Synthesis of 2H,9H-naphtho[2,3-b:7,6-b']dipyran-2,9-diones as potential DNA-reactive agents

Article abstract of DOI:10.1016/S0014-827X(98)00085-8

New 2H,9H-naphtho[2,3-b:7,6-b']dipyran-2,9-diones have been synthesized. The tetracyclic derivatives were obtained by two different synthetic pathways, both having, as a common intermediate, the 3,6-dihydroxynaphthalene-2,7-dicarboxaldehyde.

Full text of DOI:10.1016/S0014-827X(98)00085-8

Il Farmaco 53 (1998) 675–679
Synthesis of 2H,9H-naphtho[2,3-b:7,6-b%]dipyran-2,9-diones as
potential DNA-reactive agentsꢀ
Giuseppe Zagotto a,*, Manlio Palumbo a, Eugenio Uriarte b, Leonardo Bonsignore c,
Giovanna Delogu c, Gianni Podda c
a Department of Pharmaceutical Sciences, Uni6ersity of Padua, Via Marzolo 5, 35131 Padua, Italy
b Department of Organic Chemistry, Uni6ersity of Santiago de Compostela, Santiago de Compostela, Spain
c Department of Pharmaceutical Chemistry and Technology, Uni6ersity of Cagliari, Cagliari, Italy
Abstract
New 2H,9H-naphtho[2,3-b:7,6-b%]dipyran-2,9-diones have been synthesized. The tetracyclic derivatives were obtained by two
different synthetic pathways, both having, as a common intermediate, the 3,6-dihydroxynaphthalene-2,7-dicarboxaldehyde.
© 1998 Elsevier Science S.A. All rights reserved.
Keywords: Nucleic acids; Intercalation; Naphthopyrone; Tetracyclo; Carbon suboxide
b;5,4-b%]dipyran-2,8-dione derivatives, compound II is
an example, that have been tested for their ability to
intercalate between the B-DNA base pairs and possibly
exhibit photoreactivity properties [8–11].
1. Introduction
Planar aromatic or partially aromatic structures have
always been regarded as able to intercalate between the
base pairs of the DNA double helix [1–3]. This holds
true for a number of important drugs such as the
anticancer agents of the anthracenedione structure type
[4].
Other interesting compounds derived from psoralen
(I)
To further investigate the steric and electronic factors
affecting the DNA-binding and photobinding process
we planned to synthesize the following new tetracyclic
compound III:
have been investigated during the last two decades due
to their ability to form photocycloadducts between the
double bonds of the furan and pyran ring and the
double bond of the pyrimidine bases of the DNA, when
irradiated with UV-A light This produced valuable
photochemotherapeutic agents; including 8-MOP and
TMP presently in clinical use [5–7].
This may represent a probe for particular spatial
arrangements of the nucleic acids as it must interact
with DNA having distinct geometry from that in-
terzacting with the tricyclic parent compound II. This
molecule is in fact too large to intercalate into the
classical B-structure with the same orientation as II,
but can be made to recognize other, non canonical,
features of DNA. The synthetic pathway is shown in
Scheme 1.
Further research in the field of photoactive com-
pounds lead to some symmetrical 2H,8H-benzo[1,2-
ꢀ Dedicated to Professor Antonio Maccioni
* Corresponding author.
E-mail address: giuseppe@purple.dsfarm.unipd.it (G. Zagotto)
0014-827X/98/$ - see front matter © 1998 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(98)00085-8

