Design, synthesis, and biological testing of 4β-[(4-substituted)-1,2, 3-triazol-1-yl]podophyllotoxin analogues as antitumor agents

Article abstract of DOI:10.1002/ardp.200700116

A series of 4β-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin analogues have been synthesized with high regio-selectivity by employing copper(I)-catalyzed 1,3-dipolar cycloaddition of 1-O-propargyl monosaccharides with C4β-azido podophyllotoxin and C4β-azido-4′-O-demethyl podophyllotoxin. All the compounds were evaluated for their anticancer activity against a panel of six human cancer cell lines. Among these, 4′-O-demethyl podophyllotoxin congeners are showing promising anticancer activity mainly against HCT-15 (colon) and DU-145 (prostate) cells.

Full text of DOI:10.1002/ardp.200700116

126
Arch. Pharm. Chem. Life Sci. 2008, 341, 126–131
Full Paper
Design, Synthesis, and Biological Testing of 4b-[(4-
Substituted)-1,2,3-triazol-1-yl]podophyllotoxin Analogues as
Antitumor Agents
Pitta B. Reddy1, David V. Paul1, Satyam K. Agrawal2, Ajit K. Saxena2, Halmuthur M. S. Kumar1,
Ghulam N. Qazi1, 2
1 Departments of Synthetic Chemistry, Indian Institute of Integrative Medicine, Jammu-Tawi, India
2 Department of Pharmacology, Indian Institute of Integrative Medicine, Jammu-Tawi, India
A series of 4b-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin analogues have been synthesized
with high regio-selectivity by employing copper(I)-catalyzed 1,3-dipolar cycloaddition of 1-O-prop-
argyl monosaccharides with C4b-azido podophyllotoxin and C4b-azido-49-O-demethyl podophyl-
lotoxin. All the compounds were evaluated for their anticancer activity against a panel of six
human cancer cell lines. Among these, 49-O-demethyl podophyllotoxin congeners are showing
promising anticancer activity mainly against HCT-15 (colon) and DU-145 (prostate) cells.
Keywords: Copper(I) / Cycloaddition / Podophyllotoxin / Regio-selectivity /
Received: May 31, 2007; accepted: September 7, 2007
DOI 10.1002/ardp.200700116
Supporting information for this article is available from the author or on the www under
http://www.wiley-vch.de/contents/jc_2019/2008/200700116_s.pdf
Introduction
Podophyllotoxin 1 (Fig. 1) is a lignan isolated from the
roots of the North American Podophyllum peltatum Lin-
naeus, the Tibetan P. emodi Wall, or the Taiwanese species
Podophyllum pleinthum [1]. It has been known to inhibit
the assembly of tubulin into microtubules through tubu-
lin binding, but the high toxicity of podophyllotoxin has
limited its application as a drug in cancer chemotherapy
[2]. The biological activity of 1 has led to extensive struc-
tural modification resulting in several clinically useful
compounds. Many derivatives of podophyllotoxin that
are potent inhibitors of mitosis have been synthesized
and examined as antitumor agents. Among these, etopo-
side VP-16 [3], compound 2, and teniposide VM-26 [4],
compound 3, are two semisynthetic glucosidic cyclic ace-
Correspondence: H. M. Sampath Kumar, Synthetic Chemistry Division,
Indian Institute of Integrative Medicine, Jammu-Tawi-180 001, India.
E-Mail: hmskumar@yahoo.com
Fax: +91-191 254 8607
Figure 1. Structure of compounds 1–6: Podophyllotoxin, etopo-
side, teniposide, NK-611, GL-331, and TOP-53.
tals of podophyllotoxin (Fig. 1). The clinical efficacy and
intriguing mechanism of the podophyllotoxin-derived
Abbreviations: comparative molecular field analysis (CoMFA); Quantita-
tive Structure-Activity Relationship (QSAR)
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Arch. Pharm. Chem. Life Sci. 2008, 341, 126–131
4b-Podophyllotoxin Analogues as Antitumor Agents
127
Table 1. A series of nine compounds of 4b-[(4-substituted)-
1,2,3-triazol-1-yl]podophyllotoxin derivatives.
glucosides has greatly stimulated interest in further stud-
ies on the modification of the C-4 substituted of 2 for bet-
ter antitumor activity. Their clinical efficacy is due to
their ability to inhibit the enzyme DNA-topoisomerase II
by stabilizing a cleavable complex in which the DNA is
cleaved and covalently linked to enzyme. They are cur-
rently used in chemotherapy for various types of cancer,
including small cell lung cancer, testicular carcinoma,
lymphoma, and Kaposi's sarcoma [2, 5]. To improve topoi-
somerase-II inhibition and to overcome the problems of
drug resistance, myelosuppression, and poor oral avail-
ability, extensive efforts have been made world over.
