Natural furano naphtoquinones from lapachol: Hydroxyiso-β-lapachone, stenocarpoquinone-B and avicequinone-C

Article abstract of DOI:10.2174/157017811795685063

This work describes cheap and simple methods to obtain biological active furano naphthoquinones in good yields. Hydroxyiso-β-lapachone (3) was obtained in 61% yield from the reaction of lapachol (1) and MCPBA in dichloromethane using Na₂HPO₄ as the base. Reaction of 1 with MCPBA, followed by the addition of KOH/DMSO furnished both stenocarpoquinone-A (2) and avicequinone-C (5) in 20% yield. Using oxone/acetone and NaHCO₃, stenocarpoquinone-B (4) was obtained in 50% yield. The biological assays using tumor cell lines showed that 1 is, in general, less toxic than its derivatives. Compounds 4 and 5, on the other hand, were strongly active against the four tested tumor cells.

Full text of DOI:10.2174/157017811795685063

Letters in Organic Chemistry, 2011, 8, 347-351
347
Natural Furano Naphtoquinones from Lapachol: Hydroxyiso-ꢀ -Lapach-
one, Stenocarpoquinone-B and Avicequinone-C
Carlos Magno R. Ribeiro*,a, Pablo. P. de Souzaa, Letícia, L.D.M. Ferreiraa, Sharlene L. Pereiraa,
Ingrid da S. Martinsa, Rosângela de A. Epifanioa, Letícia V. Costa-Lotufob, Paula C. Jimenezb,
Cláudia Pessoab and Manoel O. de Moraesb
aPrograma de Pós-Graduação em Química, Departamento de Química Orgânica, Instituto de Química, Universidade
b
Federal Fluminense, Campus do Valonguinho, Centro, 24020-141, Niterói, Rio de Janeiro, Brazil; Departamento de
Fisiologia e Farmacologia, Universidade Federal do Ceará, P.O. Box-3157, 60430-270, Fortaleza, Ceará, Brazil
Received August 02, 2010: Revised March 21, 2011: Accepted March 21, 2011
Abstract: This work describes cheap and simple methods to obtain biological active furano naphthoquinones in good
yields. Hydroxyiso-ꢀ-lapachone (3) was obtained in 61% yield from the reaction of lapachol (1) and MCPBA in
dichloromethane using Na2HPO4 as the base. Reaction of 1 with MCPBA, followed by the addition of KOH/DMSO
furnished both stenocarpoquinone-A (2) and avicequinone-C (5) in 20% yield. Using oxone/acetone and NaHCO3,
stenocarpoquinone-B (4) was obtained in 50% yield. The biological assays using tumor cell lines showed that 1 is, in
general, less toxic than its derivatives. Compounds 4 and 5, on the other hand, were strongly active against the four tested
tumor cells.
Keywords: Lapachol, natural naphthoquinones, cyclization reactions, anticancer.
INTRODUCTION
In this work, we studied the behavior of lapachol 1 in
basic or acid epoxydation conditions using MCPBA or
oxone, demonstrating that it is possible to control product
selectivity in order to obtain such compounds in better
yields.
Prenyl naphthoquinones as lapachol 1 and its pyrano or
furano tricyclic derivatives 2-5 are natural compounds
mainly isolated from plants belonging to the Bignoniaceae
Family [1-4]. Lapachol 1 is known for its multiple biological
activities such as antileishmanial, molluscicidal, antivirus,
antibacterial, antimalarial and antifungal. Nevertheless, the
antitumor properties are definitely the most studied attributes
[1-15]. The cytotoxic activities of its natural derivatives such
as 2-5 have also been investigated, revealing that these
compounds might serve as promising anticancer agents [1-
15].
RESULTS AND DISCUSSION
Sun and coworkers found 6 as the intermediate during
lapachol 1 epoxydation in acidic conditions [21]. Using
MCPBA alone15 or adding
stenocarpoquinone-A 2 can be obtained in good yields as
mentioned above.
a
Lewis acid [21],
As lapachol 1 is a natural abundant compound, it is still
the product of choice to obtain 2-5 for pharmacological
studies. Several attempts using epoxy lapachol 6 as an
intermediate have been made in order to obtain 2-4 from
lapachol 1, further leading to the mentioned derivatives.
However, its behavior in acid solution as well as changes in
the addition order of the reagents are difficult to predict and
the result is often a mixture of different compounds [6, 15-
21]. Among all the methodologies used, the best results were
those yielding 67% of the pyrano derivative 2 from lapachol
1 [21]. Although, the mentioned naphthofurans seem to give
better results in pharmacological assays [6, 7, 11, 13, 22, 23],
none of the synthetic studies obtained hydroxyiso-ꢀ-
lapachone 3 or stenocarpoquinone-B 4 as the main products.
However, without isolation of the epoxy intermediate, the
same results were obtained by reacting lapachol 1 with
MCPBA in CH2Cl2 under different acidic condition (Table 1,
entries 1-3). By increasing temperature or medium acidity
(Table 1, entries 2 and 3), we observed a higher selectivity
towards the formation of 2.
On the other hand, under basic conditions (Table 1,
entries 4-8) an opposite behavior yielded hydroxyiso-ꢀ-
lapachone 3 as the major product. The best result was
achieved using Na2HPO4 as the base (Table 1, entry 6). With
such conditions, hydroxyiso-ꢀ-lapachone (3) was obtained in
61% yield against merely 10% of stenocarpoquinone-A 2
after purification (Scheme 1).
During these studies, we observed that the reaction
between lapachol 1 and MCPBA in dichloromethane,
followed by addition of KOH in DMSO, furnished
stenocarpoquinone-A 2 and avicequinone-C 5 as the major
products, both obtained in 20% yield after purification
(Scheme 1). In spite of the modest yield, this comprises a
*Address correspondence to this author at the Programa de Pós-Graduação
em Química, Departamento de Química Orgânica, Instituto de Química,
Universidade Federal Fluminense, Campus do Valonguinho, Centro, 24020-
141, Niterói, Rio de Janeiro, Brazil; Tel: 0552126292145;
Fax: 0552126292144; E-mail: gqocmrr@vm.uff.br
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

