Structure-Activity relationship study of the cleistriosides and cleistetrosides for antibacterial/anticancer activity

Article abstract of DOI:10.1021/ml300303g

Two known cleistriosides and six known cleistetrosides were synthesized and evaluated for anticancer and antibacterial activities. This study, for the first time, reports anticancer activity and comprehensively the antibacterial activity for these oligosa

Full text of DOI:10.1021/ml300303g

Letter
pubs.acs.org/acsmedchemlett
Structure−Activity Relationship Study of the Cleistriosides and
Cleistetrosides for Antibacterial/Anticancer Activity
Pei Shi, Michelle C. Silva, Hua-Yu Leo Wang, Bulan Wu, Novruz G. Akhmedov,*,‡
†
,∥
†,∥
†,∥
‡,∥
,†
,§
,†
Miaosheng Li,* Penny J. Beuning,* and George A. O’Doherty*
†Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
‡Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
§Protea Biosciences, Morgantown, West Virginia 26507, United States
*
S Supporting Information
ABSTRACT: Two known cleistriosides and six known cleistetrosides
were synthesized and evaluated for anticancer and antibacterial activities.
This study, for the first time, reports anticancer activity and
comprehensively the antibacterial activity for these oligosaccharide
natural products. In addition, two new unnatural cleistetroside analogues
were synthesized and tested. Biological activities for the 10
oligosaccharides against B. subtilis were found to range between 4 and
>
64 μM and for NCI-H460 human lung cancer epithelial cells between
7.5 and 90.9 μM. Similar activities were found for seven of the
oligosaccharides against the NCI panel of 60 cell lines. The degree of
acylation and location of the specific acetate groups had significant effects
on the anticancer and antibacterial activity of both the cleistriosides and
the cleistetrosides.
KEYWORDS: cleistetroside, cleistrioside, antibacterial, anticancer, palladium-catalyzed glycosylation
s part of a high-throughput-based search for new natural
products with unique structures and interesting biological
synthesis. The absolute and relative stereochemistry for one
member of the cleistetrosides (3) was confirmed by two total
A
4
5
activity, two partially acetylated trisaccharides (cleistrioside-5/-
, 1 and 2) and six partially acetylated tetrasaccharides
cleistetroside-2/-3/-4/-5/-6/-7, 3−8) natural products were
discovered (Figure 1) from the leaves and bark of trees with a
synthetic efforts by Zhang and Chen in 2007 via a traditional
carbohydrate approach. In 2010, we reported a divergent de
novo asymmetric synthesis of both cleistriosides (1 and 2) as
well as the six cleistetrosides (3−8), thus confirming the
6
(
6
1
−3
structures of the remaining members.
folk medicinal tradition.
These dodecanyl tri- and
Because of the limited amounts of natural isolates (1−3 mg),
only two [cleistrioside-5 (1) and cleistetroside-2 (3)] of these
eight oligo-rhamno-natural products were extensively evaluated
tetrarhamnoside structures with various degrees of acylation
1,2
were isolated from Cleistopholis patens and glauca. The
structures of the cleistriosides and cleistetrosides were assigned
by detailed NMR analysis and later confirmed by total
3
for antimicrobial activity. These antibacterial activities are
3
outlined in Table 1, which shows quite potent activity across a
broad range of organisms. Of particular note is that both
cleistrioside-5 (1) and cleistetroside-2 (3) showed significant
activity against several oxacillin-resistant organisms (e.g.,
3
Staphylococcus aureus ATCC 33591, Table 1). Because of the
rhamnan structural motif of the cleistriosides and cleistetro-
sides, their antibacterial activity is assumed to occur via
inhibition of mycobacterial cell wall synthesis. Similarly, the fact
that the oligo-rhamnose motif is not found in mammalian cells
7
makes them even more interesting as a potential antibiotic.
Over the years, we have been interested in the de novo
synthesis and study of partially acylated rhamnoside natural
Received: September 26, 2012
Accepted: October 30, 2012
Figure 1. Targeted cleistriosides and cleistetrosides.
