Synthesis and antitumor activity of new tetrahydrocurcumin derivatives via click reaction

Article abstract of DOI:10.1080/14786419.2021.1931181

Three new derivatives of tetrahydrocurcumin 6, 7 and 9 have been prepared as potent antitumor agents using copper(II)-catalyzed ‘click chemistry’. Their structures were identified using ¹H-NMR, ¹³C-NMR and HRMS techniques. MTT (3-(4,

Full text of DOI:10.1080/14786419.2021.1931181

Natural Product Research
Formerly Natural Product Letters
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Synthesis and antitumor activity of new
tetrahydrocurcumin derivatives via click reaction
Meitao Duan, Ahmed Mahal, Ban Mohammed, Yongyan Zhu, Huaming Tao,
Shaoyu Mai, Maysoon Al-Haideri & Quanhong Zhu
To cite this article: Meitao Duan, Ahmed Mahal, Ban Mohammed, Yongyan Zhu, Huaming
Tao, Shaoyu Mai, Maysoon Al-Haideri & Quanhong Zhu (2021): Synthesis and antitumor
activity of new tetrahydrocurcumin derivatives via click reaction, Natural Product Research, DOI:
10.1080/14786419.2021.1931181
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2021.1931181
Synthesis and antitumor activity of new
tetrahydrocurcumin derivatives via click reaction
Meitao Duana,b, Ahmed Mahalc,d,e , Ban Mohammedc,f, Yongyan Zhua,b
,
Huaming Taoa,b, Shaoyu Maia,b, Maysoon Al-Haideric and Quanhong Zhua,b
aCollege of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People’s Republic
b
of China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou,
c
People’s Republic of China; Department of Medical Biochemical Analysis, College of Health
d
Technology, Cihan University-Erbil, Erbil, Iraq; Key Laboratory of Plant Resources Conservation and
Sustainable Utilization and Guangdong Provincial Key Laboratory of Applied Botany, South China
Botanical Garden, Chinese Academy of Sciences, Guangzhou, People’s Republic of China;
f
eGuangzhou HC Pharmaceutical Co., Ltd, Guangzhou, People’s Republic of China; Environmental
Health and Science Department, College of Science, University of Salahaddin, Erbil, Iraq
ABSTRACT
ARTICLE HISTORY
Received 13 December 2020
Accepted 12 May 2021
Three new derivatives of tetrahydrocurcumin 6, 7 and 9 have
been prepared as potent antitumor agents using copper(II)-cata-
lyzed ‘click chemistry’. Their structures were identified using 1H-
NMR, 13C-NMR and HRMS techniques. MTT (3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide) assay has been carried out
to investigate the in vitro cytotoxicity against human cervical car-
cinoma (HeLa), human lung adenocarcinoma (A549), human hepa-
toma carcinoma (HepG2) and human colon carcinoma (HCT-116).
Compound 6 has showed significant inhibitory activity against
HCT-116 cell line with an IC50 value of 17.86 lM compared to tet-
rahydrocurcumin (50.96lM) and positive control etoposide
(19.48 lM) while showed no inhibitory activity against NCM460
cell line. Compounds 7 showed moderate inhibitory activity com-
pared to tetrahydrocurcumin and etoposide while compound 9
showed no obvious inhibitory activity. The results suggested fur-
ther structure modifications of tetrahydrocurcumin to improve its
anticancer activity.
KEYWORDS
Tetrahydrocurcumin; podo-
phyllotoxin; click reaction;
antitumor activity;
drug discovery
CONTACT Ahmed Mahal
ahmed.mahal@cihanuniversity.edu.iq; Quanhong Zhu
zqh@smu.edu.cn
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14786419.2021.1931181.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

2
M. DUAN ET AL.
1. Introduction
Cancer is a disease in which the cells are getting to be unusual by spreading out of
control and it is the second leading cause of death worldwide. In 2018 and according
to the WHO (World Health Organization 2018), there were 9.6 million deaths due to
cancer diseases. New potential anticancer agents have been prepared utilising molecu-
lar hybridisation method by association of pharmacophoric moieties of different bio-
active molecules (Kamal et al. 2019). This strategy was beneficial to improve the
bioactivity and properties of promising synthesised compounds. The hybrid derivatives
may interact with dual targets to overcome resistance, reduce toxicity and lower
adverse effects (Raghavendra et al. 2018; Hodon et al. 2019).