Molecular area-oriented chemical modification of podo-
phyllotoxin has revealed structural features critical for
the topoisomerase-II inhibition includes 49-demethyla-
tion, 4-epimerization, trans-lactone D ring with 2a, 3b
configuration, and free rotation of ring E. Such struc-
ture–activity relationships (SAR) [6] unambiguously dem-
onstrate that C-4 is the only molecular area tolerable to
significant structural diversification. In NK-611, com-
pound 4, (Fig. 1) the 299-hydroxyl group in the glucose
ring of 2 has been replaced with an N,N-dimethylamino
moiety. The main advantage of this compound is its supe-
rior water solubility compared to that of 2. It is currently
undergoing phase-I clinical evaluation. Two 4b-analogs
GL-331, compound 5, and TOP-53, compound 6, of podo-
phyllotoxin (Fig. 1), reported recently, have exhibited
potential anticancer activity. Compound GL-331 is a 4b-
arylamino derivative, which is currently under phase-II
clinical trials against several forms of cancer, especially
resistant malignancies [7]. GL-331, a 4b-arylamino deriv-
ative, was more active than etoposide both in vitro and in
vivo, and retained cytotoxicity against resistant cells. 4b-
alkylated derivatives TOP-53 [8], currently under phase-I
clinical trials, was a more potent topoisomerase-II inhibi-
tor than etoposide. It exhibited high activity to non-small
cell line cancer in both tumor cells and animal tumor
models [9] and showed nearly wild-type potency against a
mutant yeast type-II enzyme highly resistant to etoposide
[10].
Compound
10a
R1
R2
Yield (%)
CH3
89
10b
CH3
95
10c
10d
CH3
CH3
90
88
10e
10f
CH3
H
90
86
10g
10h
H
H
88
85
Etopophos, an etoposide prodrug in which a disodium-
phosphate salt was prepared at the 49-phenolic oxygen, is
also in phase-II clinical trials. Topoisomerase-II inhibitory
activity, antitumor spectra, and significantly different
drug-resistance profiles demonstrated by NK-611, etopo-
phos, GL-331, and TOP-53 suggested the important role of
various C-4 substitutions to the activity profiles of etopo-
side analogs and the feasibility of optimizing these com-
pounds through rational C-4 modification. This postu-
late, further reinforced by composite pharmacophore
model proposed by Mac Donald et al. [11] and the compa-
rative molecular field analysis (CoMFA) models generated
10i
H
87
by Zhiyan Xiao et al. [12] indicated that the C-4 molecular
area could accommodate considerable structural diver-
sity. The CoMFA model further demonstrated that bulky
substituents at C-4 might be favorable for topoisomerase-
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P. B. Reddy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 126–131
II inhibition and enhanced cytotoxicity [13]. Accordingly,
a lot of derivatization has been done at the C-4 position
of epipodophyllotoxin, in order to generate the lead mol-
ecules. Accordingly, numerous derivatives have been gen-
erated at C-4 position of epipodophyllotoxin and their
cytotoxicity has been evaluated. Copper-mediated click
chemistry has gained immense importance in recent
years, offering distinct advantages over the conventional
azide-terminal acetylene cycloaddition to generate tria-
zolyl moieties with very high regio-selectivity. Thus, the
copper (I)-catalyzed reaction yields exclusively the single
1,4-disubstituted isomer in about 90% yield at room tem-
perature [14], whereas the reaction under conventional
heating conditions leads to the formation of 1,4- and 1,5-
disubstituted triazole isomers [14].
