Synthesis and biological evaluation of andrographolide C-glycoside derivatives as &α-glycosidase inhibitors

Article abstract of DOI:10.1002/cjoc.201100179

A series of new andrographolide C-glycoside derivatives were synthesized by a facile route. The new compounds showed higher potency than the parent andrographolide evaluated as α-glycosidase inhibitors in the preliminary study. Copyright

Full text of DOI:10.1002/cjoc.201100179

FULL PAPER
DOI: 10.1002/cjoc.201100179
Synthesis and Biological Evaluation of Andrographolide
C-Glycoside Derivatives as α-Glycosidase Inhibitors
Yan, Lina(严琳)
Xu, Haiweib(徐海伟)
Liu, Fengwub(刘丰五)
Zhao, Jina(赵瑾)
Liu, Hongmin*,b(刘宏民)
a Institute of Chemistry ＆ Biology, Henan University, Kaifeng, Henan 475001, China
b New Drug Research & Development Center, Zhengzhou University, Zhengzhou, Henan 450001, China
A series of new andrographolide C-glycoside derivatives were synthesized by a facile route. The new com-
pounds showed higher potency than the parent andrographolide evaluated as α-glycosidase inhibitors in the pre-
liminary study.
Keywords andrographolide, β-C-glycosidic ketone, α-glycosidase inhibitor
Introduction
known to display potent activity towards glycosidases.
Among the most common and potent classes of glyco-
sidase inhibitors are glycosides, aldono-1,5-lactones,
aldono-1,5-lactams and dideoxyimino alditols (aza-
sugars).[5] Recently, there have been a rapid extension in
the field of glycobiology with carbohydrate-derived
therapeutics now entering clinical trials,[6-9] such as
Traditionally natural products have been an excellent
and reliable source for the development of new drugs.
Some natural products have been used directly while
others have served as intermediates in semi-synthetic
pathways or as the source of structural or functional
templates for drug design. In recent years, the intense
interest of glucosidase inhibitors[1] in chemistry, bio-
chemistry and pharmacology has led to many types of
natural and synthetic inhibitors, which are aiding in both
unraveling the mechanism of glucosidase action and the
development of potential pharmaceuticals.[2] In our pre-
vious study on searching for glucosidase inhibitors,
some andrographolide derivatives have been proved to
be potent and specific α-glucosidase inhibitor.[3,4] SAR
analyses indicated that (a) replacing the C-8 ethylene
moiety with an 8,17-epoxy resulted in a decrease of ac-
tivity; (b) esterification of 3,19-hydroxyl groups and (c)
the aromatic group at 3,19-hydroxyls were favorable to
the activity; (d) 15-ene-substituted derivatives of 14-
deoxy-11,12,13,14-tetradehydroandrographolide sig-
nificantly increased the α-glucosidase inhibitory activi-
ties. Furthermore, 15-alkylidene derivatives showed
best inhibition activity among the published work. It is
worth pointing out that although many 15-alkylidene
andrographolide derivatives have been synthesized in
our previous reports, the substitution groups at C-15
were all highly lipophilic bulky groups. Based on these
results we decided to introduce hydrophilic group (such
as carbohydrates) at C-15 in order to increase their hy-
drophilicity and bioactivity. On the other hand, carbo-
hydrates and glycoconjugates are a very important class
of carbohydrate-processing enzyme inhibitors and are
acarbose (GlucobayTM), voglibose (BasenTM
) and
miglitol (GlysetTM), which have been utilized medici-
nally in the treatment of type 2 diabetes for many years.
In an effort to look for possible glucosidase inhibitors,
we were interested in the incorporation of androgra-
pholide derivatives with hydrophilic carbohydrate
groups at the position of C-15 by aklylidene. At the
same time, in our previous reports, we prepared some
hydrophilic β-C-glycosidic ketones by a facile route.[10]
So three series of andrographolide C-glycoside deriva-
tives were designed and synthesized.
Results and Discussion
15-Alkylidene derivatives 3—6 (Scheme 1) were
synthesized by the reaction of compound 2 and
β-C-glycosidic ketones according to previous method.[11]
Compound 2 was obtained by refluxing andrographolide
(1) in pyridine in the presence of Al2O3.[12] β-C-Glyco-
sidic ketones were prepared following the literature
procedures.[10]
The structures of andrographolide C-glycoside de-
rivatives were elucidated by the analysis of NMR, IR
and HRMS spectra. In the HRMS spectrum of 3, the M
＋Na＋ peak at m/z 575.2382 and the M＋Na＋＋2 peak
at m/z 577.2376, as well as the 3∶1 ratio of the heights
of the two peaks (corresponding to Cl-35 and Cl-37
*
E-mail: liuhm@zzu.edu.cn; Tel./fax: +86-371-67781739
Received July 29, 2011; accepted October 8, 2011; published online February 29, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100179 or from the author.