©
XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
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a
Table 1. Antibacterial Activity of Cleistroside-5 (1) and
Cleistetroside-2 (3)
Scheme 2. Approach to the Intermediate 17
3
MIC (μg/mL)
organism
1
3
Staphylococcus aureus ATCC33591 (oxacillin-resistant)
Coagulase-negative staphylococci
Enterococcus faecalis
2
2−4
>32
2−4
2
2−4
2
Bacillus spp.
2
4−16
8
Streptococcus pneumoniae
4
Corynebacterium spp.
16
4
viridans group streptococci
4
8
,9
a
Reagents and conditions: (a) (i) Noyori (S,S), HCO Na(aq), 10 mol
products. Accordingly, the structurally novel cleistrioside and
cleistetroside potential antibiotics inspired us to develop a
divergent de novo asymmeric approach, which resulted in a
reasonably efficient approach to eight of the members of these
two classes of natural products (Scheme 1). While our de novo
2
%
CTAB, rt, 24 h; (ii) NBS, THF/H O (3:1), NaHCO ,
2
3
NaOAc·3H O, 0 °C, 1 h; (iii) Boc O, DMAP, CH Cl , −78 °C, 12
h. (b) HOCH (CH ) CH , 5 mol % Pd(PPh ) , CH Cl , 0 °C. (c)
2
2
2
2
2
2
10
3
3
2
2
2
(
i) NaBH , CeCl , CH Cl /MeOH, −78 °C, 2 h; (ii) OsO , NMO, t-
4
3
2
2
4
BuOH/acetone, rt, 12 h; (iii) TsOH, 2,2-DMP, acetone, 0 °C, 4 h. (d)
(
i) 12, 5 mol % Pd(PPh ) , CH Cl , 0 °C, 2 h; (ii) NaBH , CH Cl /
3
2
2
2
4
2
2
Scheme 1. De Novo Retrosynthetic Approach to the
Cleistriosides and Cleistetrosides
MeOH, −78 °C, 2 h; (iii) Ac O, Py, rt, 3 h; (iv) OsO , NMO, t-
BuOH/acetone, rt, 12 h. (e) (i) n-Bu SnO, MeOH, reflux, 1h; (ii) 12,
5
2
4
2
mol % Pd(PPh ) , CH Cl , 0 °C, 2 h. (f) (ClAc) O, Py, 3 h.
3 2 2 2 2
Pd(PPh ) = Pd (dba) ·CHCl /4PPh .
3
2
2
3
3
3
trisaccharides 1 or 2. By simply incorporating an additional
glycosylation/postglycosylation reaction sequence, along with
traditional two deprotections, the final two rhamno-sugars of
16
the cleistetrosides were installed onto 17. Thus, in 9−11
steps, 17 was selectively converted into the six cleistetroside
natural products 3−8. In contrast to the isolation work, this
synthetic approach provided significantly enough pure material
for detailed biological evaluation (vide infra), providing 5 mg of
both cleistriosides and between 5 and 43 mg of the
cleistetrosides (Scheme 3).
route to any particular member was not notably more efficient
than the two traditional carbohydrate approaches to cleistetro-
4
,5
side-2 (3), the approach allows for the divergent synthesis of
all eight oligo-rhamnosides (1−8) with the minimal use of
protecting groups. The overall efficiency of the route is best
exemplified by the fact that it affords sufficient quantities of
material for detailed biological investigations. Herein, we
describe our successful use of this divergent de novo approach
to the eight natural products (1−8) along with two unnatural
cleistetroside analogues (9 and 10) as well as their evaluation in
antibacterial and cytotoxicity assays.
Scheme 3. Divergent Approach to the Cleistriosides and
Cleistetrosides 1−8
Previously, we demonstrated that the eight oligosaccharides
(
1−8) could be efficiently prepared via a divergent de novo
route that derives all the sugar carbons from the achiral
6
acylfuran 11. Key to the approach was the efficient synthesis of
a common trisaccharide intermediate 17 (Scheme 2). In a
three-step asymmetric protocol, acylfuran was converted into
10,11
pyranone glycosyl donor 12,
which in turn is converted to
pyranone 13 via a Pd-catalyzed glycosylation [1:4/
12−14
Pd (dba) ·CHCl to PPh ].