As a part of our drug-discovery program, we initiated a
research program directed towards the rational design
and synthesis of lead compounds for potentially interest-
ing drugs from 4b-podophyllotoxin azides. Accordingly,
a series of novel regio-selective epipodophyllotoxin deriv-
atives (Table 1) bearing bulky 4-substituted triazoles at
the C-4 side chain have been synthesized. All these com-
pounds were evaluated for their in-vitro anticancer activ-
ity against a panel of human cancer cell lines DU-145
(prostate), PC-3 (prostate), A-549 (lung), HOP-62 (lung),
HCT-15 (colon), SF-295 (CNS).
Scheme 1. Click-chemistry strategy for the synthesis of novel tri-
azolyl-podophyllotoxins.
methane for 5 h to the corresponding iodo-derivative fol-
lowed by hydrolysis with H2O/Me2CO/barium carbonate
to 49-O-demethyl-epipodophyllotoxin [16]. The key inter-
mediate, 4b-azido-49-O-demethyl-podophyllotoxin was
obtained in excellent yield by treating the latter with TFA
and NaN3 [16]. On the other hand, epipodophyllotoxin
was obtained by the reaction of podophyllotoxin with
CH3SO3H and NaI in acetonitrile for 15 min followed by
hydrolysis with H2O/Me2CO/barium carbonate.
4b-Azido-podophyllotoxin was obtained in excellent
yield (A85%) by treating epipodophyllotoxin with TFA
and NaN3. The azides 7 and 8 obtained were allowed to
react with the above terminal-alkynes 9 in presence of
CuSO465 H2O, sodium ascorbate in t-butyl alcohol and
water (1 : 2) at room temperature to selectively get 4b-[(4-
substituted)-1,2,3-triazol-1-yl] derivatives in excellent
yield. Using this click chemistry protocol, a series of nine
compounds of 4b-[(4-substituted)-1,2,3-triazol-1-yl]podo-
phyllotoxin derivatives have been synthesized (Table 1).
Our subsequent literature survey revealed a report by
Chen et al. [17] who presented a- and b-isomers of only
three 5-substituted triazoles, the synthesis of which has
been achieved in moderate yields through the alkylidine
phosphorane dipolar cycloaddition with podophyllo-
toxin azide under benzene reflux conditions and further,
the resulting triazoles were screened against a single cell
line i. e., L1210, and the magnitude of cytotoxicity was
found to be in parity with etoposide. Carbohydrate-based
triazolyl analogues cannot be obtained by the alkylidine
phosphorane cycloaddition method. The 1,3-dipolar
cycloaddition of 4b-azidopodophyllotoxin with alkynes
under solvent-free microwave irradiation to the corre-
sponding 4b-1,2,3-triazol-1-yl-podophyllotoxins was
reported by Shi et al. [17], but the method involving
microwave irradiation leads to the formation of 1,4- and
1,5-disubstituted triazole isomers with the exception of
symmetrical alkynes. However, no biological data has
been presented for these compounds,. whereas the click
Results and discussion
Chemistry
As illustrated in Scheme 1, 4b-[(4-substituted)-1,2,3-tria-
zol-1-yl]podophyllotoxin derivatives were synthesized by
the cycloaddition reaction of C4b-azido-49-O-demethyl
podophyllotoxin and C-4b-azido-podophyllotoxin with
prop-2-ynyl-b-D-sugar pyranosides (prop-2-ynyl-b-D-gluco-
pyranoside, prop-2-ynyl-b-D-mannopyranoside, prop-2-
nyl-b-D-galactopyranoside, and prop-2-ynyl-b-D-rhamno-
pyranoside). These terminal alkynes were synthesized
according to the literature procedure in which commer-
cially available b-D-glucopyranose penta-acetate, b-D-gal-
actopyranose penta-acetate, b-D-mannopyranose penta-
acetate and b-D-rhamnoyranose tetracetate were reacted
with propargyl alcohol in the presence of BF3-Et2O cata-
lyst to obtain in high yield and selectivity, the corre-
sponding propargyl derivatives [15] followed by deacety-
lation with NaOMe in MeOH [15]. C4b-Azido-49-O-
demethyl podophyllotoxin was synthesized according to
the literature procedure in which the podophyllotoxin
was first converted to 49-O-demethyl-epipodophyllotoxin
by the inversion of 4-hydroxyl and simultaneous deme-
thylation of 49-OCH3 using CH3SO3H and NaI in dichloro-
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Arch. Pharm. Chem. Life Sci. 2008, 341, 126–131
4b-Podophyllotoxin Analogues as Antitumor Agents
129
Table 2. IC50 values (lM) of in-vitro cytotoxicity of 4b-[(4-substi-
.MS of all compounds showed the [M + Na] adduct as the
molecular ion.
