Synthesis and anti-tumor activities of methyl 2-O-aryl-6-O-aryl′-d-glucopyranosides

Article abstract of DOI:10.1016/j.bmcl.2010.03.045

A synthetic method of introducing bulky aryl groups at the 2-O- and 6-O-positions on glucopyranosides was developed. A total of 37 new compounds of this class were obtained successfully. These compounds were tested on several tumor cell lines by MTT assays, and some of them exhibited encouraging inhibitory activities. The most potent compound, CAB-SHZH-27, exhibited EC₅₀ values of 14, 12, and 10 μmol/L on A549, MDA-MB-231 and HeLa cells, respectively. A preliminary structure-activity relationship analysis indicates that the two free hydroxyl groups on the d-glucose core are indispensable for the biological activities of this class of compounds, and the aryl group at the 6-O-position has a more obvious impact than the one at the 2-O-position. An interesting 'on-off' mechanism of this class of compounds was also observed in our MTT assays, which remains to be explored.

Full text of DOI:10.1016/j.bmcl.2010.03.045

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2855–2858
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-tumor activities of methyl
2-O-aryl-6-O-aryl0-D-glucopyranosides
b,
Hefang Shi a, , Bingcheng Zhou b, , Wenwen Li b, Zhimin Shi b, Biao Yu b, , Renxiao Wang
*
*
a Key Laboratory of Marine Drugs, The Ministry of Education of China, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, PR China
b State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic method of introducing bulky aryl groups at the 2-O- and 6-O-positions on glucopyranosides
was developed. A total of 37 new compounds of this class were obtained successfully. These compounds
were tested on several tumor cell lines by MTT assays, and some of them exhibited encouraging inhibi-
Received 7 September 2009
Revised 4 February 2010
Accepted 9 March 2010
Available online 12 March 2010
tory activities. The most potent compound, CAB-SHZH-27, exhibited EC50 values of 14, 12, and 10
on A549, MDA-MB-231 and HeLa cells, respectively. A preliminary structure–activity relationship analy-
sis indicates that the two free hydroxyl groups on the -glucose core are indispensable for the biological
lmol/L
D
Keywords:
Glucopyranoside derivatives
MTT assay
activities of this class of compounds, and the aryl group at the 6-O-position has a more obvious impact
than the one at the 2-O-position. An interesting ‘on–off’ mechanism of this class of compounds was also
observed in our MTT assays, which remains to be explored.
Tumor cells
Ó 2010 Elsevier Ltd. All rights reserved.
Carbohydrate-based compounds are associated with a range of
biological activities. They thus have received special attention in
drug discovery for years. A recent review published by Meuter-
mans et al.1 pointed out that carbohydrate-based compounds are
characterized by a relatively rigid core and multiple hydroxyl
groups which can be differentially modified with orthogonally pro-
tected carbohydrate scaffolds. The unique structural diversity of
carbohydrate-based compounds allows them to be good mimetics
of known drugs or other bioactive compounds with appropriate
substituent groups installed at appropriate positions. For example,
compound 1 (Fig. 1) exhibit an IC50 value of 53 nM against human
somatostatin receptor subtype 4 (SSTR4).1,2 The well known antibi-
cell lines. The synthesis method and anti-tumor activities of this
new class of compounds are described in this Letter.
Few known compounds have phenyl ether moieties attached di-
rectly to the carbohydrate core structure. Considering that substi-
tuent at the 6-O-position is relatively easy, we aimed to introduce
N
NH2
Cl OH OH
OH
O
O
O
O
BnO
O
O
otic clindamycin (compound 2) has a D-galactose core bearing a
NH
O
lipophilic pyrrolidinyl group. Epirubicin (compound 3) bears a
tri-deoxy arabinopyranoside group, which is used primarily as an
anthracycline drug against breast cancer, ovarian cancer, gastric
cancer, lung cancer, and lymphomas.3 Thus, creating new classes
of carbohydrate-based compounds and exploring their biological
activities is an intriguing aim in medicinal chemistry.