Natural products play a vital role in drug discovery particularly in the treatment of can-
cer diseases. The major isolated phytochemical from the rhizome of turmeric Curcuma
longa which is a member of the family Zingiberaceae (Lakhan et al. 2015; Roso et al. 2016)
shows potent inhibitory activity against cancer cells (Singh and Khar 2006; Melguizo et al.
2018). Tetrahydrocurcumin, an active metabolite of curcumin in which has been demon-
strated the cytotoxicity as anticancer agent. In vitro studies have investigated the inhibi-
tory activity of tetrahydrocurcumin against human breast cancer (Han et al. 2016); cervical
cancer (Yoysungnoen et al. 2016); colon cancer (Lakowski et al. 2017); Leukemia (Tseng et
al. 2019); lung cancer (Song et al. 2018). Tetrahydrocurcumin was found to have anti-
cancer effects through various mechanisms including decrease of VEGFR levels and ter-
mination of DNA strand elongation (Pan et al. 2020). Tetrahydrocurcumin is a lead
compound compared to curcumin due to its high reactivity, instability and low bioavail-
ability (Baker 2017) and can be more stable under physiological conditions due to lacks
the a,b-double bond conjugated to the carbonyl group (Esatbeyoglu et al. 2012a, 2012b).
Podophyllotoxin (PPT) is a natural product isolated from rhizomes roots of the
podophyllum species (Suzuki et al. 2019). In vitro and in vivo studies were proved that
podophyllotoxin can bind to tubulin and inhibit microtubule polymerisation, block
tumor cell division and thus podophyllotoxin (PPT) possesses antitumor activity (Wang
et al. 2018; Zhang et al. 2018; Atanasova et al. 2019). PPT is also a scaffold of antineo-
plastic drugs such as etoposide, teniposide and etopophos (Zi et al. 2020); Nerella et
al. 2019; Wei et al. 2019).
Zidovudine (8) is indicated as HIV agent and other virus infected diseases.
Meanwhile, it also could bind preferentially to telomeres by inhibiting telomerase and
terminating telomerase DNA strand elongation leading to tumor cell senescence and
apoptosis (Gomez et al. 2012; Berrino et al. 2020). Zidovudine (AZT) has been utilised
in stage I and II clinical trials alone or in combination with other drugs for pancreatic
cancer, gastrointestinal cancers and other progressed malignancies (Gomez et
al. 2012).
Due to the importance of nitrogen containing heterocycles in medicinal chemistry
(Mahal et al 2020 keep it; Salman et al, 2020; Zinad et al. 2020, 2021) and further
chemical modifications of tetrahydrocurcumin have been developed by our group,
new pyrazole and Schiff base derivatives of tetrahydrocurcumin were synthesised.
Most of these derivatives were displayed potent anticancer activity than the parent
tetrahydrocurcumin (Mahal et al. 2017, 2019). Herein, we report the synthesis of two

NATURAL PRODUCT RESEARCH
3
Scheme 1. Synthesis, structure and numbering (as used in NMR signal assignment) of THC-4b-tria-
zolo-podophyllotoxin conjugates 6, 7 and THC-4b-triazolo-zidovudine conjugate 9. Reagents and
conditions: (a) K2CO3, propargyl bromide, DMF, N2, r.t. 24 h. (b) sodium azide, trichloromethane, tri-
fluoroacetic acid, r.t. overnight. (c) copper (II) sulfate pentahydrate, sodium ascorbate, THF, t-BuOH-
H2O, r.t. 12 h.
tetrahydrocurcumin-PPT and tetrahydrocurcumin-AZT conjugates and test their anti-
cancer activity against four human cancer cell lines (HeLa, A549, HepG2, HCT-116).

4
M. DUAN ET AL.
2 Results and discussion
2.1. Chemistry
Compounds 6, 7 and 9 were synthesised according to the steps shown in scheme 1.
Mono-tetrahydrocurcumin-alkyne 2 was obtained by the reaction of tetrahydrocurcu-
min 1 with propargyl bromide using a base of potassium carbonate (K2CO3) and a
solvent of dimethylformamide (DMF) at room temperature for 24 hours. 4b-azido-4-
deoxypodophyllotoxin (4) and 4b-azido-4-deoxy-40-demethypodophyllotoxin (5) were
prepared using the previous published procedures (Hansen et al.1993; Kamal et al.