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Chin. J. Chem. 2012, 30, 914—918

Synthesis and Biological Evaluation of Andrographolide C-Glycoside Derivatives
Scheme 1 Synthesis of compounds 2—6
derivative of 2. But it is worth pointing out that the
product 3 is a mixture of two isomers in the ratio of 1∶
1 based on their 1H NMR integrals. Similarly, the struc-
tures of 4, 5 and 6 were elucidated by the analysis of
NMR, IR and HRMS spectra.
15
O
O
14
HO
16
13
O
O
12
20 11
9
1
4
Correspondingly, other andrographolide C-glycoside
derivatives 9—16 were also synthesized by the vinylo-
gous aldol reaction. The synthetic pathways used in the
present work are outlined in Scheme 2. Compound 7
was obtained by heating 2 and paraform in THF in the
presence of H2SO4 in excellent yield. Compound 8 was
prepared by the expoxidation reaction of compound 2
with mCPBA. Fortunately, following the vinylogous
aldol reaction, most of the desired products could be
obtained with good yield. After chromatography, com-
pounds 9—16 were obtained as mixtures of isomers
based on the analysis of the NMR spectra.
17
2
3
10
5
8
(a)
7
6
HO
HO
18
19
HO
HO
2
1
O
1 R3
O
R
O
3
R1
R2
R
OH
O
R2
OH
HO
O
HO
(b)
The α-glucosidase inhibition activities of the syn-
thetic compounds were tested with the acarbose as posi-
tive control. The compounds concerned for β-gluco-
sidase showed no inhibition activity. The bioactivity
results showed that compounds 3, 4, 13—16 displayed
selective α-glucosidase inhibitory activity (Table 1), and
their α-glucosidase inhibitory activity is better than that
of the parent compound 2, which has 16.5% of inhibiton
at 100 μmol/L. Among them, compounds 3, 4, 13 with
56, 78, 72 μmol/L of IC50 respectively, showed better
activity than acarbose which is useful in reducing peak
postprandial blood glucose (PPBG) concentrations. In
the above study, all the derivatives with hydrophilic
β-C-glycosidic substitutions at C-15 were found to be
less active compared to the previous derivatives with
HO
HO
3 R1 = Cl, R2 = H, R3 = CH2OH
4 R1 = H, R2 = OH, R3 = CH2OH
5 R1 = OH, R2 = H, R3 = CH2OH
6 R1 = H, R2 = OH, R3 = H
Reagents and conditions: (a) xylene, pyridine, Al2O3, reflux, 6—10 h;
(b) 1,2-diaminoethane, methanol, refluxing, 3—5 h
isotopes respectively), indicated that the formula of 3
should be C29H41ClO8. The H NMR spectrum of 3 re-
vealed the presence of the characteristic of carbohy-
drates (δ 3—5) and the disappearation of H-15 signal
(δ 4.8). All of these indicated that 3 is a C-glycoside
1
Scheme 2 Synthesis of compounds 7—16
O
O
O
O
O
O
3
R1
R2
OH
R
O
(a)
(c)
HO
HO
O
O
O
HO
2
7
O
9
R1 = Cl, R2 = H, R3 = CH2OH
(b)
10 R1 = H, R2 = OH, R3 = CH2OH
11 R1 = OH, R2 = H, R3 = CH2OH
12 R1 = H, R2 = OH, R3 = H
O
O
O
3
O
R1
R2
OH
R
O
(c)
HO
O
O
13 R1 = Cl, R2 = H, R3 = CH2OH
14 R1 = H, R2 = OH, R3 = CH2OH
15 R1 = OH, R2 = H, R3 = CH2OH
16 R1 = H, R2 = OH, R3 = H
HO
HO
HO
HO
8
Reagents and conditions: (a) THF, H2SO4, paraform, reflux, 1 h; (b) CHCl3, mCPBA, r.t., 2 h; (c) β-C-glycosidic ketone, 1,2-diaminoethane, methanol,
refluxing, 3—5 h.
Chin. J. Chem. 2012, 30, 914—918
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915

Yan et al.
