Houttuynoid M, an Anti-HSV Active Houttuynoid from Houttuynia cordata Featuring a Bis-houttuynin Chain Tethered to a Flavonoid Core

Article abstract of DOI:10.1021/acs.jnatprod.7b00620

Houttuynoid M (1), a new houttuynoid, and the related known compound houttuynoid A (2) were isolated from Houttuynia cordata. Their structures were defined using NMR data analysis, HR-MSⁿ experiment, and chemical derivatization. Houttuynoid M is the first example of a houttuynoid with a bis-houttuynin chain tethered to a flavonoid core. A putative biosynthetic pathway of houttuynoid M (1) is proposed. The anti-herpes simplex virus (anti-HSV) activities of 1 and 2 (IC₅₀ values of 17.72 and 12.42 μM, respectively) were evaluated using a plaque formation assay with acyclovir as the positive control.

Full text of DOI:10.1021/acs.jnatprod.7b00620

Article
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Cite This: J. Nat. Prod. XXXX, XXX, XXX-XXX
Houttuynoid M, an Anti-HSV Active Houttuynoid from Houttuynia
cordata Featuring a Bis-houttuynin Chain Tethered to a Flavonoid
Core
Jiao-Jiao Li,†,⊥ Guo-Dong Chen,†,⊥ Hong-Xia Fan,† Dan Hu,† Zheng-Qun Zhou,† Kang-Hua Lan,†
Hui-Ping Zhang,§ Hideaki Maeda,§ Xin-Sheng Yao,† and Hao Gao*,†,‡
†Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of
Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, People’s Republic of China
‡State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People’s Republic of China
§RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 2300045, Japan
S
* Supporting Information
ABSTRACT: Houttuynoid M (1), a new houttuynoid, and
the related known compound houttuynoid A (2) were isolated
from Houttuynia cordata. Their structures were defined using
NMR data analysis, HR-MSn experiment, and chemical
derivatization. Houttuynoid M is the first example of a
houttuynoid with a bis-houttuynin chain tethered to a
flavonoid core. A putative biosynthetic pathway of houttuynoid
M (1) is proposed. The anti-herpes simplex virus (anti-HSV)
activities of 1 and 2 (IC50 values of 17.72 and 12.42 μM,
respectively) were evaluated using a plaque formation assay
with acyclovir as the positive control.
of about two houttuynin units) than hyperoside, which
indicated that there may be new houttuynoids with two
houttuynin units in H. cordata. Subsequent chemical inves-
tigation on H. cordata led to the isolation of houttuynoid M (1)
and its biosynthetic related known compound houttuynoid A
(2). Houttuynoid M (1) is the first example of a houttuynoid
with a bis-houttuynin chain tethered to a flavonoid core. In
addition, houttuynoid M (1) exhibited anti-HSV activity in a
plaque formation assay.
Houttuynia cordata (Saururaceae) is mainly distributed in East
and Southeast Asia.1 The dried aerial parts or fresh whole plant
of H. cordata has a long history of being used as traditional
Chinese medicine (TCM) as Yu Xing Cao (Houttuyniae
Herba). It is commonly used in relieving fever, detoxifying,
dissolving carbuncles, and draining pus.2−4 Modern pharmacol-
ogy research showed that it possesses diverse bioactivities,
including anti-inflammatory, antibacterial, antiviral, antidiabetic,
and cytotoxic activities.1,5
Because H. cordata is one of the common and important
TCMs, a large number of phytochemical investigations have
been carried out, and more than 160 compounds have been
identified, including flavonoids,6−14 phenylpropanoids,7,15−18
alkaloids,1,7,19−24 steroids,1,18,25 terpenoids,1,25 volatile oils,6
and fatty acids.24,26 A new type of flavonoid, named
houttuynoids,12−14 was discovered from H. cordata. Houttuy-
noids are composed of a flavonoid core and a houttuynin chain
and have anti-herpes simplex virus (HSV) activities.12−14
Although houttuynoids are rare and only 12 analogues have
been reported, they have already attracted much attention due
to their structural novelty and promising antiviral activity. The
total synthesis of houttuynoid B has been achieved in 2016.27
To search for additional houttuynoids from nature, the DAD
and MS charateristics of the peaks in the HPLC-DAD-MS
chromatogram of the extract of H. cordata were analyzed and
showed peaks with the DAD characteristics of hyperoside and
with 330−350 Da higher molecular weights (molecular weight
RESULTS AND DISCUSSION
■
The air-dried aerial parts of H. cordata were extracted with
EtOH−H2O (60:40, v/v). The extract was separated by
continuously different column chromatography to yield
houttuynoid M (1) and its related known compound,
houttuynoid A (2).
