Synthesis and cytotoxicity of analogues of the marine secondary metabolite, 2-deoxylapachol

Article abstract of DOI:10.3184/030823407X270437

The syntheses of four 2-substituted 1,4 naphthoquinones, related to the marine natural product 2-deoxylapachol, are reported. All four synthetic compounds were cytotoxic to WHCO1 oesophageal cancer cells.

Full text of DOI:10.3184/030823407X270437

JOURNAL OF CHEMICAL RESEARCH 2007
DECEMBER, 677–679
RESEARCH PAPER 677
Synthesis and cytotoxicity of analogues of the marine secondary
metabolite, 2-deoxylapachol
Suthananda N. Sunasseea, Albert W.W. van Wyka, Omolaja Osoniyib, Denver T. Hendricksb
and Michael T. Davies-Colemana*
aDepartment of Chemistry, Rhodes University, Grahamstown, 6140, South Africa
bDivision of Medical Biochemistry, University of Cape Town, Rondebosch, South Africa
The syntheses of four 2-substituted 1,4 naphthoquinones, related to the marine natural product 2-deoxylapachol,
are reported. All four synthetic compounds were cytotoxic to WHCO1 oesophageal cancer cells.
Keywords: 2-deoxylapachol, 1,4-naphthoquinones, oesophageal cancer
Lapachol (1), originally isolated from the heartwood of the
Brazilian tree Tabebuia avellanedae commonly known
as “pau d’arco”, has been used clinically in Brazil for the
treatment of adenocarcinoma and squamous carcinomas.1
Squamous cell oesophageal cancer (SCOC) is common in the
poor rural and peri-urban populations of South Africa, with
studies in Soweto, near Johannesburg, revealing that residents
there have a five-fold higher risk of developing this particular
cancer than the world average.2 The limitations of current
chemotherapeutic interventions against SCOC e.g. cisplatin3
coupled with the prevalence of this disease in South Africa,
has prompted us to search for new potential anti-oesophageal
cancer agents amongst the secondary metabolites produced
by marine organisms4 and to investigate, where possible, the
cytotoxicity of synthetic analogues related to selected marine
natural products.
against SCOC. Accordingly, we report here the cytotoxicity
of this compound and four synthetic analogues (3–6) to the
oesophageal cancer cell line WHCO1. The synthesis of
3–6 forms part of an ongoing structure activity relationship
(SAR) study in which we have investigated first, the effect
on the cytotoxic properties of lapachol type compounds
when the hydroxyl substituent at C-2 in 1 is effectively
relocated to the benzylic position of the side chain in 2 to give
the 2-deoxylapachol analogue, 2-(1-hydroxy-3-methyl-2-
butenyl)-1,4-naphthoquinone (3). The effect on cytotoxicity
of further elaboration of the hydroxylated side-chain in 3 was
also investigated by either shortening the side-chain e.g. 2-(1-
hydroxyethyl)-1,4-naphthoquinone (4) and 2-(1-hydroxy-2-
propenyl)-1,4-naphthoquinone (5) or extending the side-chain
by the addition of a phenyl substituent e.g. 2-(1-hydroxy-1-
phenylmethyl)-1,4-naphthoquinone (6).
The marine secondary metabolite 2-deoxylapachol
(2), isolated from extracts of a New Zealand brown alga
Landsburgia quercifolia, was also reported to be cytotoxic
to cancer cells (IC50 of 2.7 mM against P338 leukaemia
cells).5 To the best of our knowledge 2 has not been screened
Our synthetic approach to 3-6 is summarised in Scheme 1.
