Design of antineoplastic agents based on the '2-phenylnaphthalene-type' structural pattern. 4. Synthesis and biological activity of 2-chloro-3- (substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4- naphthoquinones

Article abstract of DOI:10.1021/jm9804679

The intermediate in the preparation of 1,3,7,10- tetrahydroxybenzo[b]naphtho[2,3-d]furan-6,11-dione (2), 2-chloro-5,8- dimethoxy-3-(3,5-dimethoxyphenoxy)-1,4-naphthoquinone (8h), and corresponding hydroxyl, methoxyl, and acetoxyl analogues was found to po

Full text of DOI:10.1021/jm9804679

J . Med. Chem. 1999, 42, 405-408
405
Design of An tin eop la stic Agen ts Ba sed on th e “2-P h en yln a p h th a len e-Typ e”
Str u ctu r a l P a tter n . 4. Syn th esis a n d Biologica l Activity of
2-Ch lor o-3-(su bstitu ted p h en oxy)-1,4-n a p h th oqu in on es a n d Rela ted
5,8-Dih yd r oxy-1,4-n a p h th oqu in on es
He-Xi Chang,† Ting-Chao Chou,‡ Niramol Savaraj,§ Leroy F. Liu,| Chiang Yu,| and C. C. Cheng*,†
Drug Development Laboratory, Department of Pharmacology, Toxicology & Therapeutics, The University of Kansas Medical
Center, Kansas City, Kansas 66160-7419, Laboratory of Preclinical Pharmacology, Memorial Sloan-Kettering Cancer Center,
New York, New York 10021, Department of Medicine, The University of Miami School of Medicine, Miami, Florida 33136, and
Department of Pharmacology, University of Medicine and Dentistry of New J ersey, Robert Wood J ohnson Medical School,
Piscataway, New J ersey 08854-5635
Received August 10, 1998
The intermediate in the preparation of 1,3,7,10-tetrahydroxybenzo[b]naphtho[2,3-d]furan-6,11-
dione (2), 2-chloro-5,8-dimethoxy-3-(3,5-dimethoxyphenoxy)-1,4-naphthoquinone (8h ), and cor-
responding hydroxyl, methoxyl, and acetoxyl analogues was found to possess interesting
inhibitory activities in a number of cytotoxic test systems. Activities were also noticed in some
5,8-dihydroxy-1,4-naphthoquinone derivatives. A structure-activity discussion of compounds
of this series is presented. The newly uncovered biological activity of 2-chloro-3-(substituted
phenoxyl)-1,4-naphthoquinones and 2,3-bis(substituted phenoxy)-1,4-naphthoquinones may
suggest an approach for the development of new classes of antineoplastic agents.
In tr od u ction
On the basis of the “2-phenylnaphthalene-type” struc-
tural pattern hypothesis developed in our laboratory,1
a number of novel compounds conforming to this pattern
were designed, synthesized, and evaluated biologi-
cally.2 Many of these compounds displayed interesting
antineoplastic properties, particularly in the series of
benzo[b]naphtho[2,3-d]furan-6,11-diones which showed
outstanding activity against the growth of human
promyelocytic leukemia cells (HL-60), small-cell lung
cancers (SCLC) sensitive and resistant to cisplatin
(SCLC/CDDP), National Cancer Institute’s disease-
oriented primary antitumor 60-cell line panel, and drug-
oriented primary topoisomerase II-mediated DNA
cleavages.2b
Ch em istr y
The activity of the benzo[b]naphtho[2,3-d]furan-
1,3-Dihydroxybenzo[b]naphtho[2,3-d]furan-6,11-di-
6,11-diones, represented by the 1,3-dihydroxyl com-
one (1), as we reported previously,2b was prepared by
pound 1, suggested that synthesis of derivatives with
the condensation of 2,3-dichloro-1,4-naphthoquinone
the addition of two hydroxyl groups at positions 7 and
with phloroglucinol (6a ). However, attempted synthesis
10 (i.e., structure 2) may be of interest. The logic is
of the 1,3,7,10-tetrahydroxy analogue 2 by condensing
that the two added hydroxyl functions peri to the
2,3-dichloronaphthazarin (5a ; prepared by the Friedel-
quinone carbonyl functions can form hydrogen-bonding
Crafts condensation of dichloromaleic anhydride with
linkages with the neighboring carbonyls and should
1,4-dimethoxybenzene in the presence of a molten
readily form metal chelation in vivo for improved
AlCl3-NaCl mixture,5 and the crude product was puri-
biological activity.3 A similar arrangement is thought
fied by means of a Soxhlet extractor) with 6a under the
to be responsible for the drastic enhancement of the
same reaction conditions failed to yield the desired
antineoplastic action of mitoxantrone (4) over that of
product. After a number of studies, compound 2 was
ametantrone (3).4
finally obtained by the following route.
Methylation of 5a with CH3I and Ag2O in CHCl35 gave
* Send correspondence to: C. C. Cheng, Ph.D. Tel: 913-588-4710.
a mixture of 2,3-dichloro-5,8-dimethoxy-1,4-naphtho-
quinone (5b) and 6,7-dichloro-5,8-dimethoxy-1,4-naph-
thoquinone (7) (Chart 1). These compounds were sepa-
rated by recrystallization with a mixture of CHCl3 and
Fax: 913-588-7501. E-mail: ccheng@kumc.edu.
† The University of Kansas Medical Center.
‡ Memorial Sloan-Kettering Cancer Center.
§ The University of Miami School of Medicine.
| University of Medicine and Dentistry of New J ersey.
10.1021/jm9804679 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/20/1999