2000). The reaction of compound (2) with the azides (4, 5) was carried out utlising
copper sulfate (II) pentahydrate (CuSO4ꢀ5H2O), monosodium ascorbate in THF (2 mL)
and a mixture of t-BuOH:H2O (2 mL, v:v ¼ 1:1) at room temperature for 12 h. The
obtained yields of tetrahydrocurcumin-4b-triazole-podophyllotoxin conjugates 6, 7
were 41%, 45%, respectively, and the yield of tetrahydrocurcumin-4b-triazole-zidovu-
dine conjugates were 41%. The synthesised compounds were structurally identified
1
using H-NMR, 13C-NMR and HRESI-MS techniques.
Compound 6, 7 and 9 was obtained as yellow oil and purity tested by UPLC was
96.13%, 92.55%, 100%, respectively. Scheme 1. shows the structures of newly prepared
1
compounds with atom numbering for elucidation of the structures using H-NMR, 13C-
1
NMR and mass techniques. The H-NMR spectrum revealed existing of doublet signal
at 4.7 ppm corresponding to C4‶-H indicating a cis-relationship between C3‶-H and
1
C4‶-H. The H-NMR spectrum of compound 6 indicated five singlets signals ranging
from 3.85 to 3.76 ppm corresponding to five OCH3 groups while compound 7 investi-
gated three singlet signals ranging from 3.85 to 3.80 ppm due to three OCH3 groups.
1
The H-NMR spectrum of compounds 6 and 7 revealed the presence of two signals of
at 5.98 ppm corresponding to C13‶-H2 and at 5.50 ppm due to C12-H2 groups. Three
signals for both compounds 6 and 7 between 204 to 173 due to the three CO groups
appeared in 13C-NMR spectrum. 13C-NMR spectrum indicated two signals at 144.1 and
124.8 ppm of C-13 and C-14 groups in triazole ring and revealed the presence of sig-
nals ranging from 60.92 to 56.06 ppm corresponding to three OCH3 groups. ESI-HRMS
revealed the molecular formulas of compound 6 (C46H48N3O13) and compound 7
1
(C45H46N3O13). The H-NMR spectrum of compound 9 indicated the presence of one
singlet signal at 8.45 ppm due to NH2. One singlet signal at 3.86 ppm due to the six
1
protons of OCH3 groups. The H-NMR spectrum revealed the presence of singlet signal
at 5.64 ppm due to C12-H2 group. 13C-NMR spectrum showed five singlet signals from
59.22 to 56.09 ppm due to five OCH3 groups. 13C-NMR spectrum indicated two signals
at 144.09 ppm and 122.10 ppm corresponding to C-12 and C13 of triazole ring,
respectively. Four signals corresponding to four C ¼ O groups appeared from 204 ppm
to 150 ppm in the 13C-NMR spectrum. ESI-HRMS proved the molecular formula of the
compound 9 (C34H40N5O10).
2.2. Cytotoxic activity
MTT assay was used to evaluate cytotoxic properties of the compounds against four
cancer cell lines (HeLa, A549, HepG2, HCT-116). Tetrahydrocurcumin and etoposide

NATURAL PRODUCT RESEARCH
5
were used as positive controls. The activity of the compounds 6, 7 and 9 were carried
out based on drug concentration of 50% for cell growth inhibition (IC50) as shown in
Table S1. The bioactivity of intermediates 2, 4 and 5 showed no significant difference
compared to the corresponding scaffold and compound 8, zidovudine exhibited slight
activity only against Hela cell lines. Compound 6 and 7 showed promising anticancer
activity against HCT-116 (IC50¼17.86) and HeLa (83.19 lM) cell lines. Compound 6
showed potent inhibitory activity against HCT-116 compared to positive controls of
tetrahydrocurcumin (50.96lM) and etoposide (19.48 lM). Using one-way ANOVA, com-
pound 6 showed significant difference IC50 value compared to tetrahydrocurcumin (P˂
0.05) while showed no significant difference in comparison to the etoposide (P> 0.05).
