Synthesis and Antiproliferative Activities of OSW-1 Analogues Bearing 2”-O-p-Acylaminobenzoyl Residues?

Article abstract of DOI:10.1002/cjoc.202000110

OSW-1 is a well-known natural saponin with potent antitumor activities. We have designed and prepared a small library of 22 OSW-1 analogues with a variety of p-acylamino-benzoyl groups installed at C2” of the xylose residue, wherein a regioselective (1→3)

Full text of DOI:10.1002/cjoc.202000110

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Synthesis and antiproliferative activities of OSW-1 analogues bearing 2’’-O-p-
acylaminobenzoyl residues
Authors: Lijun Sun, Di Zhu, Laura Olde Groote Beverborg, Ruina Wang, Yongjun
Dang, Mingming Ma, Wei Li,* and Biao Yu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000110.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000110.
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Chinese Journal
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CJC
中
国 化 学 - An International Journal
Synthesis and antiproliferative activities of OSW-1 analogues bearing 2’’-
O-p-acylaminobenzoyl residues
Lijun Sun,a,b Di Zhu,c Laura Olde Groote Beverborg,c Ruina Wang,c Yongjun Dang,c Mingming Ma,a Wei Li,*,d and Biao
Yu*,b
a Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China
b State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. Email: byu@sioc.ac.cn
c Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic
Medical Sciences, Fudan University, Shanghai 200032, China
d Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Email: wli@cpu.edu.cn
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
OSW-1 is a well-known natural saponin with potent antitumor activities. We have designed and prepared a small library of 22 OSW-1 analogues with a
variety of p-acylamino-benzoyl groups installed at C2’’ of the xylose residue, wherein a regioselective (1→3)-glycosylation of arabinoside 3,4-diol has been
achieved by manipulation of the protecting groups on the imidate donors. Bioassays lead to new structure-activity relationships as well as two applicable
fluorescent probes, which are found to localize to lysosomes in HeLa cells and could be used in further antitumor mechanism studies of OSW-1 in living
cells.
we envisioned SBF-1-based analogues bearing a p-amino-benzoyl
group at C2’’ of the xylose residue and an azido-substituted
aliphatic side chain on the aglycone moiety both highly active and
Background and Originality Content
OSW-1 (1) is a disaccharide saponin isolated from the bulb of
Ornithogalum saundersiae by Sashida and co-workers in the early
readily derivatizable into various probes (Figure 1). Particularly,
1990s (Figure 1).1-2 Owing to its exceptionally strong
fluorescent probes were designed, in which 4-(N,N-dimethyl
antiproliferative activities against tumor cell lines,3-9 OSW-1 (1) has
aminosulfonyl)-2,1,3-benzoxadiazole (DBD) was installed at either
attracted extensive researches on the synthesis, derivatization, and
the 2’’-(p-aminobenzoyl) group via acylation or the terminus of the
side chain via click reaction. Herein, we report the synthesis of
these new OSW-1 analogues and fluorescent probes bearing 2’’-O-
(p-acylamino-benzoyl)-xylose residues, their antiproliferative
structure-activity relationships.10-26 SBF-1 (2), a synthetic analogue
bearing an ester chain at C22,27 displays comparable antitumor
activities as the natural product. Due to its easy accessibility via
chemical synthesis, SBF-1 (2) has been used as a surrogate for OSW-
activities, and localization in HeLa cells.
1 (1) in biological studies.28-34 Very recently, we revealed that
analogue 3, with the original ester at the xylose residue being
replaced by amide, displayed even stronger antitumor activities
with the IC50 value as low as 0.11 nM against Jurkat T cell lines.35
On the other hand, the antitumor mechanism of these
molecules still remains elusive.28-34, 36-41. It is of great interest to
identify the antitumor-associated binding proteins which could be
exploited as drug targets for cancer treatment. Recently, Sakurai
and co-workers synthesized several OSW-1-based probes with
fluorescent tags installed at C3’’ or C4’’ on the xylose residue,42-47
and found these probes could localize to the ER and Golgi
apparatus in HeLa cells and induce Golgi stress.41
Based on our previous structure-activity relationship studies,
This article has been accepted for publication and undergone full peer review but has not been
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differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000110
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First author et al.