406 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Chang et al.
Ch a r t 1
CCl4;5 the red crystalline 5b was treated with 3,5-
dimethoxyphenol (6b) and Na2CO3 in DMSO at room
temperature to yield 2-chloro-5,8-dimethoxy-3-(3,5-
dimethoxyphenoxy)-1,4-naphthoquinone (8h ). Treat-
ment of 8h with palladium(II) acetate and Na2CO3 led
to cyclization to yield 1,3,7,10-tetramethoxybenzo[b]-
naphtho[2,3-d]furan-6,11-dione (9a ). Demethylation of
9a with pyridine hydrochloride gave the desired target
compound 2, albeit in low yield. Compound 9b was
obtained in a similar manner from 5b and 3-methoxy-
phenol (6e) via the intermediate 8g. Other chlorophe-
noxyl compounds (8a -8h ) were prepared from 5a or 5b
with the appropriate phenols (6a -6e) and Na2CO3 at
room temperature. Two acetoxy derivatives (8i and 8j)
were obtained by treating 8d and 8e, respectively, with
acetyl chloride.
Reactions between 2,3-dichloro-5,8-dimethoxy-1,4-
naphthoquinone (5b) and 3-methoxyphenol (6e) as well
as between 2,3-dichloronaphthazarin (5a ) and phenol
(6c) in the presence of Na2CO3 at elevated temperature
resulted in the replacement of both chloro groups with
the formation of compounds 10a and 10b, respectively,
in high yields.
tion of the topoisomerase II data, activity found in one
of the cell lines tested is often echoed in other series.
As mentioned previously, during preparation of these
chlorophenoxy intermediates from the dichloro-1,4-
naphthoquinones, when the reaction temperature was
higher than room temperature, both chlorine atoms
were replaced by the phenoxy functions. The resulting
diphenoxy compounds 10a and 10b also showed cyto-
toxic activities.
It is of interest to note that two starting materials,
2,3-dichloronaphthazarin (5a ) and 2,3-dichloro-5,8-
dimethoxynaphthoquinone (5b), also showed sensa-
tional cytotoxic activities. The isomeric 6,7-dichloro-5,8-
dimethoxy-1,4-naphthoquinone (7), on the other hand,
possessed no inhibitory activity.
Not all 5,8-dihydroxynaphthoquinone derivatives are
expected to possess cytotoxicity. A naphthoquinone
oxopyridinium inner salt 11, synthesized by us earlier
by refluxing 8b with 3-picoline,6 was found to be without
inhibitory action in our tests. Since the topoisomerase
II inhibition could not be correlated with the observed
activity and the mere presence of a quinoid structure
may not be sufficient for explaining the structure-
activity relationship, it would be difficult to address the
exact mechanism of activity of these compounds. Com-
pounds 8b, 8g, and 8h have recently been found to
possess activity in the in vivo hollow fiber assays7 at
the National Cancer Institute. Test data are listed in
Table 1.
Resu lts a n d Discu ssion
Preliminary biological evaluation of the cyclized com-
pound 1,3,7,10-tetrahydroxybenzo[b]naphtho[2,3-d]fu-
ran-6,11-dione (2) indicated that it indeed possessed
valuable, but not outstanding, cytotoxicity. The corre-
sponding tetramethoxy compound 9a and trimethoxy
compound 9b were totally inactive. On the other hand,
evaluation of the intermediate chlorophenoxy com-
pounds (including both the tetramethoxyl compound 8h
and the tetrahydroxyl compound 8c) revealed that
exciting inhibitory activity was found in several in vitro
biological systems. This interesting information led us
to evaluate other related chlorophenoxy analogues (8a -
8j), and inhibitory activities were again found in these
compounds. There is little difference in activity among
the hydroxyl, the methoxyl, or the acetoxyl substitu-
tions, and similar inhibitory action was uniformly
observed throughout the entire series. With the excep-
Exp er im en ta l Section
All melting points were taken on a Thomas-Hoover melting
point apparatus. NMR spectra were determined by the NMR
laboratory of The University of Kansas, Lawrence, KS, and
were obtained on a Bruker AM-500 (500 MHz for 1H and
125.77 MHz for 13C) spectrometer with Me4Si as an internal
standard. Elemental analyses were performed by M-H-W
Laboratories, Phoenix, AZ. Where analyses are indicated only
by symbols of the elements, analytical results obtained for
these elements were within (0.3% of the theoretical values.
Mass spectra were determined by The University of Kansas
Mass Spectrometry Laboratory, Lawrence, KS.
2,3-Dich lor on a p h th a za r in (5a ). A mixture of 100 g of
AlCl3 and 20 g of NaCl was melted in a large casserole. To the

