Design, modification of phyllanthone derivatives as anti-diabetic and cytotoxic agents

Article abstract of DOI:10.1080/14786419.2020.1788023

Twelve benzylidene derivatives, one Baeyer-Villiger oxidative, six imine derivatives were successfully designed and synthesised from phyllanthone. In the search for potential new anti-diabetic agents, phyllanthone along with its benzylidene and oxidation analogues were evaluated for enzyme inhibition against α-glucosidase. In the benzylidene series, most analogues displayed stronger activity than the mother compound. Compound 1c revealed the strongest activity, outperforming the acarbose positive control with an IC₅₀ value of 19.59 μM. Phyllanthone and its derivatives were then tested for cytotoxic activity against the K562 cell line. The imine analogues displayed the most powerful cytotoxic activity with 3cand 3d having IC₅₀ values of 57.55 and 68.02 μM, respectively.

Full text of DOI:10.1080/14786419.2020.1788023

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Design, modification of phyllanthone derivatives
as anti-diabetic and cytotoxic agents
Ngoc-Hong Nguyen, Van-Giau Vo, Hoang-Vinh-Truong Phan, Thanh-The Ngo,
Jirapast Sichaem, Thi-Phuong Nguyen, Huu-Hung Nguyen, Duc-Dung Pham,
Tien-Cong Nguyen, Van-Kieu Nguyen & Thuc-Huy Duong
To cite this article: Ngoc-Hong Nguyen, Van-Giau Vo, Hoang-Vinh-Truong Phan, Thanh-
The Ngo, Jirapast Sichaem, Thi-Phuong Nguyen, Huu-Hung Nguyen, Duc-Dung Pham,
Tien-Cong Nguyen, Van-Kieu Nguyen & Thuc-Huy Duong (2020): Design, modification of
phyllanthone derivatives as anti-diabetic and cytotoxic agents, Natural Product Research, DOI:
10.1080/14786419.2020.1788023
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1788023
Design, modification of phyllanthone derivatives as
anti-diabetic and cytotoxic agents
Ngoc-Hong Nguyena, Van-Giau Vob, Hoang-Vinh-Truong Phanc, Thanh-The
Ngoc, Jirapast Sichaemd, Thi-Phuong Nguyene, Huu-Hung Nguyenf, Duc-Dung
Phamc, Tien-Cong Nguyenc, Van-Kieu Nguyeng,h and Thuc-Huy Duongc
aCirTech Institute, Ho Chi Minh City University of Technology (HUTECH), Ho ChiMinh City, Vietnam;
bDepartment of BionanoTechnology, Gachon Medical Research Institute, Gachon University,
c
Seongnam, Korea; Department of Chemistry, University of Education, Ho Chi Minh City, Vietnam;
dResearch Unit in Natural Products Chemistry and Bioactivities, Faculty of Science and Technology,
e
Thammasat University Lampang Campus, Lampang, Thailand; NTT Hi-Tech Institute, Nguyen Tat
f
Thanh University, Ho Chi Minh City, Vietnam; Faculty of Technology, Van Lang University, Ho Chi
g
Minh City, Vietnam; Institute of Fundamental and Applied Sciences, Duy Tan University, Ho Chi
h
Minh City, Vietnam; Faculty of Natural Sciences, Duy Tan University, Da Nang, Vietnam
ABSTRACT
ARTICLE HISTORY
Received 28 March 2020
Accepted 11 June 2020
Twelve benzylidene derivatives, one Baeyer-Villiger oxidative, six
imine derivatives were successfully designed and synthesised from
phyllanthone. In the search for potential new anti-diabetic agents,
phyllanthone along with its benzylidene and oxidation analogues
were evaluated for enzyme inhibition against a-glucosidase. In the
benzylidene series, most analogues displayed stronger activity than
the mother compound. Compound 1c revealed the strongest activ-
ity, outperforming the acarbose positive control with an IC50 value
of 19.59 mM. Phyllanthone and its derivatives were then tested for
cytotoxic activity against the K562 cell line. The imine analogues
displayed the most powerful cytotoxic activity with 3cand 3d hav-
ing IC50 values of 57.55 and 68.02 mM, respectively.
KEYWORDS
Phyllanthus
(Phyllanthaceae); phyllan-