Report
Scheme 1 Synthesis of BDA-protected hemiacetal 7.
O
22
0 oC to rt;
R
20
17
1. Ac2
O,
pyridine,
OH
2. p-TolSH, BF3·OEt2 CH Cl 0 oC to rt;
,
,
2
2
O
16
O
O
2'
rt;
,
HO
HO
3. NaOCH3, CH2Cl2, CH3OH,
OH
AcO
,
4''
4.
BF
3·OEt2
2,3-butanedione,
O
O
CH(OMe)3
to rt, 35%
OH
OH
D-xylose ( )
HO
CH3OH, 0 o
C
3
HO
4
HO
2''X
3''
Y
DMAP,
PNBCl,
DIPEA,
OCH3
O
OCH3
O
CH2Cl2
rt,
,
O
O
0 oC to 91%
O
STol
STol
OPNB
=
O
O
work:
Previous
=
=
Y
1
R
OSW-1
X
OMe
=
OMe
,
O,
( ),
OH
OCH3
OCH3
11
=
5
=
2
X
Y
R
SBF-1
,
6
O,
( ),
O
O
OCH3
11
=
H
NBS, CH2Cl2
,
2O,
acetone, rt, 98%
N3
= =
NH, Y OMe
3 R
,
X
,
O
O
OH
O
OPNB
work:
Present
OCH3
11
7
=
N3
=
=
acylamino
X
,
Y
Analogues:R
groups
O,
O
N
N
=
11
,
N
Fluorescent
PEG
R
DBD
DBD
probes:
O
In our previous studies, it was found that xylosyl donor 8
bearing BDA protecting group at O3 and O4 led mainly to the
undesired (1→4)-linked disaccharide product when coupled with l-
arabinoside 3,4-diol 10,35 whereas the glycosylation with TES-
protected donor 9 offered the desired (1→3)-linked disaccharide
as the major product (Figure 2).8, 11 In order to improve the regio-
selectivity and verify our assumption that these regio-selectivities
were majorly determined by the protecting groups at O3 and O4 of
=
=
acylamino
X
Y
groups
O,
O
11
=
=
Y
N3
or
R
=
X
,
O,
NH
O
Figure 1 Structures of OSW-1 (1), its analogues, and fluorescent probes.
the donors instead of the substitutes at O2 or anomeric position,50-
53
we envisioned the TES-protected thioxyloside 11 as
a
Results and Discussion
counterpart of BDA-protected 6 in the present studies (Scheme 2).
Thus, the BDA group on 6 was removed by a mixture of 95%
CF3COOH and CH3CN (2:1), and the resulting diol was treated with
TESOTf and 2,6-lutidine in CH2Cl2 at −20 oC to give 3,4-di-O-TES
donor 11 in 89% yield (based on 6). Subjection of thioglycoside 11
into hydrolysis under the conditions of NBS and H2O in CH2Cl2 and
acetone at rt gave the corresponding hemiacetal 12 in 51% yield.
The synthesis commenced with the conversion of d-xylose into
butane-bisacetal (BDA)-protected β-thioxyloside 5 (Scheme 1).48-51
Thus, treatment of d-xylose (4) with Ac2O in pyridine provided
tetraacetyl xylose, which was subjected to condensation with p-
TolSH in the presence of BF3·OEt2. The resulting thioxyloside was
treated with NaOCH3 in a mixture solvent of CH3OH and CH2Cl2 at
rt to remove the acetyl groups;48 subsequent protection under the
conditions of 2,3-butanedione and CH(OMe)3 in the presence of
BF3·OEt2 provided 5 in an overall yield of 35% (based on 4).49-51 As
a precursor of the desired p-aminobenzoyl group for late-stage
acylation, the relatively inert p-nitrobenzoyl (PNB) group was
introduced into alcohol 5 to give 6 in 91% yield under the
conditions of PNBCl, DIPEA, and DMAP in CH2Cl2. Treatment of
thioglycoside 6 with NBS and H2O resulted in hemiacetal 7 in 98%
yield, which was a ready precursor for further preparation of
imidate and ortho-alkynylbenzoate donors.