Reductive methylation of 1,4 naphthoquinone (7) yielded 1,4-
dimethoxynaphthalene (8)6 which was subjected to standard
Vilsmeier Haack formylation to afford 1,4-dimethoxy-2-
naphthalenecarbaldehyde (9). The Grignard addition of
O
OMe
O
OMe
R
i, ii
H
iii
O
OMe
OMe
7
8
R = H
9
14 R = Br
iv
vi
OMe R1
O
O
R1
8
8a
4a
2
v
R2
R2
1'
R3
OMe
1 R1 = H, R2 = CH=C(CH3)2, R3 = OH
2 R1 = R3 = H, R2 = CH=C(CH3)2
3 R1 = OH, R2 = CH=C(CH3)2, R3 = H
4 R1 = OH, R2 = CH3, R3 = H
5 R1 = OH, R2 = CH=CH2, R3 = H
6 R1 = OH, R2 = Ph, R3 = H
10 R1 = OH, R2 = CH=C(CH3)2
11 R1 = OH, R2 = CH3
12 R1 = OH, R2 = CH=CH2
13 R1 = OH, R2 = Ph
15 R1 = H, R2 = CH=C(CH3)2
Scheme 1 i, Na2S2O4, TEAB, THF, RT; ii, KOH, Me2SO4, RT, overnight (81%); iii, POCl3, DMF, CHCl3, reflux, 96 h (91%);
iv, R – MgBr, THF, –10°C – RT, overnight (83–100%); v, CAN (2–3 equiv.), H2O, MeCN (77–94%); vi, Mg, I2, THF, reflux, 1 h,
then BrCH2CH=C(CH3)2, Li2CuCl4, THF, –10°C – RT, overnight (67%).
* Correspondent. E-mail: M.Davies-Coleman@ru.ac.za
PAPER: 07/4967

678 JOURNAL OF CHEMICAL RESEARCH 2007
published values;5 HRFABMS m/z: calcd for C17H21O2 [M + H]+
257.1542; found 257.1541.
isobutenylmagnesium bromide (prepared in situ)7 to 9 gave
10. Compounds 11–13 were accessed in similar fashion
by the addition of methyl, vinyl and phenylmagnesium
bromides respectively to 9. Cerium ammonium nitrate (CAN)
demethylation of 10–13 proceeded smoothly to yield the
corresponding naphthoquinones 3–6. Interestingly, 4 has been
synthesised previously in five steps from 7 via a circuitous
Fries rearrangement8 and more directly by the addition of
acetaldehyde to the Grignard reagent prepared from 2-bromo-
1,4-dimethoxynaphthalene (14) and magnesium.9 Although
6 has also been used as a precursor in the synthesis of
2-benzyl-1,4-naphthoquinones no details of this compound’s
preparation were provided.10 Compounds 3 and 5 have not
been synthesised before.
In order to compare the cytotoxicity of 3–6 with that of 2
it was deemed necessary to prepare sufficient 2 for screening
against the WHCO1 cell line. Two methods exist for the
preparation of this compound i.e. either via radical prenylation
of 7 with 4-methyl-3-pentenoic acid11-13 or by the addition
of prenyltriflurosilane to 7 in the presence of the Lewis acid
FeCl3.6H2O.13,14 We were, however, able to prepare 2 by
the addition of excess Grignard reagent prepared from 14 to
1-bromo-3-methyl-2-butene in THF/Li2CuCl4 to afford 1,4-
dimethoxy-2-(3-methyl-2-butenyl)-naphthalene (15) which
on CAN deprotection in the usual manner, gave 2.
Compounds 3–6 exhibited good activity (IC50 5.1, 6.4, 4.1
and 1.5 mM respectively) against the WHCO1 oesophageal
cancer cell line when compared to the cytotoxicity of
2-deoxylapachol (IC50 14.8 mM) and the commonly used
SCOC chemotherapeutic agent cisplatin (IC50 13 mM)15
against the same cell line. Interestingly, the dimethyl ethers
10–15 were not cytotoxic to WHCO1 cells. A recent study of
the cellular mechanism of the anti-oesophageal cancer activity
of series of prenylated toluquinones (originally isolated from
the endemic South African opisthobranch mollusc Leminda
millecra) has revealed that these compounds mediate cell death
by triggering the production of reactive oxygen species (ROS)
leading to the activation of signaling pathways (cJun and p38)
which ultimately induces apoptosis.16 The possibility that
compounds 2–6 may initiate apoptosis in oesophageal cancer
cells by a similar mechanism is currently under investigation.