In this study, we have designed and synthesized a class of
methyl D-glucopyranosides 4 (Fig. 1) with two aryl groups substi-
tuted at the 2-O- and 6-O-positions. Such a molecule combines
hydrophilic and hydrophobic features. They basically have a linear
shape, which may be preferable for achieving desired cell perme-
ability. These compounds were tested on several selected tumor
S
N
NH
O
NH
N
1
2
(clindamycin)
NH2
O
HO
O
OH
OH
O
O
HO
OH
O
O
X
O
O
O
Y
HO
HO
* Corresponding authors.
4
3 (epirubicin)
E-mail addresses: byu@mail.sioc.ac.cn (B. Yu), wangrx@mail.sioc.ac.cn (R.
Wang).
Authors with equal contribution.
Figure 1. Chemical structures of some carbohydrate-based bioactive compounds.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.045

2856
H. Shi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2855–2858
5 was treated with a panel of substituted sodium phenolates
O
6 steps
42%
HO
HO
O
O
(R1ONa) in ethylene glyco dimethyl ether (EGDME), and the 2,3-
epoxide was opened to form 2-position axial hydroxyl bond. The
typical by-product at this step was the dimer molecule formed
by an extra step of epoxide opening reaction. Sometimes even
the trimer could be obtained, which was not easy to separate using
silica gel flash column chromatography (see Supplementary data).
After 3-O-benzylation, TMSOCH3 with TMSOTf could make the
O
HO
OH OH
OBn
OH
D-Glucose
5
O
OH
O
(i)
(ii), (iii)
O
BnO
BnO
1,6-anhydro bond crashed to form a mixture of the
a,b-anomers
O
R1O
OBn OR1
of 7. This mixture could not be separated at this step in most cases.
Nevertheless, if exposed to different substituted sodium pheno-
lates (R2ONa), 7 could be transformed into 6-O-aryl‘ compounds
after further tosylation. After the catalytic hydrogenation step,
6a: R1 = (4-cyclohexyloxyl)-Ph, 73%
7a-7i
6b: R1 = 5,5-dioxo-dibenzothiophen-3-yl, 85%
6c
: R1 = Ph, 76%
: R1 = (2-isopropyl)-Ph, 66%
a,b-anomers could be separated by silica gel flash column chroma-
6d
6e: R1 = (3-isopropyl)-Ph, 69%
6f : R1 = (4-isopropyl)-Ph, 27%
6g: R1 = biphenyl-4-yl, 30%
tography. The desired target compounds (CAB-SHZH-01 to 34)
were obtained so (Scheme 1).
In our study, the 4-cyclohexyloxylphenol bearing a highly lipo-
philic substitute on the phenyl ring as R1OH was chosen at first to
react with 5 to obtain 6a. Considering the similarity in molecular
shape, another substituted phenol 5,5-dioxo-5H-5k6-dibenzothio-
phen-3-ol was also chosen to react with 5 to obtain 6b. In the fol-
lowing reactions, different aryl groups were appended to the
6-O-position on the carbohydrate core to produce compounds
CAB-SHZH-01 to CAB-SHZH-12 (Table 1). Here, 5,6,7,8-tetra-
hydronaphthalen-1-yl and 5,6,7,8-tetrahydro-naphthalen-2-yl
were prepared from naphthalen-1-yl and naphthalen-2-yl through
in situ reduction at a catalytic hydrogenation reaction condition.
Since this is a new class of compounds, it is difficult to predict
their potential pharmaceutical applications. Anyway, we started
our testing with tumor cell lines. The first batch of obtained
compounds (CAB-SHZH-01 to CAB-SHZH-12) were tested on three
human breast tumor cell lines, including MDA-MB-231, MDA-MB-
435, and MCF7, by standard MTT assays (see Supplementary data).