OCH3
O
OH
O
TESO
TESO
O
O
O
CCl3
NH
O
STol
HO
OMBz
AcO
NPhth
OCH3
OBn
9
10
8
Figure 2 Structure of donors 8, 9, and acceptor 10 in previous studies.
Next, hemiacetal 7 was coupled with CCl3CN in the presence
of DBU at rt (Scheme 3), and the resulting trichloroacetimidate
donor 13 was obtained in only 76% yield due to partial hydrolysis
during column purification. On the other hand, the conversion of
hemiacetal 7 into shelf-stable alkynylbenzoate donor 15 was highly
efficient upon treatment with o-hexynylbenzoic acid (14) and EDCI
in the presence of DIPEA and DMAP.54-61 Similar results were
obtained in the transformation of hemiacetal 12 into the
corresponding trichloroacetimidate 16 and alkynylbenzoate 17.
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
Scheme 2 Synthesis of TES-protected hemiacetal 12.
reaction temperature from −20 oC to −60 oC gradually increased the
proportion of 18 and decreased the proportions of 19 and
trisaccharide 20 (entries 1 to 3, entries 5 to 7, and entries 8 to 10).
The best proportion of 18 was obtained when alkynylbenzoate
donors 15 was used at −60 oC under the conditions of Ph3PAuNTf2
(0.1 equiv) and 4Å MS in CH2Cl2 (entry 10), wherein 18 was found
slightly more than 19. The most effective suppression of the
formation of trisaccharide 20 was observed in the pre-activation
glycosylation with thioxyloside donor 6 under the conditions of BSP,
1. 95% CF COOH:CH CN
(2:1)
3
3
0 oC to
rt
O
TESO
TESO
2. TESOTf,
2,6-lutidine,
STol
OPNB
CH2Cl2 –20 o 89%
,
C,
6
11
acetone,
NBS, CH2Cl2
,
O
TESO
TESO
OH
OPNB
H
rt, 51%
2O,
o
TTBP, Tf2O, and 3Å MS in CH2Cl2 at −70 C (entry 4).62-64 However,
12
the resulting molar ratio of 18/19 (1.0:1.3) was not as good as that
in entry 10 (1.0:0.90).
Scheme 3 Synthesis of xylosyl imidate and alkynylbenzoate donors.
rt
CCl3CN, DBU, CH2Cl2
,
The results above revealed that low temperature was preferred
for preparing the desired (1→3)-linked disaccharide, hence the
following glycosylation with TES-protected donors (11, 16, 17) was
conducted at −60 oC or −70 oC. No trisaccharide product was
observed under these conditions, so that only the mixture of
(1→3)-linked disaccharide 21 and (1→4)-linked disaccharide 22
was isolated and examined to give the ratios of 21/22 and the yields
of 21 (Table 1, entries 11-15). As expected, TES-protected donors
generally displayed better 3-OH selectivity than BDA-protected
donors. Although treatment of thioglycoside donor 11 with NIS and
TMSOTf at –70 oC led to a complex mixture (entry 11), the
corresponding pre-activation glycosylation with BSP, Tf2O, and
TTBP gave 21/ 22 in a ratio of 1.0:1.1 (entry 12), that was slightly
better than the 18/19 ratio of 1.0:1.3 in entry 4. However, the yield
of 21 was only 25% due to the formation of some unidentified by-
products. Gratifyingly, alkynylbenzoate donor 17 under the
catalysis of Ph3PAuNTf2 (0.2 equiv) was found to provide a
satisfactory 21/22 ratio of 1.0:0.67 and much less by-products,
giving the desired (1→3)-linked disaccharide 21 in 56% yield (entry
15). Notably this reaction was conducted at –60 oC that was
7 12
/
o
or
14
( ),
acid
CH2Cl2
-hexynylbenzoic
DMAP, DIPEA,
EDCI,
OCH3
O
O
O
TESO
O
CCl3
NH
O
CCl3
NH
TESO
O
OPNB
16
OPNB
OCH3
66%
,
13
76%
,
nBu
nBu
OCH3
O
O
TESO
TESO
O
O
O
O
OPNB
OPNB
OCH3
O
O
17
95%
,
15
,
94%
With three BDA-protected donors (6, 13, 15) and their TES-
protected counterparts (11, 16, 17) at hand, we set out to examine
their performance in the glycosylation of l-arabinoside 3,4-diol 10.