Oxidative demethylation of 15: A solution of cerium ammonium
nitrate (CAN) (0.065 g, 0.12 mmol) in water (0.1 ml) was added
dropwise to a solution of 15 (0.015 g, 0.06 mmol) in MeCN (1.5 ml)
at 0°C. The mixture was stirred (15 mins) at 0°C, diluted with water
(2 ml) and extracted with ether (3 ¥ 2 ml). The combined organic
extracts were washed with water (5 ml), sat. brine (5 ml), dried over
MgSO4 and the solvent evaporated in vacuo to give 2 as a brown oil
1
(0.0125 g, 0.06 mmol, 92%). H and 13C NMR data consistent with
published values;5 HRFABMS m/z: calcd for C15H15O2 [M + H]+
227.1072; found 227.1072.
Reductive methylation of 1,4-naphthoquinone 7:6 Tetraethyl-
ammonium bromide (TEAB, 0.5 g) was added to a solution of the
quinone 7 (2.0 g, 12.6 mmol) in THF (30 ml) and water (12 ml).
Aqueous sodium dithionite (13.16 g, 75.6 mmol) was added and
the mixture stirred at RT for 20 min. An aqueous KOH (16.32 g,
291 mmol) solution was added to the reaction mixture and, after
5 min, dimethyl sulfate (36.70 g, 291 mmol) was added dropwise.
The solution was allowed to stir (16 h) before the reaction was
quenched with water (30 ml) and extracted with CH2Cl2 (3 ¥ 20 ml).
The combined organic fractions were washed with water
(20 ml) and sat. brine (10 ml), dried over MgSO4 and concentrated
in vacuo to give a reddish oil (2.63 g). Flash chromatography of the
crude product in pure hexane afforded 8 (1.91 g, 10.1 mmol, 81%) as
1
a white crystalline solid, m.p. 87–88°C, lit.17 84–86°C; H and 13C
NMR data consistent with published values.17
Vilsmeier-Haack formylation of 8:18 A solution of 8 (0.50 g,
2.7 mmol) in chloroform (10 ml) was added to a mixture of
phosphoryl chloride (4.72 g, 31 mmol) and N,N-dimethylformamide
(2.25 g, 31 mmol). The resulting solution was refluxed (96 h) before
the reaction was carefully quenched with cold water. The reaction
mixture was extracted with CH2Cl2 (3 ¥ 10 ml) and the combined
organic fractions washed with water (1 ¥ 10 ml) and sat. brine
(1 ¥ 10 ml), dried over Na2SO4 and concentrated under reduced
pressure to give a reddish brown solid (0.66 g). Recrystallisation from
hexane afforded 9 (0.53 g, 91%) as a yellow solid, m.p. 122–123°C,
lit.19 119.5–120°C; 1H NMR data consistent with published values;19
d
C (100 MHz, CDCl3) 189.6 (s), 157.0 (s), 152.3 (s), 130.3 (s), 128.9
(d), 128.5 (s), 127.3 (d), 124.7 (s), 123.0 (d), 122.9 (d), 98.3 (d), 65.8
(q), 55.8 (q).
Preparation of 2-(1-hydroxy-3-methyl-2-butenyl)-1,4-dimethoxy-
naphthalene 10: A solution of isobutenylmagnesium bromide (1.5 g,
11.1 mmol) was prepared in situ as described previously,7 and added
dropwise via cannula to a stirred solution of 9 (0.255 g, 1.2 mmol)
in dry THF (10 ml) at –10°C. The resulting solution was stirred (2
h) at –10°C and then gradually warmed to RT. The mixture was
stirred further (1 h) before being quenched with sat. NH4Cl (10 ml)
and extracted with Et2O (3 ¥ 5 ml). The combined organic extracts
were washed with water (2 ¥ 10 ml) and sat. brine (1 ¥ 10 ml),
dried over MgSO4 and concentrated under vacuum to yield a brown
oil (0.407 g). NP HPLC (6:4 hexane/EtOAc) of the crude product
afforded 10 (0.202 g, 0.74 mmol, 62%) as a pale yellow oil, nmax
cm-1 3407, 1371, 1092, 846, 770; dH (600 MHz, CDCl3) 8.21 (1H, d,
J = 8.5 Hz), 8.01 (1H, d, J = 8.5 Hz), 7.52 (1H, t, J = 7.5 Hz), 7.45
(1H, t, J = 7.5 Hz), 6.92 (1H, s), 6.02 (1H, d, J = 8.9 Hz), 5.53 (1H,
d, J = 8.9 Hz), 4.0 (3H, s, OMe), 3.9 (3H, s, OMe), 1.88 (3H, s),
1.76 (3H, s). dC (150 MHz, CDCl3) 152.3 (s), 145.8 (s), 135.9 (s),
131.8 (s), 128.3 (s), 127.0 (s), 126.6 (d), 126.1 (d), 125.3 (d), 122.4
(d), 121.9 (d), 101.6 (d), 65.6 (d), 62.5 (q), 55.7 (q), 25.9 (q), 18.4
(q); HRFABMS m/z: calcd for C17H21O3 [M + H]+ 273.1491; found
273.1490.