FULL PAPER
Table 1 α-Glucosidase inhibition activity of andrographolide
C-glycoside derivativesa
plate. Column chromatography was carried out on silica
gel (200—300 mesh).
α-Glucosidase inhibition activityb [IC50/(μmol/L)]
General procedure for α-glucosidase inhibition assay
Compound
α-Glucosidase
Compound
α-Glucosidase
Ni
Inhibition rate was determined at 37 ℃ in 0.067
mol/L K2HPO4/KH2PO4 buffer (pH 6.8). The reaction
mixture contained 40 μL of enzyme solution, 40 μL of
inhibitor, and 20 μL of substrate. p-Nitrophenyl-α-D-
glucopyranoside, the substrate, and α-glucosidase
(Baker’s yeast) were purchased from Sigma Chemical
Co. (St. Louis, MO, USA). Acarbose (1 mmol/L) (ex-
tracted from Glucobay tablet, Bayer Pharmaceuticals
Corporation) was tested as a positive control. Both in-
hibitor and substrate were first dissolved in dimethyl-
sulfoxide (DMSO), and then diluted with 0.067 mol/L
K2HPO4/KH2PO4 buffer to make the final concentration
of DMSO 10%. The enzymatic reaction was started af-
ter incubation of the enzyme (0.04 U/mL) for 30 min in
the presence of the inhibitor (0.1 mmol/L) by the addi-
tion of substrate (0.5 mmol/L). The mixture was incu-
bated at 37 ℃ for 5 min, and the reaction was
quenched by the addition of 0.1 mol/L Na2CO3 (pH 9.8).
The absorption at 405 nm was measured immediately
and taken as the relative rate for the hydrolysis of sub-
strate. All the experiment was carried out in triplicate.
The IC50 value is the concentration of inhibitor at 50%
of enzyme activity.
2
3
4
5
6
7
8
9
16.5%
10
11
12
13
14
15
16
77.1% (56)
Ni
64.8% (78)
Ni
Nic
Ni
Ni
Ni
Ni
61.9% (72)
42.4% (100)
50.8% (89)
50.7% (91)
a Acarbose was taken as positive control. The inhibition percent-
b
age of 1 mmol/L acarbose was 56.5%. % Inhibition determined
at 100 μmol/L concentration of compound. c No inhibition at 100
μmol/L.
lipophilic aromatic groups at C-15, indicating that the
hydrophilic groups of C-15 are bad to the activity. In-
terestingly, 3 and 13, which contained chlorine-substi-
tuted C-glycosidic at C-15 were found to possess potent
activity against α-glucosidase inhibitory activity com-
pared to 2 and 8, indicating that the presence of chlo-
rine-substituted functionality at C-15 is essential for
improving the activity. In general, introduction of halo-
gen atom may significantly modify the chemical,
physical and biological activities of the natural sub-
stances.[13,14] In view of this observation, a number of
compounds which have halogen atom side chains at
C-15 are in progress.
In conclusion, series of new andrographolide
C-glycoside derivatives were synthesized using β-C-
glycosidic ketones as building blocks in one pot under
mild conditions. Some of them showed α-glucosidase
inhibition activity. Although, none of them showed bet-
ter inhibitory activity than the andrographolide deriva-
tive we have reported, the above study made the struc-
ture-activity relationship of andrograholide derivatives
for α-glucosidase inhibition activity more complete.
14-Deoxy-11,12-didehydroandrographolide (2)[12]
14-Deoxy-11,12-didehydro-3,19-metheneandro-
grapholide (7) Compound 2 (1.7 g, 5 mmol) and
paraform (182 mg, 6 mmol) in THF (20 mL) were re-
fluxed for 1 h in the presence of H2SO4. The reaction
mixture was concentrated under reduced pressure and
diluted with CHCl3 (20 mL). The CHCl3 phase was
washed with aq. Na2CO3, brine and water successively.
The organic phase was evaporated in vacuo to afford 7
(1.6 g, 4.8 mmol 95%) by crystallization from EtOAc.
