Synthesis of MeON-neoglycosides of digoxigenin with 6-deoxy- and 2,6-dideoxy-D-glucose derivatives and their anticancer activity

Article abstract of DOI:10.1016/j.bmcl.2017.06.008

Cardiac glycosides show anticancer activities and their deoxy-sugar chains are vital for their anticancer effects. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and get more potent anticancer agents, a series of MeON-neoglycosides of digoxigenin was synthesized and evaluated. First, ten 6-deoxy- and 2,6-dideoxy-D-glucopyranosyl donors were synthesized starting from methyl α-D-glucopyranoside and 2-deoxy-D-glucose. Meanwhile, the digoxigenin was obtained by acidic hydrolysis of commercially available digoxin as glycosyl acceptor. Then, a 22-member MeON-neoglycoside library of digoxigenin was successfully synthesized by neoglycosylation method. Finally, the induction of Nur77 expression and its translocation from the nucleus to cytoplasm together with cytotoxicity of these MeON-neoglycosides were evaluated. The SAR analysis revealed that C3 glycosylation is required for their induction of Nur77 expression. Moreover, some MeON-neoglycosides (2b and 8b) could significant induce the expression of Nur77 and its translocation from the nucleus to cytoplasm. However, these compounds showed no inhibitory effects on the proliferation of cancer cells, suggesting that they may not induce apoptosis of NIH-H460 cancer cells and their underlying potential and application toward cancer cells deserves future study.

Full text of DOI:10.1016/j.bmcl.2017.06.008

Accepted Manuscript
Synthesis of MeON-Neoglycosides of digoxigenin with 6-deoxy- and 2,6-di-
deoxy-d-glucose derivatives and their anticancer activity
Dong-dong Wang, Xiao-san Li, Yu-zhou Bao, Jie Liu, Xiao-kun Zhang, Xin-
sheng Yao, Xue-Long Sun, Jin-Shan Tang
PII:
S0960-894X(17)30610-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.008
BMCL 25042
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 April 2017
29 May 2017
2 June 2017
Please cite this article as: Wang, D-d., Li, X-s., Bao, Y-z., Liu, J., Zhang, X-k., Yao, X-s., Sun, X-L., Tang, J-S.,
Synthesis of MeON-Neoglycosides of digoxigenin with 6-deoxy- and 2,6-dideoxy-d-glucose derivatives and their
anticancer activity, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.06.008
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Synthesis of MeON-Neoglycosides of digoxigenin with 6-deoxy- and
2,6-dideoxy-D-glucose derivatives and their anticancer activity
Dong-dong Wang a, Xiao-san Li a, Yu-zhou Bao b, Jie Liu b, Xiao-kun Zhang b, Xin-sheng Yao a,
Xue-Long Sun c, Jin-Shan Tang a *
a
Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan
University, Guangzhou 510632, People’s Republic of China
b
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, People’s Republic of
China.
c
Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene
Regulation in Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue,
Cleveland, Ohio 44115, United States
∗ Corresponding author: Jin-Shan Tang; E-mail: gztangjinshan@126.com; Tel: +86-20-85220785;
Fax: +86-20 85221559;

ABSTRACT:
Cardiac glycosides show anticancer activities and their deoxy-sugar chains are vital
for their anticancer effects. In order to study the structure-activity relationship (SAR)
of cardiac glycosides toward cancers and get more potent anticancer agents, a series
of MeON-neoglycosides of digoxigenin was synthesized and evaluated. First, ten
6-deoxy- and 2,6-dideoxy-D-glucopyranosyl donors were synthesized starting from
methyl α-D-glucopyranoside and 2-deoxy-D-glucose. Meanwhile, the digoxigenin was
obtained by acidic hydrolysis of commercially available digoxin as glycosyl acceptor.
Then, a 22-member MeON-neoglycoside library of digoxigenin was successfully
synthesized by neoglycosylation method. Finally, the induction of Nur77 expression
and its translocation from the nucleus to cytoplasm together with cytotoxicity of these
MeON-neoglycosides were evaluated. The SAR analysis revealed that C3
glycosylation is required for their induction of Nur77 expression. Moreover, some
MeON-neoglycosides (2b and 8b) could significant induce the expression of Nur77
and its translocation from the nucleus to cytoplasm. However, these compounds
showed no inhibitory effects on the proliferation of cancer cells, suggesting that they
may not induce apoptosis of NIH-H460 cancer cells and their underlying potential and
application toward cancer cells deserves future study.
Keywords: digoxigenin, MeON-glycosylation, deoxy-sugar, anticancer, Nur77 nuclear
receptor