A three-step postglycosylation
2
3
3
3
protocol was used to stereoselectively install the desired
rhamno-stereochemistry and acetonide protecting groups. A
subsequent glycosylation, reduction, acylation, and dihydrox-
ylation sequence provided disaccharide 15 followed by a
regioselective glycosylation, and chloroacylation gives the
orthoganally protected trisaccharide 17. This 14-step synthesis
was accomplished with only two traditional (acetonide and
chloroacetate) and two nontraditional (ketone and alkene)
In addition to the six naturally occurring cleistetrosides, this
route was amenable to the synthesis of two unnatural
cleistetroside analogues 9 and 10 (Scheme 4). The new route
begins with the same trisaccharide intermediate 17, which was
reduced, chloroacylated, and dihydroxylated to form diol 18. A
regioselective acylation, glycosylation, reduction, acylation, and
dihydroxylation converted 18 into tetrasaccharide 19 in 48%
15
17,18
alcohol protecting groups.
yield.
Finally the two chloroacetates [(NH ) CS/
2 2
The enone portion of trisaccharide 17 was ready for further
elaboration into the final rhamno-sugar required for 1 and 2; in
only six steps, 17 was selectively converted into either
NaHCO /Bu NI] and acetonide (AcOH/H O) were removed
to give cleistetroside analogue 9 in 83% yield. Similarly, 18 can
be converted into 20 via a regioselective acylation,
3
4
2
B
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ACS Medicinal Chemistry Letters
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a
Scheme 4. Approach to the Cleistetrosides 9 and 10
active (4 μM). As with the Gram-(+)-like E. coli imp, the
unnatural cleistetroside 9 was more active than 10 against B.
subtilis.
Because the related acylated oligo-rhamnoside natural
21
products were reported to possess anticancer activity, we
decided to test the set of 10 oligosaccharides for their
cytotoxicity against the human lung cancer cell line (NCI-
H460). We found IC50 values for this class of natural products
at similar concentrations (7.5−90.9 μM, Table 3) as the MIC
Table 2. MIC Values for Cleistrio/Cleistetroside
a
Derivatives
MIC (μM)
E. coli
MG1655
B. subtilis
R1
R2
R3
R4
imp
JH642
1
2
3
4
5
6
7
8
9
1
H
Ac
H
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
32
32
8
Ac
H
Ac
Ac
Ac
H
H
Ac
H
>64
>64
>64
16
4
Ac
H
H
8
H
H
8
a
Reagents and conditions: (a) NaBH , CeCl , CH Cl /MeOH, −78
4
3
2
2
H
H
H
8
°
C, 2 h. (b) (ClAc) O, DMAP, Py, rt, 3 h. (c) OsO , NMO, t-BuOH/
2
4
Ac
Ac
H
Ac
Ac
H
H
Ac
Ac
Ac
Ac
>64
>64
16
4
acetone, rt, 12 h. (d) CH C(OMe) , p-TsOH, CH Cl , 0 °C, 20 min,
3
3
2
2
Ac
H
>64
8
then AcOH(aq), 20 min. (e) 12, 5 mol % Pd(PPh ) , CH Cl , 0 °C, 2
h. (f) Ac O, DMAP, Py, rt, 3 h. (g) (NH ) CS, NaHCO , Bu NI,
THF, 55 °C, 2 h. (h) 80% AcOH, 80 °C, 2 h. Pd(PPh3)2
Pd (dba) ·CHCl /4PPh .