The crude products were purified with
a flash column
chromatography to offer a mixture of the glycosylation products,
which were then run on HPLC to determine the UV absorption of
each product as a reference for their molar ratio. As depicted in
Table 1, all three BDA-protected donors (6, 13, 15) led to the full
consumption of diol 10 and provided three glycosylation products,
i.e., (1→3)-linked disaccharide 18, (1→4)-linked disaccharide 19,
and trisaccharide 20 (entries 1−10). The molar ratios of
disaccharides 18/19 were approximately equal to the ratios of their
UV absorption, whereas the UV absorption ratio of 18/20 could
reflect the change of the molar ratio given the different UV
absorptivity of the disaccharide and trisaccharide. All the three
BDA-protected donors resulted in more (1→4)-linked disaccharide
19 than (1→3)-linked disaccharide 18 (entries 1−9). Lowering the
uncommon
for
gold(I)-catalyzed
glycosylation
with
alkynylbenzoates, implying the high reactivities of these xylosyl
donors. For trichloroimidate donor 16, the glycosylation
underwent smoothly at –60 oC and the regio-selectivities were
found to be greatly dependent on the promoters. When TMSOTf
was employed (entry 13), a modest 21/22 ratio of 1.0:1.2 was
obtained similar to the 18/19 ratio of 1.0:1.1 in entry 7, whereas
the replacement with a catalytic amount of BF3·OEt2 could
significantly increase the ratio to 1.0:0.55. The best yield of 21 was
obtained in 64% using TES-protected donor 16 under the catalysis
of BF3·OEt2 in CH2Cl2 at −60 oC.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1 Glycosylation of arabinoside diol 10 with BDA-protected donors (6, 13, 15) and TES-protected donors (11, 16, 17).
OCH3
OH
OH
OCH3
O
O
O
O
O
conditions
O
O
O
O
+
HO
6 13 15 11 16 17
/
/
/
/
/
O
O
OPNB
HO
OCH3
19
AcO
AcO
OPNB
18
OBn
OCH3
OBn
AcO
10
OBn
OCH3
O
O
OH
O
H
3CO
TESO
TESO
O
O
O
O
TESO
TESO
O
O
OPNB
HO
O
OCH3
PNBO
O
AcO
OPNB
21
O
OBn
AcO
O
O
O
OPNB
OBn
22
AcO
OCH3
OBn
20
Ratio of the UV
absorption of
Ratio of the UV
absorption of
Yield of
entry
donor
Conditions
Temperature
21
18
/19
/
20
21
−
−
−
−
−
−
−
−
−
−
/22
1
−20 oC
−40 oC
−60 oC
−70 oC
−20 oC
−40 oC
−60 oC
−20 oC
−40 oC
−60 oC
−70 oC
−70 oC
−60 oC
−60 oC
−60 oC
1.0:1.9:0.98
1.0:1.6:0.75
1.0:1.2:0.54
1.0:1.3:0.23
1.0:1.6:0.52
1.0:1.4:0.60
1.0:1.1:0.40
1.0:1.6:0.77
1.0:1.3:0.67
1.0:0.90:0.44
−
−
−
−
−
−
−
−
−
−
−
2
NIS, TMSOTf, 4Å MS, CH2Cl2
BSP, TTBP, Tf2O, 3Å MS, CH2Cl2
TMSOTf, 4Å MS, CH2Cl2
6
3
4
5
6
13
7
8
9
15
11
Ph3PAuNTf2, 4Å MS, CH2Cl2
10
11
12
13
14
15
NIS, TMSOTf, 4Å MS, CH2Cl2
BSP, TTBP, Tf2O, 3Å MS, CH2Cl2
TMSOTf, 4Å MS, CH2Cl2
complex
1.0:1.1
−
25%
39%
64%
56%
−
1.0:1.2
16
17
BF3·OEt2, 4Å MS, CH2Cl2
−
1.0:0.55
1.0:0.67