These tumor cell lines were chosen since they are routinely used in
our laboratory. The results indicated that CAB-SHZH-03 and CAB-
SHZH-05 exhibit modest inhibitory activities on all three cell lines
: R1 = naphthalen-1-yl, 15%
: R1 = naphthalen-2-yl, 46%
6h
6i
OR2
HO
OH
OR1
(iv), (v), (vi)
O
HO
HO
R2O
O
R1O
O
O
4 (CAB-SHZH-01-34)
Scheme 1. Synthesis of Methyl 6-O-R2-2-O-R1-
D
-glucopyranosides CAB-SHZH-01–
34. Reagents and conditions: (i) R1OH, NaH, EGDME, reflux; (ii) NaH, BnBr, Bu4NI,
THF, 0 °C to rt; (iii) TMSOCH3, TMSOTf, 3 Å MS, CH3CN, ꢀ45 °C to 45 °C; (iv) TsCl,
Et3N, DMAP, CH2Cl2, 0 °C to rt; (v) R2OH, NaH, DMF, 80 °C; (vi) Pd/C, H2, EtOAc/
CH3OH = 2:1.
substituent R1 at the 2-O-position first. Unfortunately, the regular
method using nucleophile to replace the axial bond leaving group
to form an equatorial bond did not work. Thus, we tried to make
the precursor epoxide undergo a ring opening reaction with a
nucleophile to install two hydroxyl groups at the 2- and 3-posi-
tions with the expected configuration.
with EC50 values ranging from 17 to 36 lM. The different potency
of CAB-SHZH-05 and CAB-SHZH-11, CAB-SHZH-03 and CAB-SHZH-
09 disregarding the configuration at 1-position of the glucopyrano-
sides indicates that 4-cyclohexyloxyl-phenyl at the 2-O-position is
2,3-Epoxide 5 was prepared from D-glucose following the meth-
ods reported in literature4–10 with 42% yield in six steps. Precursor
Table 1
Chemical structures and inhibitory activities on tumor cell lines of the compounds in the first batch
HO
OH
O
HO
OH
O
O
R2O
O
R2O
O
O
S
O
O
CAB-SHZH-01-06
CAB-SHZH-07-12
O
R2
OCH3
Yielda (%)
Inhibition % at 20
lM
EC50 (lM)
b
Compds
MDA-MB-231
MDA-MB-435
MCF7
MDA-MB-231
MDA-MB-435
MCF7
CAB-SHZH-01
CAB-SHZH-02
CAB-SHZH-03
CAB-SHZH-04
CAB-SHZH-05
CAB-SHZH-06
CAB-SHZH-07
CAB-SHZH-08
CAB-SHZH-09
CAB-SHZH-10
CAB-SHZH-11
CAB-SHZH-12
Ph
Ph
a
b
a
a
a
b
a
b
b
59
17
22
22
33
13
37
65
66
32
41
38
ꢀ11
ꢀ9
64
ꢀ8
24
0
ꢀ8
ꢀ14
30
ꢀ1
16
1
4
0
12
ꢀ5
17
ꢀ4
ꢀ9
ꢀ5
51
3
45
14
7
7
15
4
N.D.
N.D.
36
N.D.
20
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
26
N.D.
26
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
18
N.D.
17
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
4-Biphenyl
5,6,7,8-Tetra-H-naphthalen-1-yl
5,6,7,8-Tetra-H-naphthalen-2-yl
5,6,7,8-Tetra-H-naphthalen-2-yl
Ph
2
Ph
ꢀ16
29
ꢀ8
30
14
4-Biphenyl
5,6,7,8-Tetra-H-naphthalen-1-yl
5,6,7,8-Tetra-H-naphthalen-2-yl
5,6,7,8-Tetra-H-naphthalen-2-yl
a
a
b
2
7
a
Yield rate of the final hydrogenation reaction.
N.D. = not determined due to poor potency observed in the preliminary screening conducted at 20 lM.
b

H. Shi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2855–2858
2857
more effective than 5,5-dioxo-5H-5k6-dibenzothiophen-3-yl for
achieving the potency of these compounds. Also, comparing the
activities of CAB-SHZH-01 to CAB-SHZH-06, one can see that 4-
biphenyl or 5,6,7,8-tetrahydro-naphthalen-2-yl at the 6-O-position
is more effective than phenyl and 5,6,7,8-tetrahydronaphthalen-yl.