1H NMR (400 MHz, CDCl3) δ: 7.15 (s, 1H), 6.57 (dd,
J＝10.0, 15.6 Hz, 1H), 6.17 (d, J＝15.6 Hz, 1H), 4.93 (s,
2H), 4.84 (s, 2H), 4.78 (d, J＝1.5 Hz, 1H), 4.54 (d, J＝
1.48 Hz, 1H), 4.22 (d, J＝13.1 Hz, 1H), 3.50 (dd, J＝
13.4, 4.7 Hz, 1H), 3.35 (d, J＝4.5 Hz, 1H), 2.48—2.46
(m, 1H), 2.33 (d, J＝9.8 Hz, 1H), 2.06—2.04 (m, 1H),
1.83—1.81 (m, 1H), 1.79—1.77 (m, 2H), 1.54—1.52
(m, 1H), 1.35—1.33 (m, 1H), 1.26 (s, 3H), 1.26—1.24
(m, 1H), 1.21—1.98 (m, 1H), 0.82 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) δ: 172.8, 144.9, 131.5, 129.4,
124.9, 88.4, 80.3, 70.3, 69.7, 59.8, 58.7, 54.7, 51.8, 39.6,
38.3, 37.7, 36.1, 26.6, 21.1, 21.0, 16.8; IR (KBr) v: 3337,
3080, 2928, 2855, 1746, 1642, 1445, 1375, 1073, 1034,
896 cm－ 1; HRMS calcd for C21H28NaO4 367.1885,
found 367.1889.
Experimental
General methods
1
The H and 13C NMR spectra were recorded on
Bruker AVANCE DPX-400 spectrometer with tetra-
methylsilane as internal standard and using CDCl3 or
DMSO as solvent. Chemical shifts (δ) were expressed
downfield from internal TMS. IR spectra were recorded
on a Nicolet IR 200 spectrophotometer. HRMS
(high-resolution mass spectra) were taken with a Q-Tof
Micromass spectrometer. Thin-layer chromatography
(TLC) was performed on glass plates precoated with
silica gel (5—40 μm) to monitor the reactions and cer-
tify the purity of the reaction products. Visualization
was accomplished by spraying the chromatograms with
10% ethanolic sulfuric acid and charring them on a hot
14-Deoxy-11,12-didehydro-8,17-epoxyandrogra-
pholide (8) Compound 2 (5.0 g, 15 mmol) and
mCPBA (2.5 g, 16 mmol) in CHCl3 (35 mL) were
stirred for 2 h. After completion of the reaction, the
mixture was washed with aq Na2CO3, brine and water
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Chin. J. Chem. 2012, 30, 914—918

Synthesis and Biological Evaluation of Andrographolide C-Glycoside Derivatives
successively. The CHCl3 phase was dried over Na2SO4,
filtered, and concentrated to yield 8 (5.0 g, 14 mmol,
96%). 1H NMR (400 MHz, CDCl3) δ: 7.16 (s, 1H), 6.51
(dd, J＝10.0, 15.6 Hz, 1H), 6.15 (d, J＝16.0 Hz, 1H),
4.79 (s, 2H), 4.22 (d, J＝10.8 Hz, 1H), 3.46 (dd, J＝4.0,
11.2 Hz, 1H), 3.37 (d, J＝11.2 Hz, 1H), 2.80 (d, J＝3.6
Hz, 1H), 2.56 (d, J＝4.0 Hz, 1H), 2.16 (d, J＝9.8 Hz,
1H), 1.27 (s, 3H), 0.96 (s, 3H); 13C NMR (100.6 MHz,
CDCl3) δ: 172.0, 143.8, 130.7, 128.4, 123.7, 80.2, 69.4,
63.8, 58.9, 57.9, 54.0, 50.7, 42.5, 38.6, 37.7, 35.2, 27.3,
22.5, 21.0, 15.8; IR (KBr) v: 3392, 2979, 2934, 2854,
1723, 1672, 1458, 1368, 1221, 1080, 1035, 983, 894
HRMS calcd for C29H42NaO9 557.2727, found
557.2724.
14-Deoxy-11,12-didehydro-15-isopro-C-glycoside-
1
andrographolide analogue (5) Yield 69%; H NMR
(400 MHz, DMSO) δ: 7.95 (s, 1H), 7.82 (s, 1H), 6.73—
6.71 (m, 1H), 6.12 (dd, J＝6.4, 15.7 Hz, 1H), 4.70 (s,
1H), 4.40 (s, 1H), 3.82 (d, J＝10.9 Hz, 1H), 3.23—3.19
(m, 9H), 2.49—2.47 (m, 1H), 2.35—2.33 (m, 1H), 1.94
(s, 3H), 1.09 (s, 3H), 0.73 (s, 3H); 13C NMR (100.6
MHz, DMSO) δ: 168.9, 168.8, 149.1, 146.0, 135.9,
133.4, 132.9, 126.2, 126.0, 124.6, 124.2, 121.7, 108.4,
82.1, 81.9, 81.1, 80.8, 78.9, 77.2, 77.0, 71.3, 71.1, 62.9,
61.0, 53.9, 42.6, 36.5, 27.9, 23.4, 23.3, 17.4, 15.7; IR
－
1
cm ; HRMS calcd for C20H28NaO5 371.1834, found
371.1836.