348 Letters in Organic Chemistry, 2011, Vol. 8, No. 5
Ribeiro et al.
O
O
O
O
O
O
OH
O
O
OH
OH
1 lapachol
2 stenocarpoquinone-A
3 hydroxyiso-lapachone
O
O
O
OH
O
O
OH
OH
O
O
O
O
4 stenocarpoquinone-B
5 avicequinone-C
6 epoxy-lapachol
Fig. (1). Lapachol 1 and derivatives 3-6.
Table 1. Results Obtained from Lapachol 1 Reaction with MCPBA in CH2Cl2
Entry
Reaction condition
Temperature
Products ratioc
2
3
1
2
3
4
5
6
7
8
9
Acida
Acida
0°C
0°C- r.t.
0°C- r.t.
0°C
1.00
1.00
1.00
1.00
1.00
1.00
0.41
0.33
0.25
0.62
0.70
5.62
HCl
NaHCO3
NaHCO3
Na2HPO4
Na2HPO4
KOH
0°C- r.t.
0°C
0°C- r.t.
0°C
1.00
2.70
b
b
KOH
0°C- r.t.
1.00
2.60
aAcid condition due to MCPBA; bComplex mixture of products;
cDetermined by 1H NMR.
MCPBA, CH2Cl2, 0°C
Na2HPO4
3 (61%)
hydroxyiso-lapachone
2 (10%)
stenocarpoquinone-A
+
1) MCPBA/ CH2Cl2, 0°C - r.t.
5 (20%)
avicequinone-C
2 (20%)
stenocarpoquinone-A
+
1
2) - OH; DMSO; 2h; 70-100°C
oxone
NaHCO3/acetone/H2O
4 (50%)
stenocarpoquinone-B
Scheme 1. Lapachol 1 reactions.
simple method to obtain avicequinone-C from lapachol.
Attempting to prepare 6 using oxone as the epoxydation
reagent [24], another interesting result was observed. Adding
an acetone/water solution of this reagent to a solution of
lapachol 1 in aqueous NaHCO3, it yielded 4 as a sole product
in 50% yield after purification. It is noteworthy to mention
that 6 was not isolated from the reaction (Scheme 1).
These results are in agreement with the epoxide ring-
opening mechanism, where acid media favors the products
based on electronic effects, naphthoquinone 2, while, in