Compound 7 showed potent inhibitory activity against HeLa (156.67 lM) and HCT-116
(114.86 lM) cell lines. However, compound 9 showed no obvious activity against four can-
cer cell lines (IC50>200lM). The selectivity index values (SI: IC50 normal cell/IC50 tumor cell) was
used to evaluate the safety and effectiveness of compounds. Although podophyllotoxin
and 40-demethoxypodoohylltoxin displayed significant anticancer bioactivity (IC50˂1.56 lM)
but it was also showed strong toxicity to human normal intestinal epithelial cell (IC50˂
1.56 lM, SI˂1). The SI of compound 6 (SI ¼ 3.96) was 4.2 times higher than tetrahydrocur-
cumin (SI ¼ 0.95) and 4.6 times higher than etoposide (SI ¼ 0.86).
3 Experimental
3.1. General experimental procedures
All reagents and solvents were obtained from commercial sources (Guangzhou
Chemical Reagent; Shanghai Bide Pharmaceutical Technology Co., Ltd; Shanghai
Macklin Biochemical Co., Ltd. Tianjin Damao Chemical Reagent Factory).
Tetrahyrdocurcumin was obtained from Shanghai D&B Biological Science and
Technology Co., Ltd. Podophyllotoxin and 40-demethoxypodoohylltoxin was purchased
from Shanghai Aladdin Co., Ltd. Zidovudine was purchased from Shanghai Yuanye Co.,
Ltd. Silica gel (200 ꢁ 300 mesh) was purchased from Yantai Jiangyou Silica Gel
Development Co., Ltd.
HRMS data were acquired in ESI mode on Orbitrap Eclipse device. UPLC data were
performed using Agilent 1290 Infinity II HDR-DAD instrument. NMR data were acquired
on AVANCE IIITM HD 600 MHz instrument. Chemical shifts (d) are given in ppm, cou-
pling constants (J) in Hz. The splitting pattern abbreviations are as follows: s ¼ singlet,
d ¼ doublet, dd ¼ doublet of doublets, ddd ¼ doublet of doublet of doublets,
t ¼ triplet, m ¼ multiplet, brs ¼ broad singlet.
3.2. General procedures for synthesis of tetrahydrocurcumin-4b-triazolopodo-
phyllotoxin conjugates 6 and 7
Copper (II) sulfate pentahydrate (10 mg) and monosodium ascorbate (2 g in 10 mL
H2O, 0.3 mL) were added to mixture of compound 2 (200 mg, 0.487 mmol) and 4b-
azido-4-deoxy-podophyllotoxin (4) (217 mg, 0.496 mmol)/or 4b-azido-4-deoxy-40-deme-
thypodophyllotoxin (5) (210 mg, 0.496 mol) in THF (2 mL) and t-BuOH-H2O (2 mL,
v:v ¼ 1:1) and stirring at room temperature until the reaction is complete (observation

6
M. DUAN ET AL.
by TLC). The residue after evaporation of the solvent was loaded onto silica gel col-
umn using DCM:EtOAC (v:v ¼ 10:1) to afford the target.
