vs. IVa, IVb and IVd). Therefore, the insecticidal activity of
podophyllotoxin-cytisine hydrids (I–IV) was not only depended on the
halogenation of podophyllotoxin, but also related to the halogenation of
cytisine.
Id
IIa
IIc
IId
IIIb
IIIc
IIId
IVa
IVb
IVc
IVd
toosendanin
62.1 ± 3.3
48.3 ± 5.8
55.2 ± 3.3
55.2 ± 3.3
41.4 ± 3.3
62.1 ± 3.3
44.8 ± 3.3
The percentages of FMRs at three growth stages of M. separata
treated with compounds Ib, Ic, IIa, IIIc, IVa, IVb, IVd and toosendanin
were shown in Fig. 2. Except compound IVd, the percentages of FMRs at
the pupal stage of of M. separata treated with compounds Ib, Ic, IIa, IIIc,
IVa and IVb were greater than 36.8%, and their largest parts of FMRs
were at the pupal stage. But the largest part of FMR of of M. separata
treated with toosendanin was at the larval stage. It suggested that
compounds Ib, Ic, IIa, IIIc, IVa and IVb may show the different mech-
anism of action against M. separata when compared with toosendanin.
As described in Fig. 3, the lethal time for 50% mortality of M. separata
treated with compounds Ib, Ic, IIa, IIIc, IVa, IVb and IVd a was 30, 29,
28, 28, 28, 30, and 28 days, respectively. These were further demon-
strated that these podophyllotoxin-cytisine hydrids showed delayed
insecticidal activity against M. separata.
(
Table 1).
To podophyllotoxin-cytisine twins (I–IV), in general, the insecticidal
′
′
′
activity of derivatives of 2 ,6 -dichloropodophyllotoxin (III) and 2 -
bromopodophyllotoxin (IV) was more potent than that of derivatives of
′
podophyllotoxin (I) and 2 -chloropodophyllotoxin (II). To podophyllo-
toxin derivatives (I), introduction of the chlorine atom on the cytisine
was important for the insecticidal activity (e.g., Ib and Ic Vs. Ia and Id);
′
to 2 -chloropodophyllotoxin derivatives (II), however, introduction of
In conclusion, to discover potential pesticide candidates from
bioactive natural products, twin insecticides I–IV were semi-prepared
from cytisine and podophyllotoxin. Compounds IIa, IIIc and IVd dis-
played greater than 2-fold pronounced insecticidal activity of podo-
phyllotoxin against armyworm. It demonstrated that introduction of two
the halogen atom on the cytisine was adverse to the insecticidal activity
′
′
(
e.g., IIa Vs. IIc and IId); to 2 ,6 -dichloropodophyllotoxin derivatives
(
III), introduction of two chlorine atoms on the cytisine was necessary to
′
the insecticidal activity (e.g., IIIc Vs. IIIb and IIId); To 2 -bromopodo-
phyllotoxin derivatives (IV), however, introduction of two chlorine
′
′
chlorine atoms at the C-2 and C-6 positions of podophyllotoxin was
Fig. 2. The percentages of FMRa at three different growth stages of M. separata treated with compounds Ib, Ic, IIa, IIIc, IVa, IVb, IVd and toosendanin.
4

Y. Zhang et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128104
necessary for the insecticidal activity; the halogen atom played an
important role for cytisines exhibiting good insecticidal activity; the
insecticidal activity of these twin insecticides was related to the halo-
genation (including the halogen atoms and their number) of podo-
phyllotoxin and cytisine. Most notably, the idea of twin insecticides for
future high value-added application of natural plants in agriculture was
addressed for the first time.
5
6
7
8
9
Che ZP, Yu X, Zhi XY, Fan LL, Xu H. J Agric Food Chem. 2013;61:8148–8155.
Che ZP, Yu X, Fan LL, Xu H. Bioorg Med Chem Lett. 2013;23:5592–5598.
Hu H, Liu SY, Cheng YC, Lee KH, Wang ZQ. J Med Chem. 1989;35:866–871.
Huang X, Lv M, Xu H. Pest Manag Sci. 2019;75:2598–2609.
Huang X, Xu H. Mini Rev Med Chem. 2020;20:369–395.
1
1
1
0
1
2
Galatsis P, Caprathe B, Gilmore J, et al. Bioorg Med Chem Lett. 2010;20:5184–5190.
Zhou W, Cao J, Wang X, Guo J, Zhao Y. Bioorg Med Chem Lett. 2017;27:1076–1080.
Lam P, Lee KK, Wong RS, et al. Bioorg Med Chem Lett. 2012;22:3213–3218.