3
2
2
2
2
2
2
3
4
0
H
Ac
Ac
>64
>64
=
a
Antibacterial activity was assessed by MIC method, which was
2
3
3
3
performed by the broth dilution method described by the National
Committee for Clinical Laboratory Standard Methods (M7-A6, 2003)
(see the Supporting Information).
glycosylation, reduction, and dihydroxylation (58% yield for
four steps). Finally, a per-acylation followed by a chloroacetate
and acetonide deprotection gave cleistetroside analogue 10 in
Table 3. Cancer Cytotoxicity of the 10 Oligosaccharides on
a
93% yield.
NCI-H460 Human Lung Cancer Epithelial Cells
With the 10 target oligosaccharides in hand, we next set out
compd
IC50 (μM)
compd
IC50 (μM)
to evaluate the structure−activity relationship (SAR) with
1
2
3
4
5
90.9
12.5
9.1
6
7
15.4
7.5
respect to their activity against three different bacteria strains.
19
We chose two Escherichia coli strains (MG1655 and imp) and
one Bacillus subtilis strain (JH642). Of the two E. coli strains,
the first (K-12 MG1655) is the wild-type Gram-(−) organism
and the second E. coli imp (K-12 BAS901) is a Gram-(+)-like
strain, which has been genetically modified (imp-4213) to
8
16.4
16.5
9.8
12.8
12.2
9
10
a
The results are an average of at least three independent experiments.
20
increases the permeability of the outer membrane. The B.
subtilis strain (JH642) is a Gram-(+) organism. Consistent with
for the Gram-(+) B. subtilis strain (4−>64 μM, Table 2). Once
again, of the two trisaccharides, cleistrioside-6 (2) was the most
active. In contrast to the antibacterial activity, we found all of
the cleistetrosides to have significant cytotoxicity (<20 μM). As
we have found for anti-B. subtilis activity, we found cleistetro-
sides-6 (7) to be the most active (7.5 μM), with cleistetrosides-
2 (3) showing similar activity (9.1 μM).
The fact that cleistetrosides-2 and -6 (3 and 7) are the most
active and cleistetroside-7 (8) is the least active in both the
anti-B. subtilis and the anticancer screens suggests the possibility
that both the anti-B. subtilis and the anticancer activities for this
class of natural products result from the same molecular target
or mode of action. To challenge this trend, we were inspired to
prepare the two unnatural cleistetrosides (9 and 10), which had
3
the findings of Hu et al., we found both of the cleistriosides
and all of the cleistetrosides were inactive against wild-type E.
coli, which suggests that the oligosaccharides are not getting
past the Gram-(−) organism cell wall. Further evidence along
these lines came from the screening against the Gram-(+) like
strain (imp), with three of the oligosaccharides showing
improved activity. Improved MIC values were found for one
of the natural trisaccharides (2, 32 μM) and one tetrasaccharide
(
6, 16 μM). Interestingly, of the two unnatural analogues (9
and 10), cleistetroside-new 1 (9, 16 μM) showed similar
4
activity to 6, which differs by only one acetate (R ). As was
suggested from the E. coli study, we found significantly greater
activity against the B. subtilis strain, where the activities ranged
from 4 to >64 μM.