Houttuynoid M (1) was obtained as a brown amorphous
powder. The molecular formula of 1 was established as
C44H58O13 (16 indices of hydrogen deficiency) from its
HRESIMS data (m/z 795.3954 [M + H]+, calcd for
C44H59O13: 795.3956). In the HR-MS2 experiment (Figure
S1, Supporting Information), the ion at m/z 817.3752 [M +
Na]+ gave the positive fragment at m/z 655.3218 [M + Na −
162]+, indicating the presence of a hexose unit in 1. The 13C
Received: July 19, 2017
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.7b00620
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Table 1. NMR Data of 1 in DMSO-d6 (600 MHz for 1H; 150
NMR spectrum showed 44 carbon signals. Combined with the
DEPT 135 experiment, these signals were classified as two
carbonyls (δC 198.7 and 177.6), 18 aromatic or olefinic carbons
[including six sp2 methines (δC 132.5, 128.3, 128.2, 110.2, 98.9,
and 93.9)], 16 sp3 nonoxygenated methylenes, two methyls (δC
13.94 and 13.90), and six hexosyl carbons (δC 101.7, 75.6, 73.0,
71.0, 67.5, and 59.7) (Table 1).
MHz for 13C)
1H−1H
e
no.
δC, mult
δH (J in Hz)
COSY
HMBC
NOESY
2
3
4
5
6
7
8
9
157.5, C
134.3, C
177.6, C
161.4, C
98.9, CH
164.7, C
93.9, CH
156.1, C
104.2, C
112.9, C
126.9, C
142.5, C
144.8, C
110.2, CH
128.2, CH
132.5, CH
The H−1H COSY and H NMR spectra of 1 revealed the
presence of four fragments, including C-5′−C-6′, C-4″−C-12″,
C-1″−C-2‴, and C-4‴−C-12‴ (Figure 1). The HMBC
correlations (Figure 1) from H-6 to C-5/C-7/C-8/C-10, H-8
to C-6/C-7/C-9/C-10, H-5′ to C-1′/C-3′, H-1″ to C-2′/C-2″/
C-3″/C-2‴/C-3‴, H-4″ to C-2″/C-3″, H-5″ to C-3″/C-4″, H-
12″ to C-10″/C-11″, H-2‴ to C-3‴/C-4‴, Hb-4‴ to C-3‴/C-
5‴/C-6‴, H-5‴ to C-3‴/C-4‴/C-6‴, H-12‴ to C-10‴/C-11‴,
and 5-OH to C-5/C-6/C-10 revealed the partial structure of
the aglycone moiety. The geometry of the Δ1″ double bond
1
1
6.16, d (1.3)
6.09, d (1.3)
8
6
5, 7, 8, 10
6, 7, 9, 10
10
1′
2′
3′
4′
5′
6′
1″
3
was determined as E by the value of JH‑1″/H‑2‴ (16.3 Hz).
6.82, d (8.2) 6′
7.67, br s 5′
7.28, d (16.3) 2‴
1′, 3′
Considering 1 from the similar biosynthetic pathway to
houttuynoid A (2), the length of the alkyl chain at C-3″
should be the same as that of houttuynoid A (2). Furthermore,
the aglycone ion at m/z 655.3218 ([M + Na − C6H10O5]+) in
the HR-MS2 spectrum showed an ion at m/z 483.1765 ([M +
Na − C6H10O5 − C10H20O2]+) in the HR-MS3 spectrum
(Figure S1, Supporting Information), which confirmed the
above deduction. On the basis of the comparison of 1D NMR
data with those of houttuynoid A (2),12 the molecular formula,
the indices of hydrogen deficiency, and the above analyses, the
structure of the aglycone of 1 was established. The NMR data
are collated in Table 1.