Ph3PAuNTf2, 4Å MS, CH2Cl2
−
Both (1→3)-linked disaccharides 18 and 21 could be used in
the subsequent preparation of OSW-1 analogues. Thus, the BDA
protecting group on 18 was removed in a mixture of 95% CF3COOH
and CH3CN (Scheme 4), and the resulting triol was subjected to TES
protection under the conditions of TESOTf and 2,6-lutidine at –20
oC to result in 23 in 62% yield. A highly efficient Pd/C-promoted
reduction was conducted at 1 atm H2 atmosphere for 3 h to convert
the nitro group into amino group with the anomeric benzyl group
being intact. The resulting 24 was then treated with Boc2O in the
presence of DMAP at rt to provide 25 in 43% yield and 26 in 35%
yield, respectively. Next, the anomeric benzyl group on 26 was
successfully removed by an enhanced 24-h hydrogenolysis with an
excess amount of Pd/C, and the resulting hemiacetal was coupled
with alkynylbenzoic acid 14. A Ph3PAuNTf2-catalyzed glycosylation
was then conducted with either azido-bearing aglycone 27 or
o
alkyne-bearing aglycone 28 at 0 C (See SI for the preparation of
28),35 and subsequent removal of the TES and Boc groups under
the conditions of CF3COOH and CH2Cl2 at rt furnished the desired
OSW-1 analogues 29 and 30 which bear a 2-O-(p-amino-benzoyl)-
xylose residue.
Alternatively, an enhanced hydrogenolysis of disaccharide 23
was employed to remove the anomeric benzyl group and
simultaneously to convert the nitro group into amino group
(Scheme 5). Subsequently selective condensation of the resulting
acetal with alkynylbenzoic acid 14 gave a mixture of epimers 31 in
61% yield with the α/β ratio of 1:10. The intact amino group was
then coupled with a variety of acyl chlorides, anhydrides, and
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim
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Running title
Chin. J. Chem.
carboxylic acids. Ph3PAuNTf2-catalyzed glycosylation of aglycone
27 and final removal of the TES groups furnished sixteen OSW-1
analogues, including 32–38 with benzoyl-derived groups, 39–46
with aliphatic acyl groups, and 47 with the fluorescent DBD group.
Scheme 4 Synthesis of OSW-1 analogues 29 and 30 bearing 2-O-(p-amino-benzoyl)-xylose residue.
1. 95% CF COOH:CH CN
(2:1)
3
3
0 o
to rt;
C
OTES
OH
OCH3
10% Pd/C, H2 1atm
,
EtOAc, 95%
O
O
O
O
2. TESOTf,
2,6-lutidine,
O
O
TESO
TESO
O
O
CH2Cl2 –20 oC 62%
,
,
AcO
OPNB
18
AcO
OPNB
23
OCH3
OBn
OBn
OBn
OTES
OTES
OTES
O
O
O
O
O
O
O
O
TESO
TESO
TESO
TESO
TESO
TESO
O
O
Boc
CH2Cl2
DMAP
2O,
AcO
AcO
AcO
O
,
O
rt
OBn
OBn
+
O
O
O
Boc2N
H2N
BocHN
26
35%
,
24
25
,
43%
O
O
9
9
O
R
O
R
OH
O
OH
O
OH
27
AcO
=
=
R
R
,
N3
(CH2)3
O
O
OH
HO
HO
28
,
HO
=
HO
O
1.10% Pd/C, H2 1 atm, EtOAc, rt;
,
29
R
,
N3 8%
,
(CH2)3
O
14
,
rt;
EDCI, DMAP, DIPEA, CH Cl
,
2 2
2.