1
the C-4 acetate (R , Ac to H) in the third rhamnose sugar
Once again, cleistrioside-6 (2) was the more active of the two
trisaccharide natural products, whereas significantly different
trends were found for the tetrasaccharides 3−10. Of the
cleistetrosides, only two were inactive against B. subtilis (8 and
removed. The removal of the same acetate in the cleistriosides
(R ) was found to improve activity. Thus, cleistetroside-new 1
(9) is analogous to the quite potent cleistetroside-2 (3), and
cleistetroside-new 2 (10) is analogous to least potent
cleistetrosides 7 (8) with the C-4 acetates having been
removed. The testing of compounds 9 and 10 clearly
4
10, >64 μM), with the rest having MICs ≤ 8 μM. In particular,
cleistetroside-2 and -6 (3 and 7) were found to be the most
C
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ACS Medicinal Chemistry Letters
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a
Table 4. Growth Inhibition GI50 Evaluation of Cleistrioside and Cleistetroside Analogues (μM)
cell type
leukemia
cell line
1
2
3
4
7
8
10
RPMI-8226
SR
4.12
3.20
6.69
6.32
8.39
4.35
7.11
3.42
7.68
6.21
5.91
9.29
6.73
8.78
2.37
7.94
4.84
7.90
1.00
1.20
2.08
1.54
7.38
1.21
3.10
0.90
1.49
1.23
1.49
7.92
5.13
6.57
0.89
2.48
1.62
4.54
1.86
1.45
9.47
7.58
7.54
8.02
4.70
1.36
6.00
1.76
4.84
9.15
7.57
8.45
5.30
7.92
1.74
8.46
2.84
3.83
8.18
8.43
8.33
8.13
7.17
2.18
7.25
6.27
6.07
8.90
5.64
9.24
6.55
7.47
5.29
8.39
0.96
0.86
1.18
0.94
1.01
0.97
0.83
0.50
0.83
0.74
0.77
3.38
0.73
1.42
0.82
0.80
0.87
0.94
1.04
0.92
0.80
0.93
0.82
0.91
0.80
0.54
0.88
0.76
0.84
0.92
0.67
0.86
0.71
0.78
0.89
1.05
0.92
0.85
0.97
0.96
1.52
0.91
0.91
0.62
0.84
0.82
0.80
2.24
0.02
0.60
0.75
0.79
0.94
0.88
nonsmall cell lung cancer
colon cancer
A549
NCI-H460
HCT-15
HT-29
CNS cancer
SF-539
SNB-75
MDA-MB-435
SK-MEL-5
OVCAR-3
ADR-R
A498
melanoma
ovarian cancer
renal cancer
CAKI-1
PC-3
prostate cancer
breast cancer
DU-145
MCF7
BT-549
a
Growth inhibition of 50% (GI ) is calculated from [(T − T )/(C − T )] × 100 = 50, which is the compound concentration resulting in a 50%
50
i
z
z
reduction in the net protein increase (as measured by SRB staining) in control cells during the compound incubation. Compounds 5, 6, and 9 were
excluded because they did not pass the initial signal dose screen (10 μM).
1
demonstrates the importance of the R group to cleistetroside
SAR. For instance, the removal of the acetate in cleistetroside-2
(
NCI-H460, the NCI screen found tetrasaccharide 8 to be one
of the most active against the full panel of cell lines, including
the NCI-H460. This discrepancy presumably arises from the
subtle differences in the two protocols.
In conclusion, we have demonstrated the utility of a de novo
asymmetric synthesis for providing sufficient quantities of
material for comprehensive SAR type study. The route was
amenable to the synthesis of unnatural oligosaccharide
analogues for further SAR studies for both anticancer and
antibacterial activities. It is worth noting that these efforts
discover previously unreported anticancer activities for this
class of acylated oligo-rhamnoside natural products. Further
SAR studies along these lines are ongoing and will be reported
in due course.
3) had a small but negative effect on its potency in both
screens. In contrast, cleistetroside-new 2 (10) possessed
dramatically different effects on its anti-B. subtilis activity
(
>64 μM) as compared to anticancer activity (<10 μM). Thus,
with the synthesis and testing of only two new structures, we
were able to find a compound that contradicted the correlation
between anti-B. subtilis and anticancer activity. This, of course,
could result from different modes of action and/or different
esterase activities in bacterial versus human cancer cells.
While there is not enough information to fully understand
the effects of the acetate groups, clearly, the location of the
individual acetate groups has a significant effect on both the
anticancer and the anti-B. subtilis activity. In contrast to the
tetrasaccharides, this effect can easily be seen in cleistriosides-5
and -6 (1 and 2), where the simple migration of a C-4 acetate
group on the terminal sugar in 1 to the C-3 position in 2
dramatically increases its cytotoxicity to both B. subtilis and
cancer cells. Interestingly, the most active tetrasaccharides (3, 7,
and 10) have a C-4 acetate and are glycosylated at the C-3
position.