676
G. Zagotto et al. / Il Farmaco 53 (1998) 675–679
Scheme 1. a, DMS, K2CO3, acetone, reflux,
2 h; b, 1. n-BuLi, Et2O, CO2, −70 to r.t., overnight. 2. CH3OH, MSA, reflux; c,
NaAlH2(OCH2CH2OCH3)2-morpholine, toluene, −10°C; d, AlCl3, CH2Cl2, r.t., overnight; e, R–NH2, ethanol–AcOH, reflux, 4 h; f, 1. ethyl
cyanoacetate, KOH, H2O, r.t., overnight. 2. HCl, reflux, 30%; g, D; h, C2O3, dioxane–acetonitrile, −70°C to r.t., 120 h; i, KOH 20%, ethanol,
reflux; j, R–OH, DCC, THF, reflux, 24 h; k, R–NH2, THF, reflux, overnight.
2. Experimental
solution of 2,7-dimethoxynaphthalene-3,6-dicarboxylic
acid dimethyl ester, 8.7 g (29 mmol), in 80 ml of toluene
was dropped in. The cooling bath was removed and the
reaction left at room temperature overnight. Water was
added to quench the reaction and the mixture was
made acidic to dissolve the aluminium hydroxide
formed. The product was extracted in ethyl acetate and
the organic phase dried and concentrated. A total of 3.9
g of IV, (56%) were obtained. M.p. 232–235°C; IR
1680, 1620, 1260, 1320, 1180, 1130, 1100, 1020, 940,
Melting points were determined by a Kofler appara-
tus and are uncorrected. FT-IR spectra were recorded
on a Perkin–Elmer system 2000 spectrophotometer us-
1
ing KBr mulls. H NMR were recorded on a Varian
Unit 300 or on a Varian Gemini 200. EI mass spectra
were obtained using a QMD 1000 (Fison Instruments)
at 70 eV. Elemental analysis (CHN) were within 0.40%
of the calculated values and were performed on a Carlo
Erba 1016 elemental analyser.
1
890, 850, 800; H NMR (CDCl3) 3.97 (s, 6H, OCH3),
Reagents and solvents were used as purchased with-
out further purification. 2,7-Dimethoxynaphthalene-
3,6-dicarboxylic acid dimethyl ester and carbon
suboxide were obtained by known literature procedures
[12–16].
7.03 (s, 2H, H1 and H8), 7.20 (s, 2H, H4 and H5),
10.44 (s, 2H, CHO).
2.2. 2,7-Dihydroxynaphthalene-3,6-dicarboxaldehyde
(V)
1
M.p. are in °C, IR frequencies in cm−1, H NMR
chemical shifts (l) in ppm and coupling constants (J) in
Hz.
Aluminium trichloride,
9
g
(70 mmol), and
dichloromethane, 20 ml, were stirred for 2 h at room
temperature and then 2,7-dimethoxynaphthalene-3,6-di-
carboxaldehyde, 3.2 g (15 mmol), was added. The
reaction mixture was stirred for 3 h at room tempera-
ture and then quenched in ice–HCl and extracted in
ethyl acetate. The organic phase was dried over magne-
sium sulfate and evaporated under reduced pressure.
The residue was crystallized from ethanol to give V
pure; 2.6 g (80%). M.p. 217–220°C; IR 3240, 1680,
1630, 1570, 1260, 1240, 1150, 1090, 1020, 980, 950, 920,
2.1. 2,7-Dimethoxynaphthalene-3,6-dicarboxaldehyde
(IV)
Toluene, 25 ml, and sodium bis(2-methoxyethoxy)-
aluminium hydride 65% in toluene, 21 ml (71 mmol),
were pooled together and cooled at −10°C. At this
temperature a solution of morpholine, 6.7 ml (77
mmol), in toluene was dropped in. The resulting reac-
tion mixture was left at −10°C for 30 min and then a
1
830, 800; H NMR (DMSO-d6) 7.09 (s, 2H, H1 and