Experimental
General procedure
1H and 13C NMR spectra were recorded on either a Bruker 400 MHz
or 600 MHzAvance NMR spectrometer in CDCl3 and were referenced
to residual protonated solvent at d 7.25 and 77.0 respectively.
HRFABMS data were acquired on a Micromass 70-70E spectrometer
and the LREI mass spectra (70 eV) were obtained on a Finnegan-
Matt GCQ mass spectrometer. Melting points were determined using
a Reichert hot-stage microscope and are uncorrected. Normal phase
semi-preparative HPLC separations were performed on a Whatman
1
Magnum 9 Partisil 10 column with an eluent flow rate of 4 ml min-
and eluting fractions detected using a Waters R401 differential
refractometer.
Oxidative demethylation of 10: Compound 10 (0.065 g, 0.24 mmol)
was demethylated with CAN (0.262 g, 0.48 mmol), vide supra, to
give a dark brown oil (0.056 g). NP HPLC (1:1 hexane/EtOAc) of
this oil afforded 3 as a dark yellow oil (0.013 g, 0.05 mmol, 23%),
Grignard synthesis of 2-deoxylapachol 2: A few drops of a solution
of 2-bromo-1,4-dimethoxynaphthalene (14)17 (0.250 g, 0.94 mmol) in
dry THF (1 ml) was added to a suspension of Mg turnings (0.036 g,
1.4 mmol) and iodine in dry THF (2 ml). The mixture was gently
warmed to initiate reflux, upon which the rest of the solution of 14
was added very slowly over 5 min. The resulting mixture was refluxed
(1 h) before being cooled to –10°C. The supernatant containing
excess 1,4-dimethoxynaphthalenylmagnesium bromide (ca 8 equiv.)
was transferred via cannula to a solution of 1-bromo-3-methyl-2-
butene (0.017 g, 0.12 mmol), Li2CuCl4 (1 ml, 0.1 mmol) and dry THF
(2 ml) at –10°C. The reaction mixture was slowly warmed to RT and
left to stir overnight, quenched with water (5 ml) and extracted with
CH2Cl2 (3 ¥ 3 ml). The combined organic phases were washed with
10% HCl (5 ml), H2O (5 ml) and sat. brine (5 ml), dried over MgSO4
and concentrated in vacuo to yield a dark brown oil (0.20 g). NP
HPLC of the oil in 96:4 hexane/EtOAc yielded 15 as a dark yellow
oil (0.020 g, 0.08 mmol, 67%), 1H and 13C NMR data consistent with
n
max cm-1 3416, 1662, 843, 775; dH (600 MHz, CDCl3) 8.06 (2H, m),
7.73 (2H, m), 6.99 (1H, s), 5.57 (1H, d, J = 8.6 Hz), 5.25 (1H, d,
J = 8.6 Hz), 1.83 (3H, s), 1.76 (3H, s); dC (150 MHz, CDCl3) 185.6
(s), 185.5 (s), 150.9 (s), 138.7 (s), 134.0 (d), 133.8 (d), 133.2 (d),
132.3 (s), 132.0 (s), 126.5 (d), 126.2 (d), 123.8 (d), 66.5 (d), 25.9 (q),
18.6 (q); calcd for C15H14O3 [M]+ 242.1196; found 242.1196.