thone derivatives;
a-glucosidase inhibition;
cytotoxic activity
CONTACT Van-Kieu Nguyen
nguyenvankieu2@duytan.edu.vn; Thuc-Huy Duong
huydt@hcmue.edu.vn
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1788023
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
N.-H. NGUYEN ET AL.
1. Introduction
Diabetes mellitus (DM), characterised by the high blood sugar level is associated with long-
term damage, dysfunction, and failure of various organs, i.e. the eyes, kidneys, nerves, heart
and blood vessels if left untreated (Tahlan and Verma 2017). There are three main types of
DM: type I, type II and gestational diabetes. a-Glucosidase inhibitors demonstrated large
clinical importance in the treatment of type II diabetes, and this therapeutic class is mainly
sustained by acarbose, miglitol and voglibose, the three of them being derived from nat-
ural products. This enzyme converted disaccharide into glucose to catalyse the breakage
of the a-1,4-glycosidic bonds (Van Beers et al. 1995; Sun et al. 2015). Thus, the inhibition of
this enzyme led to a decrease in the rate of glucose absorption for controlling the level of
glucose in type II diabetes (Sun et al. 2015; Yousefi et al. 2015).
Triterpenoids are a large class of natural isoprenoids, which exhibit a wide range of bio-
logical activities including anti-inflammatory, anticancer, antiviral, antibacterial, antimycotic,
antiulcerotic, virostatic, cytotoxic properties (Dzubak et al. 2006), and enzyme inhibitory
properties (Ohigashi et al. 1986; Tokuda et al. 1986; Lee et al. 1994; Sohn et al. 1995; Hsu
ꢀ
et al. 1997; Cardenas et al. 2004; Harmand et al. 2005; Dalla Vechia et al. 2009). Ursane-type
triterpenoids and their analogues are highly bioactive, acting as a cytotoxin (Yonemoto
et al. 2014) and antimicrobials (Wang et al. 1993; Woldemichael et al. 2003). They act as
anti-HIV agents (Kashiwada et al. 2000), inhibitors of tumorigenesis (Huang et al. 1994) and
enzymes including PTP1B (Na et al. 2010), 5-lipoxygenase (Schweizer et al. 2000), DNA poly-
merase b lyase (Chaturvedula et al. 2004), cyclooxygenase-2 (Ringbom et al. 1998), elastase
(Sun et al. 2006). However, anti-diabetic activity against a-glucosidase has not yet
been reported.
The genus Phyllanthus (Phyllanthaceae), comprising approximately 900 species
(Unander et al. 1995; Calixto et al. 1998) widely used in folk medicine to treat kidney
problems, urinary bladder disturbances, intestinal infections, diabetes and the hepatitis
B virus (Calixto et al. 1998) is a rich source of triterpenoids (Calixto et al. 1998).
Phyllanthone and phyllanthol, ursane-type triterpenoids having a 3-membered ring at C-
13/C-14 (Chiang et al. 2001; Ndlebe et al. 2008), are common in two members of the
genus Phyllanthus: Phyllanthus polyanthus (Ndlebe et al. 2008) and Phyllanthus acidus
(Duong et al. 2019; Sengupta and Mukhopadhyay 1966). To the best of our knowledge,
very few compounds containing a cyclopropyl component at C-13/C-14 have been
found in nature (Kojima et al. 1988; Chiang et al. 2001; Ndlebe et al. 2008; Ali et al.
2015). To date, only 3-acetylphyllanthol, a derivative of phyllanthol, has been synthes-
ised (Ndlebe et al. 2008) and no phyllanthone derivatives have been reported. In this
study, we prepared phyllanthone analogues via aldolization, Baeyer-Villiger oxidation,
and imine formation. Furthermore, the products were evaluated the biological activities
as a–glucosidase inhibition using Baker’s yeast method of Nguyen et al. (Nguyen et al.
2011) and cytotoxic activity towards the cancer cell line K562 using MTT method
(Nguyen et al. 2019) to investigate the new anti-diabetic and cytotoxic agents.

