New potential inhibitors of DNA topoisomerase. Part II: Design and synthesis of α-lapachone derivatives under microwave irradiation

Article abstract of DOI:10.1016/j.bmcl.2008.12.006

A new series of potential inhibitors of DNA topoisomerase II were synthesized from facile materials (aromatic aldehydes, Meldrum's acid and 2-hydroxynaphthalene-1,4-dione) under microwave irradiation. The method provides a valuable tool in designing new a

Full text of DOI:10.1016/j.bmcl.2008.12.006

Bioorganic & Medicinal Chemistry Letters 19 (2009) 828–830
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New potential inhibitors of DNA topoisomerase. Part II: Design and synthesis
of a-lapachone derivatives under microwave irradiation
b
a
a,
*
Ping Wei a, Xiaohong Zhang b, Shujiang Tu b, , Shu Yan , Hanjie Ying , Pingkai Ouyang
*
a College of Life and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, Jiangsu, 210009, PR China
b School of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of Biotechnology for Medicinal Plant, Xuzhou, Jiangsu, 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of potential inhibitors of DNA topoisomerase II were synthesized from facile materials (aro-
matic aldehydes, Meldrum’s acid and 2-hydroxynaphthalene-1,4-dione) under microwave irradiation.
The method provides a valuable tool in designing new and more potent cytotoxic analogues. This proce-
dure is advantageous both economically and environmentally.
Received 23 October 2008
Revised 1 December 2008
Accepted 3 December 2008
Available online 7 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Potential inhibitors
DNA topoisomerase II
a-Lapachone
Microwave irradiation
O
O
B
Cancer has been proven to be the second most common cause of
death after cardiovascular disease in the developed world.1 Mass
screening programs of natural products by the National Cancer
Institute have identified the quinone moiety as an important phar-
macophoric element for cytotoxic activity.2
OH
O
C
A
O
O
Naturally occurring naphthoquinones comprise an important
class of natural products with a wide range of biological activity3,4
arising from their ability to cause DNA modification. Among the
structurally diverse naphthoquinone natural products, lapachol
(a) and several 1,4- and 1,2-naphthoquinones are associated with
diverse biological activities5 and are components of antibacterial,6
fungicidal,6 antimalarial7 trypanocidal,8 antiparasitic,8 and antitu-
moral9 agents.
a
b
Lapachones are minor components in plants, therefore they are not
readily available in large quantities from natural sources. The needs
for large quantities of naturally occurring substances and their ana-
logues demand the new and convenient synthetic methods.
Keeping the availability of the starting materials, the synthetic
efficiency, and simplicity of procedures in our minds, we developed
an efficient method to prepare a new class of a-lapachone deriva-
tives with diversed structure in one pot by three-component con-
densation (Scheme 1).
One of the most important lapachol derivatives with antitumoral
activityis a-lapachone (b). Structure–activity relationship studies in
lapachones have shown that the modification to the C-ring10 leads to
significant changes in bioactivities, which are important in search-
ing for possible lead compounds with more potent pharmaceutical
activity and less toxicity. On the basis of biological properties, 1,4-
and 1,2-naphthoquinones are considered privileged structures in
medicinal chemistry,11 with the 1,4-naphthoquinones having great
cancer-preventing potential.12 In addition, more recent investiga-
O
O
O
Ar
O
ArCHO
tions have shown that
a-lapachone is an effective DNA topoisomer-
O
O
ase II inhibitorand is a potentialleadcompound for thedevelopment
of drugs for the treatment of multidrug resistant cell lines with low
expressions of topoisomerase II.13
1
+
O
O
HOAc
MWI
OH
O
2
3
O 4
* Corresponding authors. Tel.: +86 516 83500365; fax: +86 516 83403165.
E-mail address: laotu2001@263.net (S. Tu).