General procedure A
Preparation of compounds 11–13
The respective Grignard reagents (3 equiv.) were added to a stirred
solution of 9 (0.10 g, 0.46 mmol) in dry THF (3 ml) at –10°C. The
resulting solution was stirred (1 h) at –10°C and then gradually
allowed to reach RT. The mixture was stirred for a further 16 h at RT
PAPER: 07/4967

JOURNAL OF CHEMICAL RESEARCH 2007 679
before being quenched with sat. NH4Cl (10 ml) and extracted with
CHCl3 (3 ¥ 3 ml). The combined organic extracts were washed with
water (2 ¥ 5 ml) and sat. brine (1 ¥ 5 ml), dried over Na2SO4 and
concentrated under vacuum. NP HPLC (1:1 hexane/EtOAc) of the
crude products afforded the respective 1,4-dimethoxy-2-hydroxy-
naphthalene products (11–13).
Cell culture
Cells were routinely maintained at 37°C and 5% CO2. WHCO1 cells
were maintained in DMEM, supplemented with 10% fetal calf serum,
100 U/ml penicillin and 100 µg/ml streptomycin.
MTT assay
2-(1-hydroxyethyl)-1,4-dimethoxynaphthalene 11:8 (0.107 g, 0.46 mmol,
100%) white crystalline solid, m.p. 104–105°C; lit.20 101–103°C; nmax
cm-1 3401, 1598, 770; dH (400 MHz, CDCl3) 8.21 (1H, d, J = 8.5 Hz),
8.0 (1H, d, J = 8.5 Hz), 7.52 (1H, t, J = 7.5 Hz), 7.46 (1H, m), 6.90
(1H, s), 5.46 (1H, q, J = 6.4 Hz), 3.98 (3H, s, OMe), 3.90 (3H, s,
OMe), 1.56 (3H, d, J = 6.4 Hz). dC (100 MHz, CDCl3) 152.4 (s),
145.5 (s), 133.1 (s), 128.3 (s), 126.6 (d), 126.1 (s), 125.4 (d), 122.4
(d), 121.8 (d), 101.0 (d), 64.7 (d), 62.7 (q), 55.6 (q), 24.3 (q); calcd
for C14H17O3 [M + H]+ 233.1178; found 233.1177.
IC50 determinations were carried out using the MTT kit from Roche
(Cat #1465007), according to manufacturer’s instructions. Briefly,
1500 cells were seeded per well in 96 well plates. Cells were incubated
(24 h), after which aqueous DMSO solutions of each compound
(10 µl, with a constant final concentration of DMSO = 0.1%) were
plated at various concentrations. After 48 h incubation, observations
were made, and MTT (10 µl) solution added to each well. After a
further 4 h incubation, solubilisation solution (100 µl) was added to
each well, and plates were incubated overnight. Plates were read at
595 nm on an Anthos microplate reader.
2-(1-hydroxy-2-propenyl)-1,4-dimethoxynaphthalene 12: (0.092 g,
0.38 mmol, 83%); Pale yellow oil; nmax cm-1 3397, 1370, 770;
dH (400 MHz, CDCl3) 8.21 (1H, d, J = 8.3 Hz), 8.02 (1H, d, J = 8.3 Hz),
7.53 (1H, m), 7.47 (1H, m), 6.78 (1H, s), 6.15 (1H, ddd, J = 17.6,
10.4, 5.2 Hz), 5.77 (1H, br d, J = 4.9 Hz), 5.41 (1H, d, J = 17.1 Hz),
5.23 (1H, d, J = 10.5 Hz), 3.96 (3H, s, OMe), 3.90 (3H, s, OMe);
dC (100 MHz, CDCl3) 152.3 (s), 146.4 (s), 140.0 (d), 130.1 (s), 128.4
(s), 126.7 (d), 126.3 (s), 125.6 (d), 122.4 (d), 122.0 (d), 114.9 (t),
101.8 (d), 69.7 (d), 62.9 (q), 55.6 (q); calcd for C15H17O3 [M + H]+
245.1178; found 245.1177.