Cardiac glycosides are clinically used as cardiotonic agents due to their strong
inhibitory activity toward the ubiquitous cell surface Na+/K+-ATPase. Recently, the
anticancer activities of cardiac glycosides have attracted more attention.[1-3] New
findings suggested that some cardiac glycosides could selectively inhibit the
proliferation of cancer cells while leaving normal cellular proliferation unaffected.[2, 4]
Preliminary SAR analysis revealed that C3 glycosylation is very important for their
anticancer effects.[5-7] Much effort has also been made to study the effects of different
sugar substitution on their anticancer effects, including O- and N-glycosides.[8-11]
Deoxy sugars, i.e. 6-deoxy- and 2,6-dideoxy sugars, are essential constituents of a
large number of biologically active natural glycosides and are the structural
characteristic of natural derived cardiac glycosides.[12, 13] Subtle sugar modification
has a dramatically effect on their anticancer effect.[14] In this study, a series of
6-deoxy-, 2,6-dideoxy-D-glucosyl and their partially methylated derivatives were
synthesized as glycosyl donors starting from commercially available methyl
α-D-glucopyranoside and 2-deoxy-D-glucose. Meanwhile, the digoxigenin was
synthesized from acidic hydrolysis of commercially available digoxin as the glycosyl
acceptor. Glycosylation of digoxigenin with novel glycosyl donors were achieved by
MeON-neoglycosylation,[8-10, 15] a chemoselective glycosylation that employs free
reducing sugars as glycosyl donors and thereby avoids the protection/deprotection
procedures producing the desired MeON-neoglycosides. For their anticancer activity,
the MeON-neoglycosides, along with MeON-digoxigenin neoaglycones, were
evaluated for their induction of Nur77 expression and cytotoxicity toward NIH-H460
cancer cells. Nur77, in addition to its regulation of transcription in the nucleus, has
extranuclear effects in response to a variety of apoptotic agents. Upon stimulation by
apoptosis-inducing agents, Nur77 is usually induced and the induced Nur77 protein
subsequently translocate from the nucleus to the cytoplasm, where it targets
mitochondria through interaction with Bcl-2, leading to cytochrome c release and
apoptosis.[16, 17] To our knowledge, this is the first systematic synthesis of 6-deoxy-,
2,6-dideoxy-glucosyl
and
their
partially
methylated
derivatives
for
MeON-neoglycosylation of digoxigenin aiming to study the structure-activity
relationship (SAR) of cardiac glycosides toward cancers.
Synthesis of 6-deoxy-D-glucopyranose and its partially methylated derivatives as
glycosyl donors. First, 6-deoxy-D-glucopyranose (D6G1) and its partially methylated