13 Moln ´a r T, Visy J, Simon A, et al. Bioorg Med Chem Lett. 2008;18:6290–6292.
1
1
1
1
1
1
2
4
5
6
7
8
9
0
Hou QQ, Jing YF, Shao XS. Chin Chem Lett. 2017;28:1723–1726.
Zhu XL, Zhang R, Wu QY, et al. J Agric Food Chem. 2019;67:2774–2781.
Marrone PG. Pest Manag Sci. 2019;75:2325–2340.
Declaration of Competing Interest
Lv M, Sun ZQ, Li SC, Zhang S, Xu H. Bioorg Med Chem Lett. 2020;30, 127346.
Zhang B, Liu J, Chen X, Yuan G. Entomol Res. 2018;48:390–399.
Sk UH, Dixit D, Sen E. Eur J Med Chem. 2013;68:47–57.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Santos LS, Theoduloz C, Pilli RA, Rodriguez J. Eur J Med Chem. 2009;44:3810–3815.
21 Synthesis of podophyllotoxin-cytisine twin compounds (I–IV): A solution of
compounds 5–8 (0.17 mmol), 9a–d (0.19 mmol), N,N’-diisopropylcarbodiimide (DIC,
0
.24 mmol) and 4-dimethylaminopyridine (DMAP, 0.03 mmol) in dichloromethane
Acknowledgements
(
4 mL) was stirred at room temperature for 0.5–15 h. Then the mixture was diluted
by ethyl acetate (30 mL), washed by 0.1 M aq. HCl (10 mL), 5% aq. NaHCO3 (10 mL)
and brine (10 mL), dried over anhydrous Na2SO4, concentrated, and purified by
preparative thin-layer chromatography (PTLC) to produce compounds I–IV in 14%–
The present research was partly supported by National Natural Sci-
ence Foundation of China (No. 31872013).
6
1
0% yields. Data for Ia: (two rotamers, ratio: 56:44): Yield: 51%, white solid, m.p.
54-156 oC; [
α]20D = ꢀ 42 (c 2.2 mg/mL, CHCl3); IR cm-1 (KBr): 2931, 1735, 1651,
Appendix A. Supplementary data
1579, 1479, 1233, 1124, 996, 867, 799; 1H NMR (500 MHz, CDCl3) δ: 7.27–7.30 (m,
H, H-4’’), 6.80 (s, 0.56H, H-5), 6.77 (s, 0.44H, H-5), 6.50 (s, 1H, H-8), 6.44–6.48
1
(
m, 1H, H-3’’), 6.37 (s, 2H, H-2’, 6’), 6.05–6.08 (m, 1H, H-5’’), 5.95–5.97 (m, 2H,
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128104.
OCH2O), 5.85 (d, J = 6.0 Hz, 0.56H, H-4), 5.83 (d, J = 6.0 Hz, 0.44H, H-4), 4.80 (d,
J = 13.0 Hz, 0.44H), 4.66 (d, J = 13.0 Hz, 0.56H), 4.57 (d, J = 4.0 Hz, 1H, H-1),
4
3
0
2
.33–4.36 (m, 0.45H), 4.14–4.22 (m, 1.58H), 3.99–4.09 (m, 2H), 3.88–3.93 (m, 1H),
.81 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.44 (d, J = 12.5 Hz,
.44H), 3.39 (d, J = 12.5 Hz, 0.56H), 3.10 (s, 0.44H, H-7’’), 3.08 (s, 0.56H, H-7’’),
.77–2.92 (m, 3H), 2.65–2.72 (m, 1H), 2.45–2.62 (m, 4H), 2.03–2.10 (m, 2H, H-8’’).
References
1
2
3
Yu X, Che Z, Xu H. Chem Eur J. 2017;23:4467–4526.
HRMS (ESI): Calcd for C37H38N2O11Na ([M+Na]+), 709.2367; found, 709.2345.
22 Yang RG, Zhang YY, Xu H. Bioorg Med Chem Lett. 2018;28:1410–1416.
23 Hao M, Sun ZQ, Xu JW, Lv M, Xu H. J Agric Food Chem. 2020;68:4131–4143.
Beauperin M, Polat D, Roudesly F, et al. J Organometal Chem. 2017;839:83–90.
Esfandiari M, Sharifi M, Mohamadyar-Toupkanlou F, et al. Plant Cell Tiss Org. 2018;
1
33:51–61.
Nandagopal K, Halder M, Dash B, Nayak S, Jha S. Curr Med Chem. 2018;25:
693–4717.
4
4
5