2′, 2″, 3″,
2‴, 3‴
4″, 4‴a,
4‴b
2″
3″
4″
112.7, C
160.7, C
26.6, CH2
2.91, t (7.5)
1.71
5″
4″, 6″
5″
2″, 3″
3″, 4″
1″, 2‴
5″
6″
7″
8″
27.5, CH2
a
28.88, CH2 1.03−1.31
28.66, CH2 1.03−1.31
28.63, CH2 1.03−1.31
28.55, CH2 1.03−1.31
a
a
a
9″
b
10″
11″
12″
2‴
31.30, CH2 1.23
c
Based on comparison with the 13C NMR data of
galactopyranose,12 the hexose moiety of 1 was identified as
galactopyranose. After acid hydrolysis and derivatization
(Figure S2, Supporting Information), the absolute config-
uration of the galactose was determined as D according to the
procedure developed by Tanaka et al.28 The galactopyranose
unit in 1 was attached to the aglycone via a β-linkage based on
the coupling constant of the anomeric proton (δH 5.24, d, J =
6.3 Hz, H-1⁗) and the observed NOESY correlations between
H-1⁗ and H-3⁗/H-5⁗. The location of the galactopyranose
moiety to the aglycone was deduced as C-3 based on the
NOESY correlation between Ha-6⁗ and 5-OH and the
comparison of the 13C NMR data of 1 with houttuynoid A
(2).12 Therefore, the structure of houttuynoid M (1) was
elucidated as 5,7-dihydroxy-2-[7-hydroxy-2-nonyl-3-{(E)-3-ox-
ododec-1-en-1-yl}benzofuran-4-yl]-3-[{(2S,3R,4S,5R,6R)-3,4,5-
trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl}oxy]-
4H-chromen-4-one.
22.09, CH2
13.90, CH3
128.3, CH
1.25
12″
11″
d
0.84, t (7.0)
10″, 11″
6.04, d (16.3) 1″
2″, 3″, 3‴, 4″
4‴
3‴
4‴
198.7, C
38.9, CH2
a: 2.06
b: 1.99
1.19
4‴b, 5‴
4‴a, 5‴
4‴a, 4‴b 3‴, 4‴, 6‴
1″
3‴, 5‴, 6‴ 1″
5‴
6‴
7‴
8‴
9‴
10‴
11‴
12‴
1⁗
2⁗
3⁗
4⁗
5⁗
23.3, CH2
a
28.86, CH2 1.03−1.31
a
28.85, CH2 1.03−1.31
a
28.59, CH2 1.03−1.31
a
28.53, CH2 1.03−1.31
b
31.23, CH2 1.23
c
22.07, CH2 1.25
12‴
11‴
5.24, d (6.3) 2⁗
d
13.94, CH3
101.7, CH
71.0, CH
73.0, CH
67.5, CH
75.6, CH
0.87, t (6.9)
10‴, 11‴
3⁗, 5⁗
1⁗
3.33
1⁗, 3⁗
2⁗, 4⁗
3⁗, 5⁗
1⁗, 3⁗
2⁗
2⁗, 3⁗
3.32
3.63, br s
3.30
Houttuynoid A (2) was identified by comparison of its
4⁗, 6⁗a, 1⁗, 4⁗, 6⁗ 1⁗
reported 1D NMR data.12
6⁗b
Houttuynoids are a rare type of flavonoid. Houttuynoid M
(1) is the first case of a houttuynoid with a bis-houttuynin chain
tethered to the quercetin flavonoid core. Houttuynoid A (2)
may be the putative biosynthetic precursor of 1. The additional
houttuynin moeity, 3-oxododecanal, may be tethered to
houttuynoid A (2) at C-1″ by aldol condensation and further
be oxidized and decarboxylated to form 1 (Scheme 1).
The known houttuynoids exhibited anti-HSV (HSV-1/Blue)
activities in an in vitro screening model of an HSV immediate−
early promoter-directed reporter system.12−14,29 The isolated
compounds were evaluated for their inhibitory effects against
HSV (HSV-1/F) using a classical plaque formation assay with
acyclovir (ACV) as the positive control [IC50 = 0.15 μM, SI
6⁗
59.7, CH2
a: 3.39
b: 3.23
12.53, s
5⁗, 6⁗b
5⁗, 6⁗a
5-OH
6⁗a
5-OH
a−d
5, 6, 10
e
Assignment may be interchanged in each group. Indiscernible
signals from overlap or complex multiplicity are reported without
designating multiplicity.
(selectivity index, CC50/IC50) > 1333]. The result showed that
both houttuynoid M (1) (IC50 = 17.72 μM, SI > 11.29) and
houttuynoid A (2) (IC50 = 12.42 μM, SI > 16.10) displayed
anti-HSV-1 activity (Table 2).
B
DOI: 10.1021/acs.jnatprod.7b00620
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1
Figure 1. Stucture of 1 and key H−1H COSY, HMBC, and NOESY correlations of 1.