derivatives (D6G2-D6G8) were designed and synthesized as glycosyl donors.
Benzylidenated derivative of methyl-α-D-glucopyranoside (Glc-1) was the key
starting compound, which was obtained from benzylidenated derivative of
commercially available methyl α-D-glucopyranoside (Glc) (Scheme 1).[18] Glc-1 was
dibenzylated with NaH and BnBr in DMF to afford derivative Glc-2 [19]. The
intermediate Glc-2 was hydrolyzed by 1M HCl in DCM and MeOH to get derivative
Glc-3.[20] Iodination of intermediate Glc-3 with triphenylphosphine (Ph3P), iodine (I2),
and imidazole in dry toluene and then dehydrohalogenation with AIBN and Bu3SnH
to produce derivative Glc-4. [21] Next, Glc-4 was hydrogenolyzed with H2 over 10%
Pd/C in MeOH to yield methyl 6-deoxy-α-D-glucopyranoside (Glc-5). Hydrolysis of
derivative Glc-5 by 3M HCl led to obtain 6-deoxy-D-glucopyranose (D6G1).[19]
Methyl 4-O-methyl-6-deoxy-α-D-glucopyranoside (Glc-6) was prepared by
methylation of Glc-4 with NaH and CH3I in DMF and subsequent hydrogenolysis
with H2 over 10% Pd/C in MeOH.[19, 20] Derivative Glc-6 was subjected to hydrolyze
to get monomethylated 6-deoxy glycosyl donor D6G2.
Scheme 1. Synthetic route of 6-deoxy-D-glucopyranose and its partially methylated
derivatives starting from methyl α-D-glucopyranoside (Glc). Reagents and conditions:
(a) PhCH(OMe)2, TsOH⋅H2O, DMF, 60°C, 7h; (b) NaH, BnBr, DMF, 0°C→r.t., 8h. (c)
1M HCl, MeOH, DCM, 60°C, 5-7h; (d) PPh3, ImH, I2, Tol, 60°C, 3-5h; (e) AIBN,
Bu3SnH, Tol, 60°C, 3-5h; (f) 10% Pd/C, H2, MeOH, r.t. overnight; (g) 3M HCl, 80°C,
5-10h. (h) NaH, CH3I, DMF, 0°C→r.t., 3-6h; (i) Bu4NHSO4, BnBr, DCM, NaOH
(aq.), 60°C, 35h.

Preparation of monobenzylated derivatives Glc-7 and Glc-8 were achieved by
phase-transfer catalysis from the precursor Glc-1.[19, 22] The derivatives Glc-7 and
Glc-8 were methylated with NaH and CH3I in DMF and subsequent hydrolyzed by
1M HCl to yield derivatives Glc-9 and Glc-10, respectively.[20] Intermediates Glc-9
and Glc-10 were treated with Ph3P, I2, and imidazole in dry toluene for 3h at 60 °C
and then subjected to dehydrohalogenation with AIBN and Bu3SnH under 100 °C to
produce derivatives Glc-11 and Glc-12 in almost quantitative yield, respectively.[21]
Methyl
3-O-methyl-α-D-glucopyranoside
(Glc-13)
and
methyl
2-O-methyl-α-D-glucopyranoside (Glc-14) were prepared from derivatives Glc-11
and Glc-12 by catalytic hydrogenation to deprotect the benzyl groups, respectively.
Hydrolysis of Glc-13 and 14 by 3M HCl at 80 °C led to obtain the monomethylated
6-deoxy glycosyl donors (D6G3 and D6G4).[19]
The dimethylated derivatives Glc-15 and Glc-16 were achieved by methylation of
intermediates Glc-11 and Glc-12 with NaH and CH3I in DMF and subsequent
debenzylation by hydrogenolysis in high yields, respectively.[19, 20] The resultant
derivatives Glc-15 and Glc-16 were subjected to hydrolyze to yield dimethylated
6-deoxy glycosyl donors D6G5 and D6G6.[19] The precursor Glc-1 was methylated
with NaH and CH3I in DMF to get derivative Glc-17. Acidic hydrolysis of
intermediate Glc-17 with 1M HCl to yield intermediate Glc-18.[20] The 6-deoxy
dimethylated derivative Glc-19 was synthesized by iodination of intermediate Glc-18
with Ph3P, I2, and imidazole in dry toluene and then dehydrohalogenation with AIBN
and Bu3SnH.[21] Hydrolysis of intermediate Glc-19 by 3M HCl led to obtain
dimethylated 6-deoxy glycosyl donor D6G7.[19] The trimethylated derivative Glc-20
was prepared by further methylation of Glc-19 with NaH and CH3I in DMF.[20]
Hydrolysis of intermediate Glc-20 by 3M HCl yielded the trimethylated 6-deoxy
glycosyl donor D6G8.[19]
Synthesis of partially methylated 2,6-dideoxy-D-glucopyranoses as glycosyl donor.
The partially methylated methyl 2,6-dideoxy-α-D-glucopyranosides (Glc-24 and
Glc-25) were firstly prepared as depicted in Schemes 2. The commercial available
2-deoxy-D-glucopyranose was first glycosylated with MeOH catalyzed by acetyl
chloride, following by Fischer glycosylation method, and then reacted with
PhCH(OMe)2 and p-TsOH in DMF to produce benzylidenated derivative of methyl
23]
2-deoxy-α-D-glucopyranoside (Glc-21).[18,
The stereoselectivity of derivative