NATURAL PRODUCT RESEARCH
3
2. Results and discussion
In this study, 19 new derivatives (1a–1l, 2, and 3a–3f) from phyllanthone (1) were suc-
cessfully synthesised via three different routes (Scheme 1). The first route yielded ben-
zylidene derivatives of phyllanthone, 1a–1l. Phyllanthone (1) was subjected to aldol
condensation with aromatic aldehydes, including benzaldehyde, 4-fluorobenzaldehyde,
2-fluorobenzaldehyde, 4-chlorobenzaldehyde, 3-chlorobenzaldehyde, 2-chlorobenzalde-
hyde, 4-bromobenzaldehyde, 3-bromobenzaldehyde, 2-bromobenzaldehyde, 4-nitro-
benzaldehyde, 2-nitrobenzaldehyde, and 4-methoxybenzaldehyde. This produced 1a–1l
with isolated yields of 36–75.2%. Compound 1a was readily identified from its 1D-NMR
1
spectra. Comparison of the H-NMR of 1a and 1 showed that the diastereotopic methy-
lene at dH 2.94 (d, 1H, J ¼ 16.5Hz, H-1a) and 2.18 (d, 1H, J ¼ 16.0 Hz, H-1b), assignable to
1-CH2 in 1a, were replaced by the methylenes, 1-CH2 and 2-CH2 in 1. The NMR data of
synthetic compounds 1b–1l were consistent with those of 1 and were in full accordance
with their illustrated structures. The synthesis routes are shown as Scheme 1.
To explore for further derivatives, the carbonyl carbon at C-3 was modified through
oxidation using m-CPBA of 1 via Baeyer-Villiger oxidation, followed by nucleophilic
addition with different hydrazides: 2-(p-tolyloxy)acetohydrazide, 2-(m-tolyloxy)acetohy-
drazide, 2-phenylacetohydrazide, 5-chloro-2-hydroxybenzohydrazide, 2-hydroxy-5-iodo-
benzohydrazide, and 2-(benzo[d]thiazol-2-ylthio)acetohydrazide. Seven products, 2 and
3a–3f, were obtained. NMR data showed 2 to be similar to 1 with certain important
differences. These include the appearances of carbon signals at dC 174.3 and 85.7,
assignable to C-3 and C-4, respectively, in place of the dC 217.9, 47.6 in 1, indicating
7-member lactonization. This chemical feature was further reflected in the molecular
formula deduced from the HRESIMS: C30H48O2.
1
The H-NMR spectra of the series 3a-3f were expected to be complex due to cis-to-
trans thermal relaxation of hydrazide derivatives (Kitaev et al. 1970; Todeschini et al.
ꢀ
1998; Jakusova et al. 2014; Esguerra and Lumb 2017). However, the 1D-NMR data for
3a were very similar to those of 1. The observation of a carbon signal at dC 167.3,
rather than that of the ketone carbon at dC 217.9, indicating C ¼ N imine formation
between the NH2 group of the hydrazide reagent and the C ¼ O group of 1. This was
further supported by the HMBC correlation of CH3-23 (dH 1.16) and CH3-24 (dH 1.12) to
C-3 (dC 167.3). The NMR data for synthetic compounds 3b-3f were consistent with
those for 3a, and were in full accordance with their described structures.
Phyllanthone (1) and its derivatives 1a–1l and 2 were tested for inhibition of
a-glucosidase (Table S1) as well as cytotoxic activity against the K562 cell line
(Table S2). In the a-glucosidase inhibition assay, most products exhibited higher
IC50 values than the positive control (IC50 162.54 0.19 lM). The benzylidene deriv-
atives bearing ortho-halogenated groups (1c, 1f and 1i) or none substituent (1a)
(Table S1) exhibited more powerful a-glucosidase inhibition than both the original
(1, IC50 >200 mM) and the positive control. Among three derivatives 1c, 1f, and 1i,
the rank-order of potency reflected the electronic effect of the R-substituent: fluori-
nated > chlorinated > brominated with the IC50 values of 1c (19.59 mM), 1f
(129.74 mM), and 1i (154.81 mM), respectively.
In the cytotoxic activity assay, most derivatives displayed weaker activity (IC50
>100 mM) than the original. Compounds 1j, 1 l, 3c, and 3d had lower IC50 values

4
N.-H. NGUYEN ET AL.
Scheme 1. General synthesis route towards analogues 1a–1l, 2, and 3a–3f.
against the K562 cell line than the starting material (1, IC50 98.82 5.19 mM). This sug-
gested that activity reflected the role played by the specific substituents that replaced
the ketone group.
3. Experimental section
3.1. General
Solvents were distilled before use. All reagents were purchased from Sigma-Aldrich. All
reactions were monitored by silica gel 60 F254 TLC plates (Merck). Column