Natural Furano Naphtoquinones from Lapachol
Letters in Organic Chemistry, 2011, Vol. 8, No. 5
349
O
O
OH
a
O
H
acid
a
b
O
condictions
O
O
O
a
b
MCPBA
0oC or r.t
OH
6
2
1
b
O
O
O
basic
a
a
O
b
condictions
O
a
O
b
3
OH
6
Scheme 2. Lapachol 1 reaction: proposal pathway.
basic conditions, the reaction path is guided by steric factors,
naphthoquinone 3 (Scheme 2) [25, 26]. \
active. Data collected from this investigation confirmed that
the hydrogen-bond interactions of the carbonyl groups at C-1
and C-2 and the hydrogen-bond interaction of the oxygen
atom of the pyran ring are relevant features of highly active
compounds. In the present study, 4 presented the lowest IC50
for the mentioned leukemic cells followed, respectively, by
5, 3 and 2 (Table 2).
Although it is well-known that the reaction media is
crucial for the reaction route in lapachol epoxide opening-
cyclization, thus leading to different products, this work
reveals that a simpler method using MCPBA or oxone in
basic conditions can be used to obtain, furano
naphthoquinones 3 or 4, respectively, in good yields.
A couple of previous studies observed that 4 has
significant inhibitory effect on Epstein-Barr virus early
antigen, with low to moderate cytotoxicity towards the host,
Raji cells [7, 23]. Compounds 2, 3 and 5 were also
mentioned due to their potencies - though weaker, but fairly
equivalent - against the virus antigen.
Regarding the cytotoxicity towards tumor cell lines, as
evaluated herein, lapachol 1 showed, in general, less toxicity
than its derivatives. On the other hand, compound 5, as well
as 4, presented quite low IC50 values against the four tumor
cells tested (Table 2).
A prior study performed by Han et al. [9] found 5 to
possess antiproliferative and cytotoxic effects against L-929
mouse fibroblast, K-562 human leukemia and HeLa cells. In
the same study, compound 2 showed a similar scope of
activity.
EXPERIMENTAL
General
All solvents and reagents used were supplied by E.
Merck or Aldrich Co. TLC: silica gel 60 F254 plates (0.25
mm; Merck). Column chromatography (CC): silica gel 60
(0.040-0.063 mm; Merck). Melting points were determined
on a Fischer-Johns apparatus: uncorrected. H-NMR (300
MHz) and 13C-NMR (75.5 MHz) spectra: Varian 7T
3D-QSAR analysis of 51 natural and synthetic
naphtoquinone derivatives, accomplished by Perez-Sacau et
al. [15], found 2 to be highly cytotoxic against HL-60 cells,
while 3 and 4 were considered moderately, thus equally,
1
Table 2. Inhibitory Effect on Culture Cell Growth of Naphtoquinones and Tryciclic Lapachol 1 Derivatives
Compound
1
HL-60
HCT-8
SF-295
MDA-MB-435
17.43
10.38 - 29.30
3.61
2.84
1.65 - 4.89
5.22
4.28
2.07 - 8.84
5.13
3.99
2.49 - 6.42
1.53
2
3
4
5
3.30 – 3.94
1.37
4.38 - 6.22
4.13
4.73 - 5.55
2.15
1.43 - 1.63
0.49
0.99 - 1.91
0.32
3.26 - 5.24
1.48
1.94 - 2.38
1.59
0.45 - 0.56
0.31
0.21 - 0.48
1.05
1.10 - 1.99
0.41
0.35 - 7.32
0.42
0.29 - 0.32
0.42
0.73 – 1.49
0.33 - 0.50
0.39 - 0.46
0.08 – 2.18