－
1
(KBr) v: 3401, 2935, 1749, 1444, 1034 cm ; HRMS
calcd for C29H42NaO9 557.2727, found 557.2729.
14-Deoxy-11,12-didehydro-15-isopro-C-glycoside-
General procedure for synthesis of 14-deoxy-11,
12-didehydro-15-isopro-C-glycosideandrographolide
analogues
1
andrographolide analogue (6) Yield 65%; H NMR
(400 MHz, DMSO) δ: 7.98 (s, 0.4H), 7.84 (s, 0.6H),
6.77—6.75 (m, 1H), 6.15 (dd, J＝8.3, 15.7 Hz, 1H),
5.09—5.05 (m, 4H), 4.74 (s, 1H), 4.43 (s, 1H), 4.18—
4.14 (m, 1H), 3.85 (d, J＝10.8 Hz, 1H), 3.66—3.64 (m,
1H), 1.94 (s, 3H), 1.10 (s, 3H), 0.77 (s, 3H); 13C NMR
(100.6 MHz, DMSO) δ: 169.1, 168.9, 149.4, 146.2,
145.8, 136.2, 136.1, 133.3, 133.1, 126.4, 126.2, 125.2,
124.6, 122.0, 121.8, 108.6, 79.1, 79.0, 74.8, 74.2, 70.3,
70.2, 63.1, 61.2, 54.2, 42.8, 38.5, 36.7, 28.1, 23.6, 23.5,
17.2, 15.9; IR (KBr) v: 3394, 2935, 1750, 1444, 1039
14-Deoxy-11,12-didehydro-andrographolide deriva-
tives (0.45—0.9 mmol) and various β-C-glycosidic ke-
tones (0.3 mmol) in dry methanol were refluxed in the
presence of 1,2-diaminoethane (0.09 mmol). After com-
pletion of the reaction, the reaction mixture was con-
centrated under reduced pressure and diluted with
CHCl3 (10 mL) and washed with water. The organic
phase was evaporated in vacuo to afford corresponding
product by flash chromatography.
－
1
14-Deoxy-11,12-didehydro-15-isopro-C-glycoside-
cm ; HRMS calcd for C28H40NaO8 527.2621, found
527.2628.
1
andrographolide analogue (3) Yield 71%; H NMR
(400 MHz, DMSO) δ: 8.01 (s, 1H), 7.80 (s, 1H), 6.76
(dd, J＝10.4, 15.6 Hz, 2H), 6.16 (dd, J＝12.8, 15.6 Hz,
2H), 5.39—5.35 (m, 2H), 5.21—5.17 (m, 2H), 5.08—
5.06 (m, 2H), 4.79—4.77 (m, 2H), 4.78 (s, 2H), 4.44 (s,
2H), 4.34 (d, J＝2.8 Hz, 2H), 4.04—4.02 (m, 2H), 3.85
(d, J＝10.8 Hz, 2H), 3.63 (d, J＝5.6 Hz, 4H), 3.42—
3.17 (m, 13H), 2.86 (d, J＝13.6 Hz, 1H), 2.69 (d, J＝
13.6 Hz, 1H), 2.39—2.35 (m, 4H), 1.99—1.98 (m, 9H),
1.10 (s, 6H), 0.77 (s, 6H); 13C NMR (100.6 MHz,
DMSO) δ: 168.9, 168.7, 149.2, 145.9, 145.3, 136.0,
135.9, 133.2, 132.9, 126.2, 125.8, 125.2, 124.4, 121.8,
121.6, 108.4, 79.2, 79.1, 78.8, 77.3, 73.2, 73.0, 70.8,
70.1, 64.7, 62.9, 60.9, 60.0, 53.9, 42.6, 39.5, 39.3, 39.1,
38.7, 38.2, 36.5, 27.9, 23.4, 23.3, 17.5, 17.2, 15.7, 14.3;
14-Deoxy-11,12-didehydro-3,19-methene-15-iso-
pro-C-glycosideandrographolide analogue (9) Yield
74%; H NMR (400 MHz, CDCl3) δ: 7.28 (s, 1H), 6.91
1
—6.89 (m, 1H), 6.14 (d, J＝16.0 Hz, 1H), 4.92 (d, J＝
6.4 Hz, 1H), 4.80 (s, 2H), 4.56 (s, 1H), 4.43 (s, 1H),
4.13—4.11 (m, 1H), 4.04—4.02 (m, 1H), 3.78—3.66
(m, 14H), 2.05 (s, 3H), 1.24 (s, 3H), 0.94 (s, 3H); 13C
NMR (100.6 MHz, CDCl3) δ: 169.8, 148.7, 147.4, 137.6,
137.2, 132.5, 127.6, 123.4, 122.8, 122.6, 110.4, 88.5,
80.6, 79.9, 75.1, 71.6, 69.9, 63.5, 63.2, 63.0, 62.5, 61.2,
55.1, 39.4, 38.5, 38.0, 37.1, 35.4, 26.6, 22.6, 21.8, 21.7,
18.6, 16.8, 14.9; IR (KBr) v: 3426, 2941, 1753, 1097
－
1
cm ; HRMS calcd for C30H41ClNaO8 587.2388, found
587.2387.