Scheme 1. Synthetic route to
a
-lapachone derivatives 4.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.006

P. Wei et al. / Bioorg. Med. Chem. Lett. 19 (2009) 828–830
829
Table 1
Optimization of solvent and temperature for the synthesis of 4b
Table 2
Synthesis of product 4 under microwave irradiation
Entry
Solvent
T/°C
Time/min
Yield/%
Entry
Product
Ar
Time (min)
Yield (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
Glycol
EtOH
DMF
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
100
100
100
100
105
110
115
120
125
130
8
10
10
7
6
6
5
5
4
4
76
80
73
83
85
88
89
91
93
89
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-FC6H4
4-ClC6H4
4-BrC6H4
4
4
3
5
3
4
3
4
4
5
6
6
89
93
92
89
87
89
91
88
90
84
86
83
210–212
224–227
242–244
208–210
235–238
208–211
219–221
238–242
278–282
231–235
203–206
212–215
4-CH3C6H4
3-NO2C6H4
3,4-OCH2OC6H3
4-NO2C6H4
2-ClC6H4
2,4-Cl2C6H3
4-OH-3-NO2C6H3
3,4,5-(CH3O)3C6H2
Thien-2-yl
9
10
11
12
4j
4k
4l
The reaction showed in Scheme 114 was employed to optimize
the reaction conditions. Different organic solvents, containing gla-
cial acetic acid (HOAc), glycol, EtOH, and N,N-dimethylformamide
(DMF) were examined in the reaction of 4-chlorobenzaldehyde
(1b, 1.0 mmol), Meldrum’s acid (2, 1.0 mmol) and 2-hydroxynaph-
thalene-1,4-dione (3, 1.0 mmol) to investigate how the solvents
affect the yields. All reactions were carried out at the maximum
power of 200 W (initial power 100 W) at 100 °C. The results
showed that reaction with HOAc as solvent gave higher yields
and shorter reaction time compared with others (Table 1, entries
1–4). HOAc was thus chosen as the solvent for all further reactions.
Moreover, the same reaction was carried out in the range of 100–
130 °C in increments of 5 °C each time in HOAc under microwave
irradiation. When the temperature was increased from 100 to
125 °C, the yield of product 4b was improved from 83% to 93%
(Table 1, entries 4–9). However, further increase of the tempera-
ture to 130 °C did not improve the yield of product 4b. So the best
temperature for the reaction was 125 °C. In order to demonstrate
the efficiency and applicability of the methodology, we performed
the reaction of a variety of substituted aromatic as well as hetero-
aromatic aldehydes as reactants using these optimal microwave
experimental conditions [solvent, HOAc, 125 °C, 200 W (maximum
power)]. The results are summarized in Table 2. Both aromatic
aldehydes bearing either electron-donating groups (such as alkoxy
and methyl) and electron-withdrawing groups (such as nitro or ha-
lide) afforded high yields of a-lapachone derivatives 4. Moreover, a
O
HO
O
O
Ar
O
O
O
O
O
O
O
O
O
O
-H2O
O
+
3
ArCHO
CHAr
O
O
O
O
O
6
1
2
5
O
O
Ar
Ar
O
O
Ar
O
O
-CH3COCH3
-CO2
O
O
O
O
O
O
OH
O
O
O
7
8
4
Scheme 2.
Cl
O
O
O
O
O
O
HOAc
MWI
Cl
C
+
H
OH
O
O
O
O
5b
3
4b
Scheme 3. Synthetic route of compound 4b yield, 91%; time, 4 min.

830
P. Wei et al. / Bioorg. Med. Chem. Lett. 19 (2009) 828–830
2. (a) Driscoll, J. S.; Hazard, G. F., Jr.; Wood, H. B., Jr.; Goldin, A. Cancer Chemother.
Rep. 2 1974, 4, 1–27; (b) Liu, K. K.-C.; Li, J.; Sakya, S. Mini-Rev. Med. Chem. 2004,
4, 1105.
heterocyclic aldehyde, thiophene-2-carbaldehyde (Table 2, entry
12), still showed high reactivity.
The detailed mechanism is still unclear, however a plausible
pathway to products 4 is illustrated in Scheme 2. In the initial step,
the condensation between aromatic aldehydes 1 and Meldrum’s
acid 2 gave intermediate 5. Michael addition between 5 and 3 then
furnished the intermediate 6, which isomerized to 7, subsequently
underwent intramolecular cyclization and then released acetone
and carbon dioxide to give compounds 4.