Table 1
Comp.
R
Yield (%)
M.p. (°C)
170–175
184–187
192–197
M+
246
244
412
IR (cm−1
)
1H NMR (DMSO-d6)
a
b
c
OH
65
68
54
3450, 3320, 2860, 1620, 1540, 1535, 1315, 1240,
1090, 1000, 970, 895
3400, 3320, 3250, 2720, 1650, 1530, 1320, 1300,
1230, 1080, 1000, 980, 870, 760, 700
3320, 3280, 1675, 1520, 1350, 1310, 1240, 1210,
1100, 1050, 980, 940, 850, 770, 690
6.9–7.8 (m, 4H, arom), 8.0 (s, 2H, CHꢀ), 9.5 (s, 2H, NHOH),
10.2 (s, 2H, ArOH)
4.3 (s, 2H, NH2), 6.9–7.8 (m, 4H, arom), 8.0 (s, 2H, CHꢀ),
10.2 (s, 2H, ArOH)
1.1 (t, 12H, CH3, J=8.7, 1.4–1.8 (mm, 8H, CH2), 4.1 (q, 8H,
CH2, J=8.7), 6.9–7.8 (m, 4H, arom), 8.0 (s, 2H, CHꢀ), 10.1 (s,
2H, ArOH)
NH2
(CH2)2NEt2
d
OCH3
80
178–180
274
3400, 3270, 3100, 1680, 1550, 1510, 1340, 1320,
1210, 1200, 1110, 1000, 970, 810, 740
4.0 (s, 6H, OCH3), 6.9–7.8 (m, 4H, arom), 8.0 (s, 2H, CHꢀ)
/
Table 2
533
(1998)1998)
67575
67979
Comp.
R
Yield (%)
M.p. (°C)
205–210
215–221
215–216
M+
IR (cm−1
)
1H NMR (DMSO-d6)
a
b
c
OH
95
–
382
380
548
3327, 2927, 2854, 2364, 1690, 1628, 1578, 1537,
1312, 1245, 1089, 893
3753, 3678, 3327, 1680, 1626, 1579, 1378, 1346,
1272, 1245, 1187, 1089, 1048, 893
3500, 3480, 1700, 1680, 1650, 1610, 1580, 1370,
1290, 1250, 1170, 1080, 1040, 850
6.9–7.8 (m, 4H, arom), 8.0 (s, 2H, OH), 8.3 (s, 2H, CHꢀ),
9.5 (s, 2H, NH)
4.8 (s, 4H, NH2), 6.9–7.8 (m, 4H, arom), 8.3 (s, 2H, CHꢀ),
9.5 (s, 2H, NH)
1.1 (t, 12H, CH3, J=8.7, 1.4–1.8 (m, 8H, CH2), 4.1 (q, 8H,
CH2, J=8.7), 6.9–7.9 (m, 4H, arom), 8.3 (s, 2H, CHꢀ), 9.0 (s,
2H, NH)
NH2
(CH2)2NEt2
–
d
OCH3
–
190–205
410
3823, 3653, 3630, 1690, 1627, 1578, 1461, 1312,
1272, 1186, 1051, 893
4.0 (s, 6H, OCH3), 6.8–7.9 (m, 4H, arom), 8.2 (s, 2H, CHꢀ),
9.1 (s, 2H, NH)