tuted)-1,2,3-triazol-1-yl]podophyllotoxin against
human cancer cell lines.
a
panel of
Cell linesa)
Biology
Media and cell lines
Compound DU-145 PC-3
A-549 HCT-15 HOP-62 SF-295
The six human cancer cell lines used for the test were DU-
145 (prostate), PC-3 (prostate), A-549 (lung), HOP-62
(lung), HCT-15 (colon), and SF-295 (CNS). Cells were main-
tained in RPMI-1640 medium with 2 mM glutamine, sup-
plemented with 10% fetal bovine serum and containing
100 lg/mL streptomycin and 100 units/mL penicillin at
378C in an atmosphere of 5% CO2 and 90% relative
humidity in a carbon dioxide incubator.
By comparing the cytotoxic potential of these com-
pounds (Table 2) with regard to the methoxy moieties as
well as the different sugar substitutions, the following
conclusions can be drawn:
10a
10b
10c
10d
10e
10f
10g
10h
10i
25.8
42
127
221
316
94.9
268
34.6
24.3
8.62
20.8
100
125
556
59.9
15
NDb)
16
NDb)
142
178
121
NDb)
26.8
35.1
14.5
53.4
88
237
18.6
26.5
3.11
4.95
2.73
5.04
51.8 237
114
NDb)
0.93
3
8.55
2.01
6.88
7.33
7.04
7.63
1
5.27 16.1
5.96 2.51
16.2
4.8
3.57
2.14
1
8.29
5.69
Etoposide 2.97
a)
Cell lines: DU-145 (prostate), PC-3 (prostate), A-549 (lung),
HOP-62 (lung), HCT-15 (colon), SF-295 (CNS).
ND = not determined.
b)
(a) The presence of a hydroxy moiety on the ring E is
essential; compounds containing the dimethoxy moiety
(10f–10i) are more active than those containing a trime-
thoxy moiety (10a–10e). (b) Introducing the 499-substi-
tuted, sugar-based compounds led to enhanced cytotoxic
activity and it is in par with etoposide. (c) Compounds in
which the sugar moiety is per-acylated (10b) are having
less activity than compounds where there are free sugars.
(d) From the IC50 values of entire ring E-containing dime-
thoxy-substituted compounds, it was found that the
activity was at par with different sugar-substituted deriv-
atives viz., glucose-, galactose-, rhamnose-, and mannose-
bearing analogues. (e) It was found that these compounds
generally exhibited promising activity against the two
cell lines, DU-145 and HCT-15. (f) Among all the com-
approach presented by us being environmentally benign
and high yielding, provides a library of structurally dis-
tinct 4-substituted podophyllotoxin triazolyls and the
cytotoxicity evaluation has been performed against a
panel of six human cancer cell lines, but few are found to
exhibit an impressive cytotoxicity.
1
All the products were characterized by H-NMR, 13C-
NMR, IR, ESI-MS, and elemental analysis. In1H-NMR, cycli-
zation of azides to triazoles was confirmed by the shift of
the 4-a H to around d 6 and the resonance of H-5 in the
triazole ring in the aromatic region. The structure was
further supported by the 13C-NMR, which showed all the
carbon signals corresponding to triazole derivatives. ESI-
Table 3. The log-p values of compound 10a–10i and etoposide.
Entry
Log p
n OHNHa)
n ONb)
Mass (amu) n Violationsc) n Rotbd)
MPSA (A0 2 e)
)
Volume (A0 3)
10a
10b
10c
10d
10e
10f
10g
10h
–0.504
+1.877
–0.504
–0.504
+0.504
–0.78
–0.78
–0.78
+0.228
+0.698
4
0
4
4
3
5
5
5
4
3
16
20
16
16
15
16
16
16
15
13
657.63
825.78
657.63
657.63
641.63
643.60
643.60
643.60
627.60
588.56
2
2
2
2
2
2
2
2
2
2
9
17
9
9
8
8
8
8
7
202.57
193.34
202.57
202.57
182.34
213.56
213.56
213.56
182.345
160.86
551.82
697.86
551.82
551.82
543.56
534.29
534.29
534.29
526.03
493.50
10i
Etoposide
5
a)
n OHNH = number of OH and NH groups.
n ON = number of O and N atoms.
n Violations = number of violations of Lipinski rule.
n Rotb = number of rotatable bonds.
b)
c)
d)
e)
MPSA = molecular polar surface area.