NATURAL PRODUCT RESEARCH
1
5
chromatography was performed on silica gel 60–120 mesh. H and 13C-NMR spectra
were recorded on Bruker 500 and 400 MHz spectrometers using TMS as the internal
standard. Mass spectra were obtained on an Agilent ESI-QTOF instrument.
3.2. Isolation of phyllanthol
Air-dried P. acidus twigs and leaves (5.5 kg) were ground into a powder and exhaust-
ively extracted at room temperature with methanol (3 ꢀ 10 L). The filtered solution
was evaporated under reduced pressure to afford a residue (225 g). This crude extract
was subsequently reextracted using solvents of n-hexane, n-hexane–ethyl acetate (1:1),
and ethyl acetate to yield n-hexane (54.5 g), n-hexane–ethyl acetate (16.3 g) and ethyl
acetate (25.8 g) extracts. The n-hexane extract was subjected to silica gel column chro-
matography (CC) using a solvent system of n-hexane–ethyl acetate (8:2 to 0:1) to
obtain six fractions (H1-H6). Fraction H3 was resuspended in methanol to afford phyl-
lanthol (8.1 g) as a white amorphous powder.
3.3. Preparation of phyllanthone from phyllanthol
Phyllanthol (I, 200 mg, 0.485 mmol) dissolved in acetic acid (37.4 mL) was treated with
50 mL of Jones reagent (Shittu et al. 2016) prepared by adding K2Cr2O7 (0.45 g) and
16.8 mL H2SO4 3 M to 100 mL water. The mixture was heated at 100 ꢁC for 3 hours
under stirring. The organic layer gained after extracting of the mixture with ethyl ace-
tate–water (1:1) was washed with brine and dried over anhydrous Na2SO4. The residue
was subjected to silica gel column chromatography (CC) eluted with n-hexane–ethyl
acetate–acetone–acetic acid (8:0.2:0.1:0.01) to yield phyllanthone (1).
3.4. General procedure for the synthesis of benzaldehyde derivatives of
phyllanthone
A solution of phyllanthone (1, 70 mg, 0.165 mmol), NaOH (35 mg, 0.875 mmol) in etha-
nol (7 mL) was stirred at 55 ꢁC for 15 min. Appropriate aromatic aldehydes (0.33 mmol)
and ethanol (7 mL) were added. The mixture was stirred for 2 h at 55 ꢁC. The reaction
mixture was partitioned between ethyl acetate–water (1:1) to yield an organic layer.
This was pooled, washed with brine and dried over anhydrous Na2SO4. The residue
was subjected to silica gel column chromatography eluted with n-hexane–ethyl acet-
ate (100:1) to afford the products.
3.5. Synthesis of phyllanlactone
Phyllanthone (1, 35.5 mg, 0.084 mmol) was added to a solution of m-CPBA (16 mg,
0.093 mmol) in chloroform (3.6 mL). The mixture was stirred at 40 ꢁC for 3.5 h. After
extraction with ethyl acetate–water (1:1 v/v), an organic layer was obtained. This was
washed with brine and dried over anhydrous Na2SO4. The residue was purified by nor-
mal phase silica gel column chromatography with n-hexane–ethyl acetate–acetone–
acetic acid (10:0.4:0.1:0.01) as an eluent to yield phyllanlactone (2).

6
N.-H. NGUYEN ET AL.
3.6. General procedure for the synthesis of derivatives 3a–3f
Hydrazides were prepared using the methods described in Supplementary material. To
a solution of phyllanthone (1, 30 mg, 0.071 mmol) in ethanol–acetic acid (5.4 mL, 3:1,
v/v (was added appropriate hydrazides (0.212 mmol). The mixture was refluxed
at 60 ꢁC for 2 h 30 min under stirring. The mixture partitioned between chloroform-
ethanol-water (1:1:0.5 v/v/v). Organic layers were pooled, washed with brine and dried
over anhydrous Na2SO4. The solvent was removed and the organic layers were dis-
solved in methanol. The precipitate was finally washed with ethyl acetate–methanol
(1:1) to afford a pure product.
4. Conclusions
Phyllanthone analogues were prepared via aldolization, Baeyer-Villiger oxidation and
imine formation. We tested the products for a–glucosidase inhibition as well as cyto-
toxic activity towards the cancer cell line K562. The modification of phyllanthone to
benzylidene enhanced activity against a-glucosidase. The benzylidene analogues of
phyllanthone displayed stronger a-glucosidase inhibition. The 2-fluorobenzylidene ana-
logue (1c) was demonstrated to be a promising a-glucosidase inhibitor, having an IC50
value of 19.59 mM. The imine derivatives were more cytotoxic to the K562 cell line
than the benzylidene analogues. Among the products, compound 3c exhibited the
strongest activity (IC50 57.55 mM). Further investigation into a-glucosidase inhibition of
the derivatives (3a–3f) as well as cytotoxicity of the potential products are necessary
for completing biological data.
Supplementary material
Supplementary material relating to this article is available online, alongside Tables
S1–S2 and Figures S1–S71.
Disclosure statement
No potential conflict of interest was reported by the authors.
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