Glc-21 may be controlled by steric hindrance effect from 4,6-O-benzylidene acetal,
thus leading to the α-O-glycosylation. Also, the β isomer of Glc-21 could undergo
anomerization under heating condition, leading to generate thermodynamically stable
intermediate Glc-21.[24, 25] Methylation of the free 3-OH of intermediate Glc-21 with
NaH and CH3I yielded derivative Glc-22 in 98% yield. However, iodination and
subsequent dehydrohalogenation of methyl 2-deoxy-3-O-methyl-α-D-glucopyranoside
produced by acid hydrolysis of Glc-22 failed to produce the 2,6-dideoxy derivative.
Alternatively, treatment of intermediate Glc-22 with NBS and AIBN in the presence
of barium carbonate (BaCO3), following the Hanessian-Hullar protocol, successfully
afforded the brominated derivative Glc-23 in 71% yield.[26] Intermediate Glc-23 was
reduced
with
LiAlH4
in
THF
to
yield
methyl
3-O-methyl-2,6-dideoxy-α-D-glucopyranoside (Glc-24) in high yield.[27] Hydrolysis of
derivative Glc-24 by 3M HCl yielded monomethylated 2,6-dideoxy glycosyl donor
D6G9. Next, methylation of intermediate Glc-24 with NaH and CH3I gave methyl
3,4-O-dimethyl-2,6-dideoxy-α-D-glucopyranoside (Glc-25) in 36% yield. Hysrolyaia
of Glc-25 yielded dimethylated 2,6-dideoxy glycosyl donor D6G10.
Scheme 2. Synthesis of partially methylated 2,6-dideoxy-D-glucopyranose derivatives.
Reagents and conditions: (a) AcCl, MeOH, 50°C, 3h; (b) PhCH(OMe)2, TsOH⋅H2O,
DMF, 60°C, 7h; (c) NaH, CH3I, DMF, 0°C→r.t., 3-6h; (d) NBS, AIBN, CCl4, BaCO3,
75°C, 2h; (e) LiAlH4, THF, 50°C, 5h; (f) 3M HCl, 80°C, 5-10h.
Synthesis of MeON-digoxigenin neoaglycones as glycosyl acceptor. Preparation of
MeON-digoxigenin neoaglycones were initiated from commercially available digoxin