To gain a more complete understanding of the anticancer
activities, the set of 10 acylated oligo-rhamnosides (1−10) were
screened against the NCI panel of 60 cell lines. Of the 10
compounds screened, three (5, 6, and 9) did not pass the initial
single dose assay. A representative subset (two from the nine
tissue types) of these results is outlined in Table 4 (for the
results of the full 60 cell lines, see the Supporting Information).
Because these experiments were run under different conditions
ASSOCIATED CONTENT
■
*
S
Supporting Information
Assay protocols, statistical analysis data, synthetic procedures,
characterization data, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*
*
*
*
E-mail: Novruz.Akhmedov@mail.wvu.edu.
E-mail: Miaosheng.Li@proteabio.com.
E-mail: P.Beuning@neu.edu.
E-mail: G.ODoherty@neu.edu.
Author Contributions
∥
The order of these authors is alphabetical. The manuscript was
written with contributions from all authors. B.W. and M.L. were
responsible for the synthesis. P.S. was responsible for
compound evaluations with help from M.C.S. and H.-Y.L.W.
N.G.A. was responsible for compound characterization.
(
e.g., time) and measure different parameters (e.g., protein
concentrations vs mitochondrial activity), it is difficult to
directly compare the activities. However, some interesting
trends can be seen as well as differences. For instance, the data
from the NCI screen and our H460 MTT assay both show
compounds 3, 7, and 10 to have similar anticancer activity, with
Funding
We thank NIH (GM090259), NSF (CHE-1213596 to G.A.O.
and MCB-0845033 to P.J.B.), the American Cancer Society
(RSG-12-161-01-DMC to P.J.B.), and the Research Corpo-
8
being an outlier. Similarly, the unnatural tetrasaccharide 10
was significantly more active than 9. In contrast to our data for
D
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ACS Medicinal Chemistry Letters
Letter
ration for Science Advancement (Cottrell Scholar for P.J.B.) for
their support of our research.
Notes
(16) Shan, M.; Xing, Y.; O'Doherty, G. A. De Novo Asymmetric
Synthesis of an α-6-Deoxyaltropyranoside as Well as its 2-/3-Deoxy
and 2,3-Dideoxy Congeners. J. Org. Chem. 2009, 74, 5961−5966.
(
17) Guo, H.; O'Doherty, G. A. De Novo Asymmetric Synthesis of
The authors declare no competing financial interest.
the Anthrax Tetrasaccharide via a Palladium Catalyzed Glycosylation
Reaction. Angew. Chem., Int. Ed. 2007, 46, 5206−5208.
ACKNOWLEDGMENTS
■
(18) Guo, H.; O'Doherty, G. A. De Novo Asymmetric Synthesis of
Anthrax Tetrasaccharide and Analogue. J. Org. Chem. 2008, 73, 5211−
We are grateful to Prof. Yon Rojanasakul (West Virginia
University) and Dr. Todd A. Stueckle (West Virginia
University) for providing NCI-H460 cancer cells and Prof.
Kim Lewis (Northeastern University) for the wild-type E. coli
and imp strains and Prof. Alan D. Grossman (Massachusetts
Institute of Technology) for the B. subtilis strain.
5
220.
(19) Chen, Q.; Mulzer, M.; Shi, P.; Beuning, P. J.; Coates, G. W.;
O’Doherty, G. A. De Novo Asymmetric Synthesis of Fridamycin E.
Org. Lett. 2011, 13, 6592−6595.
(20) Sampson, B. A.; Misr, R.; Benson, S. A. Identification and
characterization of a new gene of Escherichia coli K-12 involved in
outer membrane permeability. Genetics 1989, 122, 491−501.
DEDICATION
■
(21) Cui, B.; Chai, H.; Santisuk, T.; Reutrakul, V.; Farnsworth, N. R.;
Cordell, G. A.; Pezzuto, J. M.; Kinghorn, A. D. Novel Cytotoxic
Acylated Oligorhamnosides from Mezzettia leptopoda. J. Nat. Prod.
This work is dedicated to Dr. Josephine O'Doherty on the
occasion of her 75th birthday.
1
998, 61, 1535−1538.
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