3.2.1. 1,7-Bis(4-hydroxy-3-methoxyphenyl) heptane-3,5-dione-[4ß-(1,2,3-trizaol-1-yl-
4-deoxypodophyllotoxin)] ether (6)
1
Yellow oil, (184.53 mg, 0.217 mmol, 45%). H-NMR (600 MHz, CDCl3): d 6.92 (s, 1H, ArH),
6.79 (dd, J ¼ 7.8, 1.2 Hz, 2H, ArH), 6.64 (s, 1H, ArH), 6.62 (t, J ¼ 1.8 Hz, 2H, ArH), 6.59
(ddd, J ¼ 7.8, 3.6, 2.4 Hz, 2H, ArH), 6.51 (s, 1H, ArH), 6.30 (s, 1H, ArH), 5.98 (dd, J ¼ 28.8,
2.4 Hz, 2H), 5.51 (s, 2H, CH2), 4.74 (d, J ¼ 5.4 Hz, 1H), 4.33 (dd, J ¼ 9.0, 7.2 Hz, 1H), 4.16
(t, J ¼ 6.6 Hz, 1H), 3.85 ꢁ 3.76 (m, 15H, OMe), 3.12 (d, J ¼ 7.2 Hz, 1H), 2.97 (s, 1H),
2.881 ꢁ 2.880 (m, 1H), 2.74 ꢁ 2.67 (m, 6H), 1.61 (s, 3H). 13C-NMR (150 MHz, CDCl3) d
204.54 (C-10), 204.49 (C-100), 173.25 (C-120’), 152.97 (C-30’’, 50’’), 149.53 (C-60), 148.22 (C-
6, 50), 146.57 (C-60’, 70’), 144.51 (C-5), 144.13 (C-13), 137.76 (C-10’’, 40’’), 134.37 (C-2),
133.30 (C-20), 132.44 (C-90’, 100’), 124.81 (C-14), 122.65 (C-3), 120.94 (C-30), 114.46 (C-4),
111.23 (C-1, 50’), 110.67 (C-10, 40), 108.78 (C-80’), 108.39 (C-20’’, 60’’), 102.12 (C-130’), 77.37
(C-11, 12), 67.41 (C-40’), 66.16 (C-110’), 60.92 (C-80’’), 58.68 (C-70), 56.51 (C-7), 56.06 (C-
70’’), 44.70 (C-10’), 43.77 (C-20’), 41.75 (C-9, 90), 37.26 (C-30’), 29.18 (C-80), 23.89 (C-8). ESI-
HRMS Calcd for C46H48N3O13 [M þ H]þ:850.3182, found 850.3193.
3.2.2. 1,7-Bis(4-hydroxy-3-methoxyphenyl) heptane-3,5-dione-[4ß-(1,2,3-trizaol-1-yl-
4-deoxy-4ꢀ-demethoxypodophyllotoxin)] ether (7)
1
Yellow oil, (162.95 mg, 0.217 mmol, 45%). H-NMR (600 MHz, CDCl3) d 6.92 (s, 1H, ArH),
6.79 (dd, 2H, J ¼ 7.98, 1.44 Hz, ArH), 6.63 (s, 1H, ArH), 6.62 ꢁ 6.61 (m, 2H, ArH), 6.59
(ddd, J ¼ 8.16, 3.18, 2.04, 2H, ArH), 6.51 (s, 1H, ArH), 6.32 (d, 1H, ArH), 5.98 (dd, 2H),
5.48 (d, J ¼ 16.98 Hz, 3H), 4.73 (d, J ¼ 4.98, 1H, CH), 4.32 ꢁ 4.31 (m, 1H), 4.16 (t, 1H),
3.83 (s, 12H, OMe), 3.13 ꢁ 1.60 (12H, CH2). 13C-NMR (150 MHz, CDCl3) d 204.54 (C-10,
100), 173.32 (C-120’), 149.52 (C-60), 148.17 (C-30’’, 50’’), 146.75 (C-6, 50), 146.55 (C-60’, 70’),
144.49 (C-5), 144.11 (C-13), 134.56 (C-10’’, 40’’), 133.46 (C-2), 132.44 (C-20), 129.86 (C-90’,
100’), 124.79 (C-14), 122.64 (C-3), 120.93 (C-30), 114.44 (C-4), 111.21 (C-1, 50’), 110.67 (C-
10, 40), 108.74 (C-80’), 107.97 (C-20’’, 60’’), 102.10 (C-130’), 67.42 (C-11, 12), 66.16 (C-40’,
110’), 58.69 (C-70), 56.69 (C-7), 56.05 (C-70’’), 44.71 (C-10’), 43.60 (C-20’), 41.84 (C-9, 90),
37.18 (C-30’), 29.17 (C-80), 23.89 (C-8). ESI-HRMS Calcd for C45H46N3O13
[M þ H]þ:836.3025, found 836.3025.
3.3. General procedures for synthesis of tetrahydrocurcumin-4b-triazolopodo-
zidovudine conjugate (9)
Copper (II) sulfate pentahydrate (10 mg) and monosodium ascorbate (2 g in 10 mL
H2O, 0.3 mL) were added to mixture of compound 2 (200 mg, 0.487 mmol) and zidovu-
dine (8) (108 mg, 0.406 mmol) in THF (2 mL) and t-BuOH-H2O (2 mL, v:v ¼ 1:1) and stir-
ring at room temperature until the reaction is complete (observation by TLC). The
residue after evaporation of the solvent was loaded onto silica gel column using
DCM:EtOAC (v:v ¼ 10:1) to afford the target.