(Dig) (Scheme 3). Peracetylation of digoxin with Ac2O in pyridine and subsequent
regioselective acid-catalyzed hydrolysis of the sugar chain linked at C3 provided the
intermediate Dig-1 in 83% yield for two steps. Intermediate Dig-1 was oxidized with
Dess-Martain periodinane to yield ketone Dig-2 in high yield.[28] The resulting ketone
Dig-2 was converted to the corresponding methoxyimines (Dig-3) as a mixture of E
and Z configurations with methoxyamine hydrochloride salt in the presence of a weak
organic base (pyridine). The methoxyimine Dig-3 was subsequently reduced using
t-BuNH2⋅BH3 in 10% HCl to give a separable 2:1 mixture of C3 diastereomers
(Dig-4/5, α/β).[8, 29] Deprotection of the C12 acetyl protecting group by subsequent
zemplén deacylation with CH3ONa at room temperature afforded the requisite
neoaglycones Dig-6 (six steps, 22.0% overall yield) and Dig-7 (six steps, 12.0%
overall yield), respectively.[30] The stereochemistry of C3 for each diastereomer
(Dig-6 or Dig-7) was assigned based upon a comparison of chemical shifts of the H-3
protons (3S for 3.25 ppm, br s; 3R for 2.93-2.88 ppm, m) and C3 carbons (3S for 55.1
ppm; 3R for 60.4 ppm).[8, 10]
Scheme 3. Synthesis of MeON-digoxigenin neoaglycones as glycosyl acceptor.
Reagents and conditions: (a) Ac2O/pyr, 90°C, 12h; (b) 0.1M H2SO4, MeOH, 90 °C, 3h;
(c) Dess-Martin, DCM, r.t.,12h; (d) CH3ONH2⋅HCl, MeOH, pyr, r.t., 5h; (e)
t-Bu-NH2⋅BH3, 10% HCl (aq), EtOH, 0°C, 4h; (f) CH3ONa, MeOH, r.t., 8h.
Synthesis of MeON-neoglycosides of digoxigenin by neoglycosylation. With suitable
MeON-digoxigenin neoaglycones and 6-deoxy- and 2,6-dideoxy sugar glycosyl
donors in hand, the synthesis of novel MeON-neoglycosides was conducted by

neoglycosylation method (Scheme 4).[8, 11] First, optimization of the neoglycosylation
with D/L-glucopyranose was investigated and revealed a typical DMF/acetic acid (3: 1)
at 45 °C for 48 h as the best condition to afford the desired MeON-neoglycosides
while minimizing side reaction. Glycosylation of most glycosyl donors with
MeON-digoxigenin was accomplished under the optimized condition. Unfortunately,
we couldn’t get the desired MeON-neoglycosides from trimethylated donor D6G8 for
an unknown reason. We investigated with different solvents, type of organic acids,
reaction temperature, and equivalent of nucleophilic catalyst as well. It may be due to
three O-methyl (OMe) substitutions’ electronic donating property, especially, the
2-OMe, which reduces the electrophilicity of the C-1. In addition, free D- and
L-glucopyranoses were used as glycosyl donors to generate MeON-neoglycosides.
Eventually, a 22-member glycoside library was created in an average isolation yield
of 20%. The glycosidic bond of all the MeON-glycosides was characterized as β
1
orientation according to their H NMR spectra analyses, which is consistent with the
reported neoglycosides adopting 1,2-transanomer exclusively.[10, 15]
Scheme 4. Synthesis of novel MeON-neoglycosides of MeON-digoxigenin.
Induction of Nur 77 expression and inhibitory effects on cancer cell proliferation.
Cardiac glycosides exhibit strong anticancer effects by targeting Na+/K+-ATPase and
involving complex signaling pathways.[1, 3, 5] Our previous work suggested that some
cardiac glycosides showed strong inhibitory effects on the proliferation of cancer
cells.[31] Meanwhile, some cardiac glycosides could induce the Nur77 expression of
cancer cells in a dose and time dependent manner. Further study demonstrated that

induction of Nur77 expression and its subsequent translocation from the nucleus to
the cytoplasm are critical events in apoptosis induction by cardiac glycosides in
cancer cells, which underlay the new mechanism of action for cardiac glycosides
toward cancer cell.[31, 32] In this study, the induction of Nur77 expression for the
synthesized MeON-neoglycosides (1a-11a and 1b-11b) and its aglycones (Dig-6 and
Dig-7) were evaluated by western blot (Figure 1). Digoxin was used as positive
control. As a result, most of MeON-neoglycosides, especially, MeON-neoglycosides
2b, 8b, and 2a-4a exhibited significant induction of Nur77 expression at a
concentration of 20 nM compared with the positive control digoxin (Dig), but not the
aglycones, which suggested that C3 glycosylation is required for their induction of
Nur77 expression. Meanwhile, we evaluated the translocation of induced Nur77 from
the nucleus to cytoplasm treated by MeON-neoglycosides in NIH-H460 cells. We
found that some MeON-neoglycosides (2b, 5b, 8b, 1a, and 7a-10a) could
significantly induce the translocation of induced Nur77 from the nucleus to cytoplasm
(Figure 2).
Figure 1. Induction of Nur77 expression by MeON-neoglycosides. NIH-H460 cells
were incubated for 3h with neoaglycones and MeON-neoglycosides (20 nM), and
Nur77 expression was determined by Western blotting using anti-Nur77 antibody.