－
1
IR (KBr) v: 3391, 2935, 1744, 1077, 1031 cm ; HRMS
calcd for C29H41ClNaO8 575.2388, found 575.2382.
14-Deoxy-11,12-didehydro-15-isopro-C-glycoside-
14-Deoxy-11,12-didehydro-3,19-methene-15-iso-
pro-C-glycosideandrographolide
analogue
(10)
Yield 79%; 1H NMR (400 MHz, CDCl3) δ: 7.36 (s, 1H),
7.28 (s, 1H), 6.92—6.88 (m, 2H), 6.11 (d, J＝15.6 Hz,
2H), 4.90 (d, J＝5.4 Hz, 2H), 4.78 (s, 2H), 4.52 (s, 3H),
4.00 (d, J＝10.4 Hz, 4H), 3.77—3.24 (m, 23H), 2.00 (s,
3H), 1.96 (s, 3H), 1.42 (s, 3H), 1.41 (s, 3H), 0.91 (s, 6H);
13C NMR (100.6 MHz, CDCl3) δ: 169.8, 168.8, 148.1,
146.5, 145.6, 136.7, 136.4, 131.9, 131.5, 126.8, 124.6,
122.8, 122.2, 121.7, 109.5, 87.7, 79.7, 79.3, 78.4, 77.3,
74.1, 73.6, 70.1, 69.7, 69.1, 61.7, 54.3, 46.4, 38.7, 37.7,
37.3, 36.4, 34.6, 25.9, 21.8, 20.9, 17.8, 17.6, 16.1; IR
1
andrographolide analogue (4) Yield 74%; H NMR
(400 MHz, DMSO) δ: 8.00 (s, 1H), 7.85 (s, 1H), 6.77—
6.75 (m, 1H), 6.16 (dd, J＝7.8, 15.8 Hz, 1H), 4.74 (s,
1H), 4.44 (s, 1H), 3.85 (d, J＝10.8 Hz, 1H), 3.59 (d, J＝
10.8 Hz, 1H), 3.23—3.19 (m, 9H), 2.71 (d, J＝13.6 Hz,
1H), 1.90 (s, 3H), 1.10 (s, 6H), 0.77 (s, 6H); 13C NMR
(100.6 MHz, DMSO) δ: 168.9, 168.8, 149.2, 145.9,
145.2, 135.9, 135.8, 133.4, 133.0, 126.0, 125.8, 124.8,
121.9, 121.7, 108.4, 81.0, 80.8, 78.9, 78.4, 78.2, 73.9,
70.6, 70.5, 62.9, 61.5, 61.0, 60.9, 53.9, 42.6, 39.5, 39.3,
39.1, 38.7, 38.2, 36.5, 34.7, 27.9, 23.4, 23.3, 17.6, 17.3,
－
1
(KBr) v: 3420, 2939, 1753, 1094 cm ; HRMS calcd for
C30H42NaO9 569.2727, found 569.2735.
－
1
15.7; IR (KBr) v: 3403, 2935, 1749, 1081, 1037 cm ;
14-Deoxy-11,12-didehydro-3,19-methene-15-iso-
Chin. J. Chem. 2012, 30, 914—918
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
917

Yan et al.