All parameters of the Table were calculated using molinspiration software.
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P. B. Reddy et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 126–131
pounds synthesized, compound 10f, which contained a Synthesis of compound 10b
To a solution of 10a (2 mmol) in acetic anhydride (6 mL), pyri-
dimethoxy moiety on ring E and a glucose moiety on the
triazolyl ring, was found to be the most promising in this
study.
In Table 3, a list of QSAR parameters for the derivatives
is presented comparing them with the standard etopo-
side, a drug derived from podophyllotoxin itself. Similar
to etoposide, the molecular weight of each analogue gen-
erated by us exceeded the Lipinski limit (etoposide M.W.
588.56). The log P values of the derivatives ranged
between –0.78 to +1.87.
In conclusion, a series of novel 4b-[(4-substituted)-1,2,3-
triazol-1-yl]podophyllotoxin derivatives were synthesized
and screened for anticancer activity against a panel of six
human cancer cell lines. From the derived cytotoxicity
data it was found that all the compounds with a dime-
thoxy moiety on ring-E are having activity comparable
with that of the standard drug etoposide. It was observed
that compound 10f is most active among all the screened
compounds, and even more potent than etoposide
against the above studied cell lines.
dine (1.5 mL) was added and stirred at room temperature for 6 h.
After completion, water was added (40 mL) and extracted with
ethylacetate (2620 mL). The combined extracts were dried over
Na2SO4 and evaporated on rotary evaporator to give white solid
(95%).
25
Spectral data (10f): mp. 208–2108C; [a]D –36.86 (c = 0.8,
MeOH); IR (KBr): 1058, 1126, 1239, 1458, 1591, 1774, 2923,
1
3440 cm– 1; H-NMR (200 MHz, CD3OD): 3.19–3.36 (m, 8H, C11-
CH2b, C2-CH, C3-CH, C3999-CH, C4999-CH, C5999-CH, C6999-CH2), 3.65–3.79
(m, 8H, C11-CH2a, C2999-CH, C39-OCH3, C59-OCH3), 4.38 (d, J = 7.6 Hz,
2H, C699-CH2O), 4.75–4.79 (m, 2H, C1999-CH, C1-CH), 5.98 (d, J =
4.3 Hz, 2H, OCH2O), 6.26 (d, J = 3.8 Hz, 1H, C4-CH), 6.38 (s, 2H, C29-
CH, C69-CH), 6.65 (s, 1H, C8-CH), 6.68 (s, 1H, C5-CH), 7.83 (s, 1H, C599-
C=CH-N);13C-NMR (50 MHz, CD3OD): 38.58 (C-3), 44.80 (C-1), 45.21
(C-4), 56.82 (26OCH3), 59.93 (C-2), 63.07 (C-6999), 68.86 (C-699), 69.00
(C-11), 71.63 (C-4999), 75.00 (C-3999), 76.55 (C-5999), 78.10 (C-2999), 103.27
(-OCH2O-), 103.91 (C-1999), 109.35 (C-29, C-69), 111.25 (C-5, C-8),
124.36 (C-49), 126.12 (C-599), 133.41 (C-10), 135.63 (C-9), 136.57 (C-
19), 144.57 (C-6), 147.65 (C-499), 150.81 (C-7), 152.23 (C-39, C-5'),
173.26 (C-12); ESI MS [M + Na]+: 666.2; Anal. calcd. (C30H33N3O13):
C: 55.99, H: 5.17, N: 6.53; found C: 55.92, H: 5.11, N: 6.51; Anal.
calcd. (C30H33N3O13): C: 55.99, H: 5.17, N: 6.53; found C: 55.92, H:
5.11, N: 6.51.
Authors thank CSIR, New Delhi, for the award of fellowships to
the graduate students.
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The authors have declared no conflict of interest.
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