NATURAL PRODUCT RESEARCH
7
3.3.1. 1,7-Bis(4-hydroxy-3-methoxyphenyl) heptane-3,5-dione-3ꢀ-(1,2,3-trizaol-1-yl)-
3ꢀ-deoxythymidine (9)
Yellow oil, (135.12 mg, 0.200 mmol, 41% yield). 1H-NMR (600 MHz, CDCl3): d 8.45 (s,
1H), 6.79 (dd, J ¼ 8.4, 2.4 Hz, 2H, ArH), 6.64 (dd, J ¼ 5.4, 2.4 Hz, 2H, ArH), 6.59 (ddd,
J ¼ 8.4, 3.6, 1.8 Hz, 2H, ArH), 6.16 (t, J ¼ 6.6 Hz, 1H, ArH), 5.64 (d, J ¼ 21.0 Hz, 2H),
5.23 ꢁ 5.20(m, 1H), 4.31 ꢁ 4.30 (m, 1H), 4.13(t, J ¼ 7.2 Hz, 1H), 3.98 (dd, J ¼ 12, 2.4 Hz,
1H), 3.86 (s, 6H, OMe), 3.72 (dd, J ¼ 12.6, 2.4 Hz, 1H), 3.15 (dd, J ¼ 7.2, 2.4 Hz, 1H),
2.77 ꢁ 2.72(m, 6H), 1.94 (d, J ¼ 1.2 Hz, 3H), 1.60 (s, 8H), 1.25 (s, 1H). 13C-NMR (150 MHz,
CDCl3) d 204.57 (C-10, 100), 163.39 (C-70’), 150.38 (C-60’, 60), 146.59 (C-6, 50), 144.64 (C-
5), 144.09 (C-13), 137.94 (C-90’), 132.62 (C-2), 132.54 (C-20), 122.10 (C-14), 121.06 (C-3,
30), 114.53 (C-4), 111.57 (C-1), 111.46 (C-10, 40), 111.35 (C-80’), 89.18 (C-30’), 85.21 (C-11,
20’), 66.53 (C-12, 10’), 61.89 (C-50’), 59.22 (C-70), 56.09 (C-7), 44.45 (C-9), 44.33 (C-90),
37.40 (C-40’), 29.16 (C-8), 29.10 (C-80), 12.60 (C-100’). ESI-HRMS Calcd for C34H40N5O10
[M þ H]þ:678.2770, found 678.2784.
4. Conclusions
We have synthesised three new tetrahydrocurcumin-4b-triazolo conjugates using cop-
per catalyzed azide-alkyne cycloaddition (CuAAC) reaction and tested their inhibitory
activity against four human cancer cell lines. Compound 6 showed potent antiprolifer-
ative bioactivity with satisfactory selectivity against HCT-116 cell line (IC50¼17.86 lM,
SI ¼ 4.09) superior to parent tetrahydrocurcumin and positive control of etoposide.
We conclude that the modification of tetrahydrocurcumin leading to compound 6
using click reaction can enhance cytotoxic activity against anti-colon cancer cell lines
and meanwhile reduced toxicity of podophyllotoxin and 40-demethoxypodophyllotoxin
as well. Further modifications of tetrahydrocurcumin leading to improve its anticancer
activity are recommended.
Disclosure statement
No potential conflict of interest was reported by authors.
Funding
This work was financially supported by Natural Science Foundation of Guangdong Province
(Grant No. 2017A030313775, Grant No. 2019A1515011822). Ahmed Mahal acknowledges the
Chinese Academy of Sciences (CAS) for support through the CAS President’s International
Fellowship Initiative (2016PM032) and Cihan University as well.
ORCID
Ahmed Mahal
http://orcid.org/0000-0002-6977-3752

8
M. DUAN ET AL.
References
Atanasova MD, Sasheva P, Yonkova IM, Doytchinova IA. 2019. Modelling the interaction and pre-
diction of mictrotubule assembly inhibition of podophyllotoxin and its derivatives by molecu-
lar docking. Bulg Chem Commun. 51(4):513–520.
Baker M. 2017. Deceptive curcumin offers cautionary tale for chemists. Nature. 541(7636):
144–145.