678
G. Zagotto et al. / Il Farmaco 53 (1998) 675–679
Table 3
Comp.
R
M.p. (°C)
\300
M+
594
711
IR (cm−1
)
1H NMR (DMSO-d6)
a
b
1-(4-nitrophenyl)
1760, 1630, 1250, 1150, 1090,
980, 970, 860, 810
1760, 1630, 1230, 1170, 1080,
1000, 970, 850
6.9–8.2 (m, 12H, arom),
7.3 (s, 2H, CHꢀ)
6.9–8.4 (m, 8H, arom),
7.3 (s, 2H, CHꢀ)
1-(2,4,6-trichlorophenyl)
176–180
H8), 7.19 (s, 2H, H4 and H5), 10.30 (s, 2H, CHO);
10.97 (s, 2H, OH).
2.5. General procedure for the synthesis of compounds
VIII a–d
Carbon suboxide (3.2 mmol) was added over 1 h at
−70°C to a stirred solution of VII a–d (1.6 mmol)
dissolved in a mixture of 50 ml of anhydrous 1,4-diox-
ane and 30 ml of acetonitrile. Then the reaction was left
to stir at 0°C for 5 h and at room temperature for 120
h. The solvent was evaporated under reduced pressure
and the residue treated with diisopropyl ether. The
resulting solid was crystallized from methanol. Data are
shown in Table 2.
2.3. 2H,9H-naphtho[2,3-b:7,6-b%]dipyran-2,9-dione (III)
2,7-Dihydroxynaphthalene-3,6-dicarboxaldehyde, 2.1
g (10 mmol), sodium hydroxide in water (20% w/v), 20
ml, and ethyl cyanoacetate, 3.4 g (30 mmol), were
mixed and stirred at room temperature overnight. Hy-
drochloric acid, 180 ml, was added and the reaction
mixture refluxed for 30 min and then cooled. The solid
2H,9H-naphtho[2,3-b:7,6-b%]dipyran-2,9-dione-3,8-di-
carboxylic acid (VI) was filtered and crystallized from
acetic acid. M.p. 239–242°C; IR 3300, 1750, 1630,
1240, 1160, 1080, 1000, 980, 870, 810; 1H NMR
(DMSO-d6) 7.91 (s, 2H, H11 and H12), 8.66 (s, 2H, H5
and H6), 8.83 (s, 2H, H4 and H7); mass 352 (M+). The
diacid was then decarboxylated in refluxing diphenyl
ether or by sublimation at 250°C and 0.02 mmHg, to
yield III; 0.49 g (30%). M.p.\300°C; IR 1750, 1630,
1230, 1150, 1040, 1000, 980, 860, 800; 1H NMR
(DMSO-d6) 6.58 (d, 2H, J=9.50, H3 and H8), 7.95 (s,
2H, H11 and H12), 8.22 (d, 2H, J=9.50, H4 and H7),
8.48 (s, 2H, H5 and H6); mass (EI) 264 (M+), 253, 236,
224, 208, 196, 181, 165, 151.
2.6. General procedure for the synthesis of compounds
IX a, b
To a solution of VI, 1 g (2.8 mmol), and 1.2 g (5.8
mmol) of 1,3-dicyclohexylcarbodiimide, in 100 ml of
warm anhydrous THF a solution of 5.6 mmol of the
phenol derivative, in 90 ml of anhydrous THF was
added slowly. The resulting mixture was refluxed 24 h
and cooled. The urea was filtered off and the THF
evaporated under reduced pressure. The residue dis-
solved in a solution of acetone and lead acetate. The
starting material is recovered as lead salt while the
mother liquor is concentrated under reduced pressure
and the residue crystallized from methanol. Data are
shown in Table 3.
The diacid VI was also obtained by hydrolysis of
compounds VIII a–d in refluxing 20% aqueous potas-
sium hydroxide.
3. Results and discussion
2.4. General procedure for the synthesis of compounds
VII a–d
3.1. Synthetic strategy
To 2,7-dihydroxynaphthalene-3,6-dicarboxaldehyde,
1.1 g (5 mmol), dissolved in a mixture of 20 ml of
ethanol and 0.2 ml of glacial acetic acid, 10 mmol of
the appropriate H2N–R were added and the solution
refluxed 4 h. The solvent was removed under reduced
pressure and the residual oil dissolved in hexane and
crystallized by addition of methanol. Data are shown in
Table 1.
The synthetic work started from the reported prepa-
ration of 7-hydroxy-4%-methyl naphtho(2,3;6%,5%)-a-py-
rone [17], but it was soon realized that any synthetic
pathway using an electrophile to extend the tricyclic
system to the target compound III would not work.
This is because the b position on the naphthalene ring
was less nucleophilic than the a position. So, the 2,7-
dimethoxynaphthalene-3,6-dicarboxilic acid dimethyl

G. Zagotto et al. / Il Farmaco 53 (1998) 675–679
679
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sodium bis(2-methoxyethoxy)aluminium hydride to the
dicarboxaldehyde and this method gave better results
than the reduction to the alcohol with DIBAL and the
subsequent oxidation with manganese dioxide or the
Rosenmund reduction in our hands. To hydrolize the
ethers aluminium chloride was preferred, but pyri-
dinium chloride or hydrobromic acid were also suitable.
To cyclize the obtained 2,7-dihydroxynaphthalene-
3,6-dicarboxaldehyde to the desired tetracyclic linear
target III two different pathways were followed. First a
Knoevenagel type reaction was attempted with ethyl
cyanoacetate as the active methylene compound. The
reaction product was the 2H,9H-naphtho[2,3-b:7,6-b%]-
dipyran-2,9-dione-3,8-dicarboxylic acid (VI), that was
thermally decarboxylated to the desired 2H,9H-
naphtho[2,3-b:7,6-b%]dipyran-2,9-dione.
The reaction of carbon suboxide with aromatic
azomethines, oximes and hydrazones bearing an ortho
-hydroxy, -amino, mercapto substituent to give, respec-
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derivatives has been described previously [16]. A mech-
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this synthetic pathway few amide derivatives have been
obtained, but the reaction seems quite flexible. The
amides were then hydrolized to the carboxylic acid VI.
Other useful intermediates were the active esters IX.
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