2-(1-hydroxy-1-phenylmethyl)-1,4-dimethoxynaphthalene 13: (0.125 g,
0.43 mmol, 93%) white crystalline solid; m.p. 123–125°C; nmax cm-1
3407, 1370, 770, 702; dH (600 MHz, CDCl3) 8.22 (1H, d, J = 8.4 Hz),
8.02 (1H, d, J = 8.4 Hz), 7.52 (2H, t, J = 7.6 Hz), 7.47 (2H, m), 7.45
(2H, d, J = 8.1 Hz), 7.32 (2H, t, J = 7.6 Hz), 7.24 (1H, t, J = 7.3 Hz),
6.80 (1H, s), 6.36 (1H, s), 3.92 (3H, s, OMe), 3.80 (3H, s, OMe);
Rhodes University, the University of Cape Town, the
South African National Research Foundation (NRF), the
South African Network for Coastal and Oceanographic
Research (SANCOR) and Rhodes University are thanked
for their financial support. SNS gratefully acknowledges
student support in the form of a DAAD Third Country
Scholarship.
Received 30 November 2007; accepted 13 December 2007
Paper 07/4967
doi: 10.3184/030823407X270437
d
C (150 MHz, CDCl3) 152.2 (s), 146.5 (s), 143.7 (s), 131.4 (s), 128.3
References
(d), 127.3 (d), 126.7 (d), 126.4 (d), 126.3 (s), 125.6 (d), 122.5 (d),
122.0 (d), 102.4 (d), 71.0 (d), 62.6 (q), 55.6 (q); calcd for C19H19O3
[M + H]+ 295.1134; found 245.1133.
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General procedure B
CAN demethylation of compounds 10–13
Separate solutions of compounds 11–13 in acetonitrile and water
were oxidised with a solution of CAN (2–3 equiv.) in water, as
previously described for the preparation of 2, and purified by
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2-(1-hydroxyethyl)-1,4-naphthoquinone 4:8 (0.035 g, 0.17 mmol,
77%) yellow powder; 86–87°C; lit.20 87-88°C; nmax cm-1 3430, 1662,
720; dH (400 MHz, CDCl3) 8.02 (2H, m), 7.70 (2H, m), 6.99 (1H,
s), 5.00 (1H, q, J = 6.4 Hz), 1.48 (3H, d, J = 6.43 Hz). dC (100 MHz,
CDCl3) 185.4 (s), 185.3 (s), 153.0 (s), 134.0 (d), 133.8 (d), 132.7 (d),
132.1 (s), 131.8 (s), 126.4 (d), 126.1 (d), 65.0 (d), 22.6 (q); calcd for
C12H11O3 [M + H]+ 203.0708; found 203.0709.
2-(1-hydroxy-allyl)-1,4-naphthoquinone 5: (0.031 g, 0.14 mmol,
70%) brown oil; nmax cm-1 3419, 1662, 1594, 754; dH (600 MHz,
CDCl3) 8.05 (2H, m), 7.72 (2H, m), 7.0 (1H, s), 6.00 (1H, ddd,
J = 16.7, 10.4, 5.8 Hz), 5.46 (1H, d, J = 17.2 Hz), 5.36 (1H, br d,
J = 4.2 Hz), 5.27 (1H, d, J = 10.4 Hz); dC (150 MHz, CDCl3) 185.2
(s), 185.1 (s), 150.0 (s), 137.0 (d), 134.0 (d), 133.8 (d), 133.6 (d),
132.1 (s), 131.8 (s), 126.4 (d), 126.2 (d), 117.3 (t), 69.8 (d); calcd for
C13H11O3 [M + H]+ 215.0708; found 215.0709.
2-(1-hydroxy-1-phenylmethyl)-1,4-naphthoquinone 6: (0.041 g,
0.16 mmol, 94%) brown oil, nmax cm-1 3427, 1662, 726, 700; dH
(600 MHz, CDCl3) 8.00 (1H, d, J = 7.4 Hz), 7.96 (1H, d, J = 7.4 Hz),
7.67 (2H, m), 7.42 (2H, d, J = 7.5 Hz), 7.31 (2H, t, J = 7.5 Hz), 7.24
(1H, m), 7.05 (1H, s), 5.90 (1H, s); dC (150 MHz, CDCl3) 185.3 (s),
184.9 (s), 151.0 (s), 140.3 (s), 134.0 (d), 133.8 (d), 133.5 (d), 132.1
(s), 131.9 (s), 128.7 (d), 128.7 (d), 128.4 (d), 126.9 (d), 126.9 (d),
126.5 (d), 126.1 (d), 70.8 (d).
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PAPER: 07/4967