FULL PAPER
pro-C-glycosideandrographolide
analogue
(11)
14-Deoxy-11,12-didehydro-8,17-epoxy-15-isopro-
Yield 69%; 1H NMR (400 M Hz, CDCl3) δ: 7.41 (s, 1H),
7.32 (s, 1H), 6.91—6.89 (m, 1H), 6.14 (d, J＝15.6 Hz,
1H), 4.90 (s, 2H), 4.78 (s, 2H), 4.29 (s, 2H), 4.26—3.42
(m, 14H), 2.01 (s, 3H), 1.41 (s, 3H), 0.92 (s, 3H); 13C
NMR (100.6 MHz, CDCl3) δ: 169.7, 148.8, 147.3, 147.1,
132.6, 132.3, 127.9, 127.7, 122.9, 110.3, 88.5, 87.3,
83.1, 81.0, 80.6, 79.9, 72.4, 69.9, 64.8, 62.5, 55.0, 39.5,
38.5, 38.0, 37.1, 26.6, 25.9, 22.6, 21.7, 18.5, 18.1, 16.8;
C-glycosideandrographolide analogue (15) Yield
74%; H NMR (400 MHz, DMSO) δ: 7.98 (s, 0.3H),
1
7.88 (s, 0.7H), 6.34—6.32 (m, 1H), 6.10—6.08 (m, 1H),
5.20—5.16 (m, 2H), 5.03 (d, J＝4.2 Hz, 1H), 4.56 (s,
1H), 4.15 (s, 1H), 4.15—3.65 (m, 5H), 1.97 (s, 3H),
1.13 (s, 6H), 0.90 (s, 3H); 13C NMR (100.6 MHz,
DMSO) δ: 168.7, 145.9, 132.8, 132.0, 131.8, 123.8,
81.9, 81.0, 80.7, 79.4, 78.6, 77.0, 71.1, 62.9, 58.5, 53.6,
53.0, 49.9, 45.9, 42.5, 40.3, 38.0, 36.3, 35.6, 27.4, 23.3,
21.7, 17.3, 15.7; IR (KBr) v: 3403, 2935, 1748, 1038
－
1
IR (KBr) v: 3400, 2939, 1753, 1445, 1026 cm ; HRMS
calcd for C30H42NaO9 569.2727, found 569.2740.
14-Deoxy-11,12-didehydro-3,19-methene-15-iso-
－
1
cm ; HRMS calcd for C29H42NaO10 573.2676, found
573.2662.
pro-C-glycosideandrographolide
analogue
(12)
Yield 59%; 1H NMR (400 MHz, CDCl3) δ: 7.95 (s, 1H),
7.82 (s, 1H), 6.73—6.71 (m, 1H), 6.12 (dd, J＝6.4, 15.7
Hz, 1H), 4.70 (s, 1H), 4.40 (s, 1H), 3.82 (d, J＝10.9 Hz,
1H), 3.25—3.11 (m, 9H), 2.49—2.47 (m, 1H), 2.35—
2.33 (m, 1H), 1.94 (s, 3H), 1.09 (s, 3H), 0.73 (s, 3H);
13C NMR (100.6 MHz, CDCl3) δ: 168.9, 168.8, 149.1,
146.0, 135.9, 133.4, 132.9, 126.2, 126.0, 124.6, 124.2,
121.7, 108.4, 82.1, 81.9, 81.1, 80.8, 78.9, 77.2, 77.0,
71.3, 71.1, 62.9, 61.0, 53.9, 42.6, 36.5, 27.9, 23.4, 23.3,
14-Deoxy-11,12-didehydro-8,17-epoxy-15-isopro-
C-glycosideandrographolide analogue (16) Yield
1
67%; H NMR (400 MHz, DMSO) δ: 7.92 (s, 0.4H),
7.80 (s, 0.6H), 6.31—6.29 (m, 1H), 6.09—6.07 (m, 1H),
5.04—4.98 (m, 4H), 4.14—4.12 (m, 1H), 3.81 (d, J＝
10.9 Hz, 1H), 3.64—3.62 (m, 1H), 3.38—3.17 (m, 6H),
3.17—3.15 (m, 1H), 3.07—3.05 (m, 1H), 2.91—2.89
(m, 1H), 2.67—2.64 (m, 2H), 2.46—2.44 (m, 1H), 2.19
—2.17 (m, 1H), 1.91 (s, 3H), 1.06 (s, 3H), 0.88 (s, 3H);
13C NMR (100.6 MHz, DMSO) δ: 168.7, 146.0, 145.6,
133.1, 132.8, 132.0, 126.1, 125.8, 125.1, 124.5, 123.8,
123.7, 78.8, 78.5, 78.4, 74.6, 74.0, 70.1, 70.0, 62.9, 58.6,
58.5, 53.6, 49.9, 42.5, 38.0, 35.7, 35.0, 27.4, 23.3, 21.7,
－
1
17.4, 15.7; IR (KBr) v: 3425, 2939, 1751, 1063 cm ;
HRMS calcd for C29H40NaO8 539.2621, found
539.2630.