Scheme 1. Putative Biosynthetic Pathway of Compound 1
h each). After filtration and evaporation in vacuo, 7.47 kg of crude
extract was obtained. The crude extract was separated by an AB-8
macroporous resin column (20 × 130 cm) with EtOH−H2O (10:90,
44:66, 95:5, v/v) to give three fractions (F1−F3). Fraction F3 (177.4
g) was separated by silica gel CC (8 × 50 cm) with CHCl3−MeOH
(95:5, 90:10, 85:15, 80:20, 70:30, 50:50, 0:100, v/v) to afford fractions
3.1−3.5. Fraction 3.3 (35.2 g) was subjected to MPLC on ODS CC (3
× 35 cm) eluted with a gradient of MeOH−H2O (68:32 to 100:0, v/v)
to afford fractions 3.3.1−3.3.7.
Table 2. Anti-HSV Activities of Compounds 1 and 2
a
no.
CC50 (μM)
IC50 (μM)
SI
1
>200
>200
>200
17.72
12.42
0.15
>11.29
>16.10
>1333
2
ACV
a
SI (selectivity index) = CC50/IC50.
Fraction 3.3.2 (6.6 g) was separated by preparative HPLC with a
Cosmosil Packed C18 column [eluted with MeOH−H2O−HCOOH
(70:30:0.1, v/v/v), 8 mL/min] to yield fractions 3.3.2.1−3.3.2.10.
Fraction 3.3.2.4 (872.7 mg) was subjected to preparative HPLC with a
Cosmosil Packed C18 column [eluted with CH3CN−H2O−HCOOH
(40:60:0.1, v/v/v), 8 mL/min] to afford 2 (tR: 83.3 min, 584.5 mg).
Fraction 3.3.5 (4.1 g) was subjected to Sephadex LH-20 CC (11 ×
96 cm) eluted with MeOH to afford fractions 3.3.5.1−3.3.5.8. Fraction
3.3.5.3 (385.0 mg) was separated by preparative HPLC with a
Phenomenex Kinetex C8 column [eluted with CH3CN−H2O−
HCOOH (56:44:0.1, v/v/v), 8 mL/min] to give 1 (tR: 55.6 min,
19.2 mg).
EXPERIMENTAL SECTION
General Experimental Procedures. The details of the reagents
and the instruments used in this work are provided in the Supporting
Information.
Plant Material. The plant material was purchased from the
Qingping market of traditional Chinese medicine, Guangdong
Province, China, in September 2014. In addition, it was identified as
the dried aerial parts of H. cordata by Dr. Ying Zhang, College of
Pharmacy, Jinan University.
■
Extraction and Isolation. The dried aerial parts (50.0 kg) of H.
cardata were extracted twice with 600 L of EtOH−H2O (60:40, v/v, 2
C
DOI: 10.1021/acs.jnatprod.7b00620
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Houttuynoid M (1): brown amorphous powder; [α]2D9 −34 (c 0.5,
MeOH); UV (MeOH) λmax (log ε) 205 (3.91), 256 (3.78), 305 (3.53)
nm; IR (KBr) νmax 3421, 2922, 2854, 2362, 1651, 1606, 1498, 1461,
1359, 1303, 1195, 1072, 1025, 996 cm−1; ESIMS (positive) m/z 1611
[2 M + Na]+, 817 [M + Na]+; HRESIMS (positive) m/z 795.3954 [M
Open Fund of State Key Laboratory of Pharmaceutical
Biotechnology (Nanjing University) (KF-GN-201412). Assis-
tance with the proper usage of scientific English was provided
by Dr. L. J. Sparvero at the University of Pittsburgh.
1
+ H]+ (calcd for C44H59O13, 795.3956); H and 13C NMR data see
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ACS Publications website at DOI: 10.1021/acs.jnat-
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Details of general experimental procedures, HR-MSn
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AUTHOR INFORMATION
Corresponding Author
*Phone/fax: +86-20-85228369. E-mail: tghao@jnu.edu.cn (H.
Gao).
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was financially supported by grants from the
National Natural Science Foundation of China (81422054 and
3171101305), the Guangdong Natural Science Funds for
Distinguished Young Scholar (S2013050014287), the Guang-
dong Special Support Program (2016TX03R280), the
Guangdong Province Universities and Colleges Pearl River
Scholar Funded Scheme (H.G., 2014), K. C. Wong Education
Foundation (H.G., 2016), the 111 Project of Ministry of
Education of the People’s Republic of China (B13038), and the
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D
DOI: 10.1021/acs.jnatprod.7b00620
J. Nat. Prod. XXXX, XXX, XXX−XXX