Encouraged by the anti-tumor activities exhibited by CAB-
SHZH-03 and CAB-SHZH-05, we launched another round synthesis
by transplanting the three important groups identified in the first
batch of compounds onto the 6-O- and the 2-O-positions on the
glucopyranosides. Some other substituted phenols were used to re-
act with 5. Additional epoxide ring opening compounds 6c–6i were
obtained so, expanding the diversity of R1. Here, R2 used on these
new compounds included 4-biphenyl, 5,6,7,8-tetrahydronaphtha-
len-2-yl, and 4-cyclohexyloxyl-phenyl group, which had been
proved effective for the biological activities of this class of com-
pounds. Compounds CAB-SHZH-13 to CAB-SHZH-27 (Table 2) were
obtained through the same synthetic route. Here, the 4-biphenyl
group on some compounds, to our surprise, was found to be hydro-
genated to 4-cyclohexylphenyl group besides the reduction of
naphthalenyl to 5,6,7,8-tetrahydronaphthalenyl group.
marized in Table 2, CAB-SHZH-03 and CAB-SHZH-13 to 18 have
different aryl groups as R1 but all share the same biphenyl group
as R2. Their potency on MDA-MB-231 cells are essentially the same
(EC50 P 32 l
M), indicating that modification of R1 is not that
important when R2 is an appropriate aryl group. In contrast, CAB-
SHZH-03, CAB-SHZH-05, CAB-SHZH-23, CAB-SHZH-24, and CAB-
SHZH-27 have the same 4-cyclohexyloxylphenyl group as R1 and
different aryl groups as R2. They do exhibit notably different po-
tency on MDA-MB-231 with EC50 = 12–36 lM. This observation
further supports that modification on R2 has priority over R1 in
terms of exploring the biological activities of this class of
compounds.
The most potent compound among all of the compounds ob-
tained by us is CAB-SHZH-27, which has EC50 values of 14, 12,
and 10 lmol/L on A549, MDA-MB-231 and HeLa cells, respectively
(Table 2). Three derivatives of this compound, that is, CAB-SHZH-
35 to 37, were prepared by protecting the two free hydroxyl groups
on the D-glucose core with different substituent groups (Table 3).
They were also tested on the three tumor cell lines. Interestingly,
these compounds lost the inhibitory activities demonstrated by
CAB-SHZH-27 completely. One may suspect that the structure–
activity relationship observed for this class of compounds arises
from different levels of general lipophilicity or cell permeability.
The second batch of compounds were tested on A549 (human
alveolar epithelial cell), MDA-MB-231 (human breast tumor cell),
and HeLa (human cervical tumor cell) cells by MTT assays. As sum-
Table 2
Chemical structures and inhibitory activities on tumor cell lines of the compounds in the second batch
HO
OH
HO
OH
HO
OH
O
OR1
OR1
OR1
O
O
O
O
O
O
O
O
O
CAB-SHZH-13-18
CAB-SHZH-19-20
HO OH
CAB-SHZH-21-24
HO
OH
OR1
O
R2O
O
O
O
O
O
O
CAB-SHZH-25-27
CAB-SHZH-28-34
–OCH3
R1
R2
Yielda (%)
EC50 (lM)
b
Compds
A549
MDA-MB-231
HeLa
CAB-SHZH-13
CAB-SHZH-14
CAB-SHZH-15
CAB-SHZH-16
CAB-SHZH-17
CAB-SHZH-18
CAB-SHZH-19
CAB-SHZH-20
CAB-SHZH-21
CAB-SHZH-22
CAB-SHZH-23
CAB-SHZH-24
CAB-SHZH-25
CAB-SHZH-26
CAB-SHZH-27
CAB-SHZH-28
CAB-SHZH-29
CAB-SHZH-30
CAB-SHZH-31
CAB-SHZH-32
CAB-SHZH-33
CAB-SHZH-34
Ph
Ph
4-Biphenyl
4-Biphenyl
4-Biphenyl
4-Biphenyl
4-Biphenyl
4-Biphenyl
b
5
17
68
23
44
36
8
21
14
50
10
45
17
15
33
23
48
15
49
6
N.D.