Berrino E, Angeli A, Zhdanov DD, Kiyukhina AP, Milaneschi A, Luca AD, Bozdag M, Carradori S,
Selleri S, Bartolucci G, et al. 2020. Azidothymidine “Clicked” into 1,2,3-Triazoles: First Report
on Carbonic Anhydrase–Telomerase Dual-Hybrid Inhibitors. J Med Chem. 63(13):7392–7409.
Doello K, Ortiz R, Alvarez PJ, Melguizo C, Cabeza L, Prados J. 2018. Latest in Vitro and in Vivo
Assay, Clinical Trials and Patents in Cancer Treatment using Curcumin: A Literature Review.
Nutr Cancer. 70(4):569–578.
Esatbeyoglu T, Huebbe P, Ernst IMA, Chin D, Wagner AE, Rimbach G. 2012a. Curcumin – vom
€
Molekul zur biologischen Wirkung. Angew Chem. 124(22):5402–5427.
Esatbeyoglu T, Huebbe P, Ernst IMA, Chin D, Wagner AE, Rimbach G. 2012b. Curcumin-from mol-
ecule to biological function. Angew Chem Int Ed. 51(22):5308–5332.
Gomez DE, Armando RG, Alonso DF. 2012. AZT as a telomerase inhibitor. Front Oncol. 06(2):113.
Han X, Deng S, Wang N, Liu YF, Yang XB. 2016. Inhibitory effects and molecular mechanisms of
tetrahydrocurcumin against human breast cancer MCF-7 cells. Food Nutr Res. 60:30616.
Hansen HF, Jesen RB, Willumsen AM, Norsko-Lauritsen N, Ebbesen P, Nielen PE, Buchardt O.
1993. New compounds related to podophyllotoxin and congeners: synthesis, structure eluci-
dation and biological testing. Acta Chem Scand. 47(12):1190–1200.
Hodon J, Borkova L, Pokorny J, Kazakova A, Urban M. 2019. Design and synthesis of pentacyclic
triterpene conjugates and their use in medicinal research. Eur J Med Chem. 15(182):111653.
Jadala C, Sathish M, Anchi P, Tokala R, Lakshmi UJ, Reddy VG, Shankaraiah N, Godugu C, Kamal
A. 2019. Synthesis of combretastatin-A4 carboxamidest that mimic sulfonyl piperazines by a
molecular hybridization approach: in vitro cytotoxicity evaluation and inhibition of tubulin
polymerization. Chem Med Chem. 14(24):2052–2060.
Kamal A, Laxman N, Ramesh G. 2000. Facile and efficient one-pot synthesis of 4b-arylaminopo-
dophyllotoxins: Synthesis of DNA topoisomerase II inhibitors (NPF and W-68). Bioorg Med
Chem Lett. 10(18):2059–2062.
Lai CS, Ho CT, Pan MH. 2020. The cancer chemopreventive and therapeutic potential of tetrahy-
drocumin. Biomolecules. 10(6):831.
Lakhan SE, Ford CT, Tepper D. 2015. Zingiberaceae extracts for pain: a systematic review and
meta-analysis. Nutr J. 14:50.
Mahal A, Wu P, Jiang ZH, Wei XY. 2017. Synthesis and cytotoxic activity of new tetrahydrocurcu-
min derivatives bearing pyrazole moiety. Nat Prod Bioprospect. 7(6):461–469.
Mahal A, Wu P, Jiang ZH, Wei XY. 2019. Schiff bases of Tetrahydrocurcumin as potential anti-
cacer agents. ChemistrySelect. 4(1):366–369.
Nerella S, Kankala S, Paidakula S, Gavaji B. 2019. Synthesis of D-ring modified acid hydrazide
derivatives of podophyllotoxin and their anticancer studies as tubulin inhibiting agents.
Bioorg Chem. 94:103384.
Novaes J, Lillico R, Sayre C, Nagabushanam K, Majeed M, Chen Y, Ho E, Oliveira A, Martinez S,
Alrushaid S, et al. 2017. Disposition, metabolism and histone deacetylase and acetyltransfer-
ase inhibition activity of tetrahydrocurcumin and other curcuminoids. Pharmaceutics. 9(4):45.