3.
4.
=
27 28
H2N
/
Ph PAuNTf
MS, CH Cl 0 οC;
,
2 2
,
,
4Å
rt
30 R
9%
2
,
,
3
CF3COOH, CH2Cl2
,
Scheme 5 Synthesis of OSW-1 analogues 32–47 bearing 2-O-(p-acylamino-benzoyl)-xylose residue.
nBu
OTES
rt
1.10% Pd/C, H2 1 atm, EtOAc,
,
OTES
O
14
61%,
rt,
,
2.
EDCI, DMAP, DIPEA, CH Cl
O
,
TESO
TESO
2
2
O
O
O
O
TESO
TESO
α
:
=
1:10)
β
(
O
AcO
O
O
AcO
OPNB
23
OBn
O
31
H2N
1. aRCl, DIPEA, DMAP, CH2Cl2 0 °C to rt;
,
O
12
or b
or
chloride,
DIPEA Et N
ROH,
,
2,4,6-trichlorobenzoyl
or
O
3
N3
OH
toluene THF, rt, then DMAP, CH2Cl2 rt;
,
O
O
O
or c
or d
AcO
R
DIPEA, DMAP,
rt;
CH2Cl2
,
2O,
N
N
S
O
O
OH
O
N
HO
Me
2SnCl2
THF, rt;
DBD-COCl,
,
2,4,6-collidine,
HO
HO
O
27
,
2.
Ph PAuNTf,
MS, CH Cl 0 oC;
,
4Å
3
2
2
N
d47
O
rt
3. CF3COOH, CH2Cl2
,
20%
O
,
O
RHN
O
O
O
O
O
F
O
F
O
F
CF3
N
N
CF3
8%
CN
NO2
16%
O
F
O
28%
a37
a36 22%
38 14%
a35
b
a33 11%
a32
,
,
,
,
,
a34 7%
,
,
O
O
O
O
O
O
O
O
4
O
CN
O
CF3
O
8
c42
13% b43
,
b46
22%
,
c44
8%
,
b41
b40
b45
23%
26%
,
,
b39
11%
,
8%
,
33%
,
Compound 38 was coupled with DBD-PEG2-alkyne 48 via a Cu-
catalyzed click reaction in the presence of tris[(1-benzyl-1H-1,2,3-
triazol-4-yl)methyl]amine (TBTA) and sodium ascorbate in DMF
and H2O. The crude product was purified by HPLC to afford the
desired probe 50 with the saponin residue connecting the
fluorescent DBD tag via a flexible and hydrophilic PEG linker.
Similar coupling of compounds 32, 38, and 47 with biotin-PEG4-
alkyne 49 via click reaction provided three probes (i.e., 51–53) with
the biotin group extended from the aglycone side chain.
With these 22 OSW-1 analogues at hand, we evaluated their
antiproliferative activities against Jurkat T tumor cell lines and
CRL1999 normal cell lines (Table 2). Compounds 29 and 30 bearing
p-aminobenzoyl group at C2’’ displayed similarly potent activities
as OSW-1 (1) and SBF (2) bearing the p-methoxybenzoyl group.
With an IC50 value of 1.0 nM, alkyne derivative 30 was found 10
Chin. J. Chem. 2019, 37, XXX－XXX
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First author et al.