N.A.
34
N.D.
36
N.D.
33*
29*
32*
35*
19
N.A.
33*
26
18
14
14
29
*
a
a
b
a
a
b
a
b
a
b
a
a
a
a
b
a
b
a
b
(2-Isopropyl)-Ph
(3-Isopropyl)-Ph
(3-Isopropyl)-Ph
(4-Isopropyl)-Ph
(3-Isopropyl)-Ph
(3-Isopropyl)-Ph
(4-Isopropyl)-Ph
(4-Isopropyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
5,6,7,8-Tetra-H-naphthalen-2-yl
5,6,7,8-Tetra-H-naphthalen-1-yl
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
33
35*
30*
31
35*
32*
32
5,6,7,8-Tetra-H-naphthalen-2-yl
5,6,7,8-Tetra-H-naphthalen-2-yl
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyloxyl)-Ph
(4-Cyclohexyl)-Ph
(4-Cyclohexyl)-Ph
(4-Cyclohexyl)-Ph
(2-Isopropyl)-Ph
(2-Isopropyl)-Ph
(3-Isopropyl)-Ph
(3-Isopropyl)-Ph
(3,4-Dimethoxy)-Ph
(3,4-Dimethoxy)-Ph
(3,5-Dimethoxy)-Ph
N.A.
N.A.
35
25
26
N.A.
40*
32
27
25
18
17
28
12
20
25
37*
14
25
10
44*
36*
40*
38*
N.A.
N.A.
N.A.
41*
33*
41*
30*
N.A.
N.A.
N.A.
42*
47*
39*
28*
N.A.
N.A.
N.A.
a
a
44
16
a
Yield rate of the final hydrogenation reaction.
b
The data without an asterisk are derived from fitting the dose-dependent inhibition curves; the data with an asterisk are estimated since the dose-dependent inhibition
M; N.A. = no obvious activity was observed up to
curves are abnormal; N.D. = not determined due to poor potency observed in the preliminary screening conducted at 20
50 M.
l
l

2858
H. Shi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2855–2858
Table 3
most all active compounds could completely kill the tumor cells in
our test at a concentration lower than 50 M. Consequently, the
EC50 values for most compounds determined by us are in a rela-
tively narrow range between 10 and 40 M (Tables 1 and 2). In
Chemical structures and inhibitory activities on tumor cell lines of several derivatives
of CAB-SHZH-27
l
RO
OR
27
CAB-SHZH-
R=H
l
other words, these compounds behaved basically in an ‘on–off’
manner in our MTT assay on tumor cells. We suspect that there
is a special trans-membrane mechanism for this class of com-
pounds, which is activated only upon a certain condition. Once
these compounds enter the tumor cells, they are quite potent to
regulate some biological processes. Our hypothesis, however, re-
mains to be explored in the future.
RI/RBr, NaH,
O
THF, 0 oC to rt
O
O
O
35
36
CAB-SHZH-
CAB-SHZH-
R=CH3
R=Allyl
CAB-SHZH-37 R=Bn
O
a
Compds
R
Yield (%)
EC50
(lM)
In summary, we have developed a new synthetic method to
introduce bulky aryl groups at both the 2-O- and 6-O-positions
A549
MDA-MB-231
HeLa
CAB-SHZH-35
CAB-SHZH-36
CAB-SHZH-37
CH3
Allyl
Bn
94
86
78
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
on D-glucopyranoside. A class of 37 new compounds were success-
fully obtained in our study. They have been tested on several se-
lected tumor cell lines, some of which exhibited encouraging
inhibitory activities against tumor cell growth. Moreover, an inter-
esting ‘on–off’ mechanism was observed for some active com-
a
N.A. = No obvious activity was observed up to 50 lM.
pounds in our MTT assay.