Raghavendra NM, Pingili D, Kadasi S, Mettu A, Prasad SVUM. 2018. Dual or multi-targeting inhib-
itors: The next generation anticancer agents. Eur J Med Chem. 143:1277–1300.
Salman GA, Zinad DS, Mahal A. 2020. Design, synthesis, and biological evaluation of new quin-
oline-based heterocyclic derivatives as novel antibacterial agents. Monatsh Chem. 151(10):
1621–1628.
Singh S, Khar A. 2006. Biological effects of curcumin and its role in cancer chemo-prevention
and therapy. Anti-Cancer Agents Med Chem. 6(3):259–270.

NATURAL PRODUCT RESEARCH
9
Song GQ, Lu HH, Chen F, Wang YM, Fan WB, Shao WF, Lu HQ, Lin B. 2018. Tetrahydrocurcumin
induced autophagy via suppression of PI3K/Akt/mTOR in non-small cell lung carcinoma cells.
Mol Med Rep. 17(4):5964–5969.
Suzuki S, Suzuki H, Tanaka K, Yamamura M, Shibata D, Umezawa T. 2019. De novo transcriptome
analysis of needles of Thujopsis dolabrata var. hondae. Plant Biotechnol. 36(2):113–118.
Tseng YH, Chiou SS, Weng JP, Lin PC. 2019. Curcumin and tetrahydrocurcumin induce cell death
in Ara-C-resistant acute myeloid leukemia. Phytother Res. 33(4):1199–1207.
Wang J, Long L, Chen YZ, Xue YS, Zhang L. 2018. Design, synthesis and antineoplastic activity of
new hybrids of podophyllotoxin and indirubin against human leukaemia cancer cells as multi-
functional anti-MDR agents. Bioorg Med Chem Lett. 28(10):1817–1824.
Wei JB, Chen JH, Ju PJ, Ma L, Chen L, Ma WD, Zheng T, Yang GY, Wang YX. 2019. Synthesis and
biological evaluation of 4b-N-acetylamino substituted podophyllotoxin derivatives as new
anticancer agents. Front Chem. 7(253).
World Health Organization (WHO). 2018. https://www.who.int.
Yoysungnoen B, Bhattarakosol P, Changtam C, Patumraj S. 2016. Effects of Tetrahydrocurcumin
on Tumor Growth and Cellular Signaling in Cervical Cancer Xenografts in Nude Mice. Biomed
Res Int. 2016:1781208.
Zerazion E, Rosa R, Ferrari E, Veronesi P, Leonelli C, Saladini M, Ferrari AM. 2016. Phytochemical
compounds or their synthetic counterparts? A detailed comparison of the quantitative envir-
onmental assessment for the synthesis and extraction of curcumin. Green Chem. 18(6):
1807–1818.
Zhang X, Rakesh KP, Shantharam CS, Manukumar HM, Asiri AM, Marwani HM, Qin HL. 2018.
Podophyllotoxin derivatives as an excellent anticancer aspirant for future chemotherapy: A
key current imminent needs. Bioorg Med Chem. 26(2):340–355.
Zi CT, Yang Y, Dong FW, Kong QH, Ding ZT, Zhou J, Jiang ZH, Hu JM. 2020, Synthesis and anti-
tumor activity of camptothecin- 4b-triazolopodophyllotoxin conjugates. Nat Prod Res. 34(16):
2301–2309.
Zinad DS, Mahal A, Al-Amiery A. 2020. An efficient synthesis of novel imidazo-aminopyridinyl
derivatives from 2-chloro-4-cyanopyridine. Org Prep Proced Int. 52 (4):361–367.
Zinad DS, Mahal A, Mohapatra RK, Sarangi AK, Pratama MRF. 2020. Medicinal chemistry of oxa-
zines as promising agents in drug discovery. Chem Biol Drug Des. 95 (1):16–47.
Zinad DS, Mahal A, Shareef OA. 2020. Antifungal activity and theoretical study of synthesized
pyrazole-imidazole hybrids. IOP Conf Ser Mater Sci Eng. 770 (1):012053.
Zinad DS, Mahal A, Siswodihardjo S, Pratama MRF, Mohapatra R. 2021. 3D-Molecular Modeling,
Antibacterial Activity and Molecular Docking Studies of Some Imidazole Derivatives. Egypt J
Chem. 64(1):93–105.