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time more potent than azide derivative 29 against Jurkat T,
implying that the terminal group at the aglycone side chain could
influence the antiproliferative activities. For those with an
additional benzoyl-derived residue at the p-amino group, i.e., 32–
33 and 35–36 with either an electron-donating methoxyl group or
an electron-withdrawing nitro or nitrile group, were found to
retain the potent activities with IC50 values against Jurkat T in the
range of 2.5–15 nM, which was consistent with the previous
presumption that a variation at this site could be tolerable.3, 46, 65-
containing 38 also significantly descended, excluding it from
further use as a photoaffinity probe.
On the other hand, compounds 39–42 bearing short aliphatic
acyl residues showed better activities than the aforementioned
benzoyl-derived analogues against Jurkat T cell lines with IC50
values in the range of 1.1–5.9 nM (Table 2). Increased IC50 values
were observed on those bearing electron-withdrawing nitrile or
trifluoromethyl groups (e.g. 43 and 44) as well as the analogues
with long acyl chains. Particularly, compound 46 bearing a very
long hydrophobic side chain lost the antiproliferative activities
against CRL1999 normal cell lines.
66
The p-trifluoromethylbenzoyl derivative 37 was less potent,
whereas compound 34 bearing 2,4,6-trifluorobenzoyl group was
found to be inactive. Moreover, the activities of the diazirine-
Scheme 6 Synthesis of OSW-1 probes bearing DBD or biotin residues.
•
rt
48 49
TBTA, sodium ascorbate,
O
5H
DMF/H
2O,
/
CuSO4
,
2O,
O
32 38 47
/
/
10
10
N
N
O
O
O
N
N
N
N
OH
OH
O
O
O
O
AcO
AcO
O
O
OH
O
O
OH
HO
HO
O
HO
HO
HO
HO
O
O
O
O
O
O
O
O
N
RHN
S
CF3
H
O
O
N
N
H
N
O
HN
O
O
N
O
O
N
50
16%
,
N
S
O
=
H
N
O
H
O
H
N
N
N
S
O
N
O
O
S
51
R=
, 74%,
53
R
, 96%,
O
O
N
N
O
O
N
O
O
O
O
N
N
O
48
=
52
CF3
N
R
, 71%,
H
HN
O
S
N
O
O
O
O
N
H
O
N
H
H
49
Table 2 Antiproliferative activities of the synthetic OSW-1 analogues and probes against Jurkat and CRL1999 cell lines.
IC50 (nM)
Jurkat
12
IC50 (nM)
Jurkat
1.0
Compounds
Compounds
CRL1999
17
CRL1999
7.0
29
32
34
36
38
40
42
44
46
50
52
Taxol
30
33
35
37
39
41
43
45
47
51
53
5.1
27
15
19
>1000
2.5
>1000
9.0
7.4
14
89
96
>100
2.7
>100
13
1.1
3.8
2.7
8.1
5.9
9.1
58
49
33
78
51
78
>100
60
>1000
>100
>100
36
2.8
59
21
82
18
>100
>1000
7.7
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Chin. J. Chem. 2019, 37, XXX－XXX
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It is interesting to find that compound 47 with a bulky DBD
group at C2’’ still retained excellent activities against Jurkat T cell
lines (Table 2), making it a useful fluorescent probe for mechanism
studies in living cells. The addition of a PEG-linked biotin group to
the aglycone side chain on 47 decreased the activities of the
resulting derivative 53. And similar decrease of activity was
observed in the transformation of 32 into its biotin-PEG-
conjugated 51. Nevertheless, similar transformations of the
diazirine derivative 38 into its biotin-PEG-conjugated 52 and DBD-
PEG-linked 50 were found to increase the activities against Jurkat
cells.
further studies on the mechanisms of action of this important type
of anticancer compounds.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
We acknowledge the financial support from the National
Natural Science Foundation of China (21672248 and 21621002),
E-Institutes of Shanghai Municipal Education Commission
(E09013), the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20020000), and the K. C. Wong
Education Foundation.
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c Department, Institution, Address 3
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&
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&
Co. KGaA,
Weinheim
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