3. (a) Thomson, R. H. Naturally Occurring Quinones IV: Recent Advances; Blackie
Academic and Professional: London, 1997; (b) Thomson, R. H. Naturally
Occurring Quinones III: Recent Advances; Chapman and Hall: London, 1987.
4. (a) Hudson, A. T. Spec. Publ. R. Soc. Chem. 1988, 65, 266; (b) Elleff, S.; Kennaway, N.
G.; Buis, N. R. M.; Darley-Usmar, U. M.; Capaldi, R. A.; Bank, W. J.; Chance, B. Proc.
Natl. Acad. Sci. USA 1984, 81, 3529; (c) Powis, G. Pharmacol. Ther. 1987, 35, 57.
5. Ravelo, A.; Estévez-Braun, A.; Chávez-Orellana, H.; Pérez-Sacau, E.; Mesa-
Silverio, D. Curr. Top. Med. Chem 2004, 4, 241.
6. Guiraud, P.; Steiman, R.; Campos-Takaki, G. M.; Seigle-Murandi, F.; Simeon de
Buochberg, M. S. Planta Med. 1994, 60, 373.
7. (a) de Andrade-Neto, V. F.; Goulart, M. O. F.; da Silva Filho, J. F.; da Silva, M. J.;
Pinto, M. C. F. R.; Pinto, A. V.; Zalis, M. G.; Carvalho, L. H.; Krettli, A. U. Bioorg.
Med. Chem. Lett. 2004, 14, 1145; (b) Pérez-Sacau, E.; Estévez-Braun, A.; Ravelo,
A. G.; Gutiérrez, D.; Giménez, A. Chem. Biodiversity 2005, 2, 264.
8. (a) Goulart, M. O.; Zani, C. I.; Tonholo, J.; Freitas de Abreu, F. C.; Oliveira, A. B.;
Raaslan, D. S.; Starling, S.; Chiari, E. Bioorg. Med. Chem. Lett. 1997, 7, 2043; (b)
Ferreira, V.; Jorqueira, A.; Souza, A.; da Silva, M.; de Souza, M.; Gouvea, R.;
Rodrigues, C.; Pinto, A.; Castro, H.; Santos, D.; Araujo, H.; Bourguignon, S.
Bioorg. Med. Chem. 2006, 14, 5459.
9. (a) Fujiwara, A.; Mori, T.; Lida, A.; Ueda, S.; Nomura, T.; Tokuda, H.; Nishino, H. J.
Nat. Prod. 1998, 61, 629; (b) Krishnan, P.; Bastow, K. F. Biochem. Pharmacol. 2000,
60, 1367; (c) Pérez-Sacau, E.; Estévez-Braun, A.; Ravelo, A. G.; Ferro, E. A.; Tokuda,
H.; Mukainaka, T.; Nishino, H. Bioorg. Med. Chem. 2003, 11, 483; (d) Suzuki, M.;
Amano, M.; Choi, J.; Park, H. J.; Williams, B. W.; Ono, K.; Song, C. W. Radiat. Res.
2006, 165, 525; (e) Lee, J. I.; Choi, D. Y.; Chung, H. S.; Seo, H. G.; Woo, H. J.; Choi, B.
T.; Choi, Y. H. Exp. Oncol. 2006, 28, 30; (f) Woo, H. J.; Park, K.-Y.; Rhu, C.-H.; Lee, W.
H.; Choi, B. T.; Kim, G. Y.; Park, Y.-M.; Choi, Y. H. J. Med. Food 2006, 9, 161.
10. Sacau, E. P.; Esteveg-Braun, A.; Ravelo, A. G.; Ferro, E. A.; Tokuda, H.;
Mukainaka, T.; Nishino, H. Bioorg. Med. Chem. 2003, 11, 483.
11. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; Di Pardo, R. M.; Freindinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotte,
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kimkel, K. A.; Springer, J. P.; Hirshfield,
J. J. Med. Chem. 1988, 31, 2235; (b) Mason, J. S.; Morize, I.; Menard, P. R.;
Cheney, D. L.; Hulme, C.; Labandiniere, R. F. J. Med. Chem. 1999, 42, 3251.