350 Letters in Organic Chemistry, 2011, Vol. 8, No. 5
Ribeiro et al.
instrument in CDCl3 (Me4Si as internal standard); chemical
shifts are in ppm and coupling constants are given in Hz. IR
spectra were recorded on films or KBr pellets with a Perkin
Elmer 1420 spectrometer.
(3:7) as eluent. Avicequinone-C 55: orange crystal; m.p.:
o
1
137-138 C; H NMR (300 MHz, CDCl3): ꢀ 1.70 (6H, s),
6.82 (1H, s), 7.70-7.75 (2H, m), 8.20-8.13 (2H,m). 13C NMR
(75 MHz, CDCl3): ꢀ 28.3 (2 C); 80.4; 115.4; 117.8; 126.2 (2
C); 130.8; 131.4; 131.5; 133.9; 152.4; 179.8; 181.8. I.R.
Stenocarpoquinone-A 2; 3´-Hydroxyiso-ꢀ-lapachone 3:
Typical Procedure in Acid Condictions
(KBr):
ꢁ
2924; 2853; 1674; 1643; 1570 cm-1.
Stenocarpoquinone-A 2: RMN 1H e 13C see above.
m-Chloroperoxybenzoic acid (0.121mg; 0.70 mmol) was
added to a solution of lapachol (1) (100 mg; 0.45 mmol) in
10 mL of CH2Cl2 at 0 oC under magnetic stirring. After 18 h,
Stenocarpoquinone-B 4
Oxone (720 mg; 1.1 mmol) was added to a solution of
lapachol 1 (100 mg; 0.41 mmol) and NaHCO3 (177 mg; 2
mmol) in acetone (1.85 mL) at 0oC under magnetic stirring.
After 7h, 2 drops of HCl were added at 25oC and the
resulting solution was extracted with CH2Cl2 (2 x 25 mL).
The organic layers were dried over MgSO4 anhydrous and
concentrated in vacuo. The crude product was purified by
column chromatography on silica gel using ethyl
acetate:hexane (3:7)3 as eluent, to yield 54 mg (50%) of
stenocarpoquinone-B. Stenocarpoquinone-B 415 [2,3-
dihydro-2-(2-hydroxypropan-2-yl)naphtho[2,3-b]furan-4,9-
o
a white precipitate was formed at 25 C; it was filtrated and
the filtrate was extracted with a 5% NaHCO3 solution (2 x 10
mL). The combined organic layers were dried with MgSO4
anhydrous and concentrated in vacuo.
The crude product was purified by column
chromatography on silica gel 60 using ethyl acetate:hexane
1
(3:7) as eluent. Stenocarpoquinone-A 215: H NMR (300
MHz, CDCl3): ꢀ 1.46 (3H, s), 1.52 (3H, s), 2.63 (1H, dd, J =
17.7 and 5.2 Hz), 2.83 (1H, dd, J = 17.7 and 4.8 Hz), 3.93
(1H, t, J = 5.2 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.66 (1H, t, J =
7.7 Hz), 7.84 (1H, d, J = 7.7 Hz), 8.05 ( 1H, d, J = 7.7 Hz).
13C NMR (75 MHz, CDCl3): ꢀ 179.4; 178.6; 161.7; 134.8;
132.0; 130.8; 130.0; 128.6; 124.3; 110.3; 81.5; 68.1; 25.1;
1
dione]15: H NMR (300 MHz, CDCl3): ꢀ 1.26 (3H, s), 1.41
(3H,s), 3.17 (2H, d, J = 10 Hz), 4.85 (1H, t, J =10 Hz), 7.75-
7.66 (2H, m), 8.06-8.09 (1H, m). 13C NMR (75 MHz,
CDCl3): ꢀ 182.0; 177.6; 159.8; 134.0; 132.8; 132.7; 131.3;
126.1; 125.9; 124.8; 92.0; 71.5; 28.2; 25.6; 24.0.
1
25.0; 22.0. 3´-Hydroxyiso-ꢁ-lapachone 315: H NMR (300
MHz, CDCl3): ꢀ 1.29 (3H, s), 1.42 (3H,s), 3.07 (1H, dd, J =
15.6 and 8.8 Hz), 3.15 (1H, dd, J = 15.6 and 10 Hz), 4.94
(1H, dd, J = 10 and 8.8 Hz), 7.56 (1H, m), 7.66 (2H, m),
8.06 (1H, m). 13C NMR (75 MHz, CDCl3): ꢀ 180.9; 175.2;
170.0; 134.4; 131.9; 130.4; 129.3; 127.1; 124.4; 115.8; 93.4;
71.8; 27.2; 25.5; 24.2.
CONCLUSION
This work reveals simple and cheap methods to easily
provide furano ꢀ- or ꢂ- naphthoquinones from lapachol (1)
for research groups which aim to study the biological
activities of these compounds.
Stenocarpoquinone-A 2; 3´-Hydroxyiso-ꢀ-lapachone 3:
Typical Procedure in Basic Condictions
m-Chloroperoxybenzoic acid (0.219 mg; 1.27 mmol) was
added to a solution of lapachol (1) (242 mg; 1 mmol) in 10
mL of CH2Cl2 and NaHCO3 (191 mg; 2.27 mmol), Na2HPO4
(0.322 mg; 2.27 mmol) or KOH (0.127 mg; 2.27 mmol) at 0
oC or room temperature with magnetic stirring. After 24 h,
the mixture was extracted with 10% HCl solution (2 x 10
ACKNOWLEDGEMENTS
We wish to thank CNPq, and FAPERJ for the financial
support, in the form of grants and fellowships.
o
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and 3´-Hydroxyiso-ꢁ-lapachone 3 data, see above.
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