14-Deoxy-11,12-didehydro-8,17-epoxy-15-isopro-
C-glycosideandrographolide analogue (13) Yield
71%; 1H NMR (400 MHz, DMSO) δ: 7.95 (s, 1H), 6.29
(dd, J＝10.0, 15.6 Hz, 1H), 6.07 (dd, J＝12.4, 15.6 Hz,
1H), 5.32 (d, J＝4.4 Hz, 1H), 5.17 (d, J＝5.6 Hz, 1H),
5.01 (d, J＝4.4 Hz, 1H), 4.75—4.73 (m, 1H), 4.29 (d,
J＝3.6 Hz, 1H), 4.12 (d, J＝5.2 Hz, 1H), 3.98 (dd, J＝
7.2, 14.0 Hz, 1H), 3.80 (d, J＝10.8 Hz, 1H), 3.59—3.57
(m, 2H), 3.39—3.37 (m, 1H), 3.33—3.28 (m, 5H), 3.24
—3.16 (m, 2H), 2.80 (d, J＝12.8 Hz, 1H), 2.65 (d, J＝
4.4 Hz, 1H), 2.49—2.46 (m, 2H), 2.34 (dd, J＝9.4, 14.2
Hz, 1H), 2.19—2.17 (m, 1H), 1.95 (s, 3H), 1.06 (s, 3H),
0.88 (s, 3H); 13C NMR (100.6 MHz, DMSO) δ: 168.9,
145.4, 132.9, 132.1, 126.1, 125.2, 123.7, 79.2, 78.7,
77.3, 73.2, 70.9, 64.7, 62.9, 61.0, 60.0, 58.6, 53.6, 49.9,
42.5, 38.0, 35.7, 34.6, 27.4, 23.3, 21.8, 17.3, 15.8, 14.3;
－
1
17.0, 15.8; IR (KBr) v: 3410, 2933, 1748, 1038 cm ;
HRMS calcd for C28H40NaO9 543.2570, found
543.2568.
Acknowledgment
We are grateful to the National Natural Science
Foundation of China (No. 20902086) and the Natural
Science Foundation of Henan Province (No.
112300410179) for financial support of this work.
References
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1
IR (KBr) v: 3410, 2938, 1742, 1038 cm ; HRMS calcd
for C29H41ClNaO9 591.2337, found 591.2325.
14-Deoxy-11,12-didehydro-8,17-epoxy-15-isopro-
C-glycosideandrographolide analogue (14) Yield
78%; 1H NMR (400 MHz, DMSO) δ: 7.95 (s, 1H), 7.81
(s, 1H), 630 (dd, J＝9.9, 15.6 Hz, 1H), 6.12 (dd, J＝6.7,
15.6 Hz, 1H), 3.99 (dd, J＝7.0, 14.2 Hz, 1H), 3.81 (d,
J＝12.4 Hz, 1H), 3.56—3.17 (m, 10H), 2.99—2.97 (m,
1H), 2.89—2.85 (m, 2H), 2.66—2.64 (m, 1H), 2.48 (d,
J＝4.5 Hz, 1H), 2.18 (dd, J＝4.1, 9.7 Hz, 1H), 1.95 (s,
3H), 1.06 (s, 3H), 0.88 (s, 3H); 13C NMR (100.6 MHz,
DMSO) δ: 169.1, 169.0, 146.2, 145.4, 133.5, 133.1,
132.1, 132.0, 126.1, 126.0, 125.9, 125.1, 124.1, 123.9,
81.2, 81.0, 78.9, 78.5, 74.8, 74.1, 63.1, 61.7, 60.2, 58.8,
53.8, 50.1, 45.9, 42.7, 38.2, 35.9, 34.9, 27.6, 23.5, 21.9,
21.2, 17.8, 17.5, 16.0, 14.5; IR (KBr) v: 3409, 2933,
1747, 1038 cm － 1; HRMS calcd for C29H42NaO10
573.2676, found 573.2662.
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(Zhao, X.)
918
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 914—918