12. (a) Itoigawa, M.; Ito, C.; Tan, H. T.-W.; Okuda, M.; Tokuda, H.; Nishino, H.;
Furukawa, H. Cancer Lett. 2001, 174, 135; (b) Kapadia, G. J.; Balasubramanian,
V.; Tokuda, H.; Konoshima, T.; Takasaki, M.; Koyama, J.; Tagahaya, K.; Nishino,
H. Cancer Lett. 1997, 113, 47.
The observation of compound 4b in the reaction of 5b with 3 in
the same conditions (Scheme 3) provided the evidence supporting
this proposed mechanism.
Structures of all the products were characterized by IR, 1H NMR,
13C NMR and elemental analysis. All the data are conformity with
the structures.
In conclusion, an efficient MW-assisted multi-component
tandem reaction to constitute the
a-lapachone derivatives has
been developed. The reaction is easy to perform in high yields by
using inexpensive starting materials. The operational simplicity,
combined with environmental friendly aspect, make this new het-
erocycle synthetic strategy highly attractive and promising for the
development of compounds of potential synthetic interest. Addi-
tionally, the newly synthesized a-lapachone analogues may pres-
ent potential inhibitive ability of DNA topoisomerase II. Further
efforts are underway to explore their bioactivity and the results
will be reported in due course.
Acknowledgments
We are grateful for financial support from the National Science
Foundation of China (No. 20672090) and Natural Science Founda-
tion of the Jiangsu Province (No. BK2006033), Six Kinds of Profes-
sional Elite Foundatin of the Jiangsu Province (No. 06-A-039) and
Graduate Foundation of Xuzhou Normal University (No.
08YLB028).
13. (a) Krishnan, P.; Bastow, K. F. Cancer Chemother. Pharmacol. 2001, 47, 187; (b)
Krishnan, P.; Bastow, K. F. Biochem. Pharmacol. 2000, 60, 1367.
14. The general procedure for 4 was as follows: A mixture of aromatic aldehyde 1
(1.0 mmol), Meldrum’s acid 2 (1.0 mmol), 2-hydroxynaphthalene-1,4-dione 3
(1.0 mmol), and glacial acetic acid (2.0 mL) was added to the reaction vessel of
the monomodal EmrysTM Creator microwave synthesizer and allowed to react
under microwave irradiation at 200 W power (initial power 100 W) and 125 °C
for several minutes. The automatic mode stirred helps in mixing and the
uniform heating of the reactants. Upon completion, monitored by TLC, the
reaction vessel was cooled to room temperature. The solid compound was
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.12.006.
collected by filtration, and recrystallized from EtOH (95%) to give pure
a-
lapachone derivatives 4. Compound 4c: mp: 242–244 °C; 1H NMR: d 8.12–8.10
(m, 1H, ArH), 8.01–7.99 (m, 1H, ArH), 7.93–7.87 (m, 2H, ArH), 7.52 (d, 2H,
J = 8.8 Hz, ArH), 7.31 (d, 2H, J = 8.4 Hz, ArH), 4.59 (dd, 1H, J1 = 1.2 Hz, J2 = 7.2 Hz,
CH), 3.41 (dd, 1H, J1 = 7.6 Hz, J2 = 16.0 Hz, CH2), 2.91 (dd, 1H, J1 = 1.2 Hz,
J2 = 16.0 Hz, CH2); 13C NMR (100 MHz) (d, ppm): 182.55, 176.95, 165.19,
152.15, 138.91, 134.49, 134.24, 131.78, 130.95, 130.89, 129.22, 126.05, 125.91,
References and notes
1. WHO
Cancer.
Available
from:
<http://www.who.int/hpr/NPH/docs/
m
, cmÀ1): 1792, 1681, 1660. Anal. Calcd
gs_cancer.pdf>, <http://www.who.int/dietphysicalactivity/publications/facts/
cancer/en/>.
124.27, 120.68, 35.47, 33.95. IR: (KBr,
for C19H11BrO4: C, 59.55; H, 2.89. Found: C, 59.74; H, 2.92.