Figure 2. Efects of MeON-neoglycosides on translocation of the Nur77 protein from
the nucleus to the cytoplasm. NIH-H460 cells were treated with 20 nM
MeON-neoglycosides for 3 h. Endogenous Nur77 expression was immunostained
with anti-Nur77 antibody. Cells were costained with DAPI to visualize the nuclei.

Next, cytotoxicity of all the MeON-neoglycosides was assayed by MTT assay.
However, all MeON-neoglycosides didn’t show inhibitory effects on the proliferation
of NIH-H460 cancer cells at a concentration of 50 nM (viability rate > 90%) (Figure
3). Nur77 (also known as TR3 or NGFI-B), an orphan member of the nuclear receptor
superfamily, controls both survival and death of cancer cells.[16, 17] Recent studies
demonstrated that the Nur77 activities are regulated through its subcellular
localization. In the nucleus, Nur77 functions as an oncogenic survival factor,
promoting cancer cell growth. In contrast, it is a potent killer when migrating to
mitochondria, where it binds to Bcl-2 triggering cytochrome c release and apoptosis.
[33]
Our studies found that some MeON-neoglycosides (2b and 8b) could significant
induce the expression of Nur77 and its translocation from the nucleus to cytoplasm.
But, they didn’t demonstrate obvious inhibitory effects on the proliferation of cancer
cells, suggesting that they may not induce apoptosis of NIH-H460 cancer cells.
Recent findings demonstrated that Nur77 may also mediate the crosstalk
between inflammation and mitophagy to maintain homeostasis.[34] As
inflammatory mitochondrial dysfunction is implicated in the development of a range
of metabolic diseases and cancer, their underlying potential and application of
MeON-neoglycosides toward cancer cells deserves future study.
Figure 3. Viability rates of MeON-neoglycosides (1a-11a and 1b-11b) and their
corresponding aglycones toward NIH-H460 cells. NIH-H460 cells were incubated for
48h with neoaglycones and MeON-neoglycosides (50 nM), and cell viability was
assayed by the MTT method.

In conclusion, we have designed and successfully synthesized a series of
MeON-neoglycosides of digoxigenin with novel 6-deoxy- and
2,6-dideoxy-D-glucopyranosyl donors. We investigated their anticancer activity by
examine the induction of Nur77 expression and its translocation from the nucleus to
cytoplasm together with cytotoxicity toward NIH-H460 cancer cells of these
MeON-neoglycosides. Overall, we found that some novel MeON-neoglycosides
showed strong induction of Nur77 expression and its translocation from the nucleus to
cytoplasm by neoglycosylation modification, but their potential biological function is
not clear and deserves future research.
Acknowledgement
We are grateful to Ms. L. Wang, Ms. X.Y. Shen, Mr. Y.C. Ren and Dr. Y. Yu for the
HR ESI-MS and NMR measurements. This work was supported by National Natural
Science Foundation of China (No 81673320, 81502406), the State Key Laboratory of
Drug Research (No SIMM1601KF-09), and the National 111 Project of China (No.
B13038), and Fujian young teacher education research project (JA14009).
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2017. xx.xxx.
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Graphical Abstract:
Designing and synthesizing a 22-member MeON-neoglycoside library of digoxigenin
and evaluating their anticancer activity