A preliminary structure–activity
relationship of this class of compounds has been obtained, suggest-
ing that their inhibitory activities on tumor cell lines are the con-
sequence of a specific mechanism. We hope that our study adds
new knowledge to the organic chemistry of carbohydrate deriva-
tives as well as their potential pharmaceutical applications.
1.00
0.75
0.50
0.25
0.00
Acknowledgments
The authors are grateful to the financial supports from the Chi-
nese National Natural Science Foundation (Grants Nos. 20772149
& 90813006), the Chinese Ministry of Science and Technology
(Grant No. 2009ZX09501-002), and the Science and Technology
Commission of Shanghai Municipality (Grant No. 074319113).
The authors also thank Dr. Lihong Zhang, Dr. Xun Li, Dr. Xinglong
Zhang, Yan Li, and Zhengxi Zhang for their technical supports.
-1
0
1
2
log[µM]
Figure 2. Dose-dependent cytotoxicity of CAB-SHZ H27 on MDA-MB-231 cells.
Nevertheless, this set of results provides convincing evidence that
this class of compounds achieve their inhibitory activities on tu-
mor cells through a specific mechanism, in which the two free hy-
Supplementary data
droxyl groups at the 3- and 4-positions on the
an indispensable role.
Moreover, the second batch of compounds reveal a subtle role
of the methoxyl group at the 1-position: the inhibitory activities
D-glucose core play
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.03.045.
References and notes
of the a-anomer on three tumor cell lines are generally more obvi-
ous than the b-anomer of the same chemical structure, although
the difference is only marginal. This trend can be observed virtually
on all pairs of a- and b-anomers, including CAB-SHZH-13/14, CAB-
1. Meutermans, W.; Le, G. T.; Becker, B. ChemMedChem. 2006, 1, 1164.
2. Prasad, V.; Birzin, E. T.; McVaugh, C. T.; van Rijn, R. D.; Rohrer, S. P.; Chicchi, G.;
Underwood, D. J.; Thornton, E. R.; Smith, A. B., III; Hirschmann, R. J. Med. Chem.
2003, 46, 1858.
SHZH-16/17, CAB-SHZH-19/20, CAB-SHZH-21/22, CAB-SHZH-23/
24, CAB-SHZH-28/29, and CAB-SHZH-30/31 (Table 2). This result
also prompts that there is a specific mechanism behind the biolog-
ical activities of this class of compounds. Otherwise, one probably
should not observe such a consistent trend.
Most interestingly, an unexpected phenomenon was observed
in our MTT assay: The dose-dependent inhibition curves of most
active compounds are steep rather than a normal smooth S-shape
curve (Fig. 2). It seems that these compounds are not up-taken by
3. Vahid, B.; Marik, P. E. Chest 2008, 133, 528.
4. Czernecki, S.; Leteux, C.; Veyrieres, A. Tetrahedron Lett. 1992, 33, 221.
5. Tailler, D.; Jacquinet, J.-C.; Noirot, A.-M.; Beau, J.-M. J. Chem. Soc., Perkin Trans. 1
1992, 3163.
6. Leteux, C.; Veyrières, A. J. Chem. Soc., Perkin Trans. 1 1994, 2647.
7. Liang, Y.-Z.; Franz, A. H.; Newbury, C.; Lebrilla, C. B.; Patten, T. E.
Macromolecules 2002, 35, 3402.
8. Hawley, J.; Bampos, N.; Aboitiz, N.; Jiménez-Barbero, J.; López de la Paz, M.;
Sanders, J. K. M.; Carmona, P.; Vicent, C. Eur. J. Org. Chem. 2002, 2002, 1925.
9. Gehle, D.; Flörke, U.; Krohn, K. Acta Crystallogr., Sect. E 2005, 61, o664.
10. Xue, J.; Guo, Z. Tetrahedron Lett. 2001, 42, 6487.
tumor cells up to a concentration around 10
lM, and then for some
reasons they come into effect at higher concentrations. In fact, al-