Design of Antineoplastic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 407
Ta ble 1. Inhibitory Action of 2-Chloro-3-phenoxy-
1,4-naphthoquinones and Related Compounds
(CDCl3): δ 12.40, 12.09, 7.32, 7.30, 7.19, 6.62, 6.59, 6.55, 4.97.
13C NMR (CDCl3): δ 180.2, 179.2,160.2,159.8,157.3, 156.9,
153.3, 134.2, 131.0, 130.6, 130.5, 111.3, 110.7, 110.4, 108.5,
104.2. MS: m/ z 332 (M+). Anal. (C16H9ClO6) C, H, Cl.
2-Ch lor o-3-(3,5-d ih yd r oxyp h en oxy)n a p h th a za r in (8c)
was prepared in a similar manner by stirring 0.9 g of 5a , 0.45
g of phloroglucinol (6a ), 0.45 g of Na2CO3, and 45 mL of DMSO
for 2 h. Silica gel column purification (CH2Cl2:EtOAc, 9:1 then
1:1) gave 35% yield of pure 8c as a brown solid, mp 138 °C.
1H NMR (DMSO): δ 12.03 (s, 1H, C8-OH), 11.72 (s, 1H, C5-
OH), 9.50 (s, 2H, C3′- and C5′-OH), 7.43 (d, J ) 8.2 Hz, 1H,
C7-H), 7.40 (d, J ) 8.2 Hz, 1H, C6-H), 5.98 (s, 1H, C4′-H),
5.95 (s, 2H, C2′ and C6′-H). MS: m/ z 348 (M+). Anal. (C16H9-
ClO7) C, H, Cl.
2-Ch lor o-3-(3-m eth oxyp h en oxy)n a p h th a za r in (8d ) was
prepared by stirring a mixture of 0.4 g of 5a , 0.3 g of
3-methoxyphenol (6e), 0.4 g of Na2CO3, and 15 mL of DMSO
at room temperature for 3 h. Silica gel column (CH2Cl2) was
used for purification. The yield of this brownish red solid was
73%, mp 153-154 °C. MS: m/ z 346 (M+). Anal. (C17H11ClO6)
C, H, Cl.
2-Ch lor o-3-(3,5-d im eth oxyp h en oxy)n a p h th a za r in (8e)
was prepared in a similar manner by stirring 3.2 g of 5a , 2.8
g of 3,5-dimethoxyphenol (6b), 3.2 g of Na2CO3, and 100 mL
of DMSO at room temperature for 3.5 h and by purifying the
crude product through a silica gel column (CH2Cl2) as a brown-
red solid. The yield was 65%, mp 168 °C. MS: m/ z 376 (M+).
Anal. (C18H13ClO7) C, H, Cl.
2-Ch lor o-5,8-dim eth oxy-3-(3-h ydr oxyph en oxy)-1,4-n aph -
th oqu in on e (8f) was prepared by stirring 1.2 g of 5b, 1.0 g
of resorcinol (6d ), 1.4 g of Na2CO3, and 120 mL of DMSO at
room temperature for 11 h. After recrystallization from
1-BuOH, pure 8f was obtained as a red solid in 50% yield, mp
207 °C. 1H NMR (DMSO): δ 9.66 (s, 1H, C3′-OH), 7.61 (d, J )
8.8 Hz, 1H, C7-H), 7.58 (d, J ) 8.8 Hz, 1H, C6-H), 7.07 (s, 1H,
C2′H), 6.41-6.50 (m, 3H, C4′-, C5′- and C6′-H), 3.88 (s, 3H,
C8-OCH3), 3.82 (s, 3H, C5-OCH3). MS: m/ z 360 (M+). Anal.
(C18H13ClO6) C, H, Cl.
2-Ch lor o-5,8-d im e t h oxy-3-(3-m e t h oxyp h e n oxy)-1,4-
n a p h th oqu in on e (8g) was prepared by stirring 1.0 g of 5b,
0.6 g of 3-methoxyphenol (6e), 0.6 g of Na2CO3, and 40 mL of
DMSO at room temperature for 8 h. Pure product was obtained
by recrystallization from EtOH as a red solid. The yield was
89%, mp 174-175 °C. MS: m/ z 374 (M+). Anal. (C19H15ClO6)
C, H, Cl.
2-Ch lor o-5,8-d im eth oxy-3-(3,5-d im eth oxyp h en oxy)-1,4-
n a p h th oqu in on e (8h ) was prepared by stirring 2.0 g of 5b,
1.2 g of 3,5-dimethoxyphenol (6b), 1.2 g of Na2CO3, and 80
mL of DMSO at room temperature for 2 h. It was recrystallized
from 1-BuOH to give 2.6 g (93% yield) of 8h as red crystals,
mp 184-185 °C. MS: m/ z 404 (M+). Anal. (C20H17ClO7) C, H,
Cl.
2-Ch lor o-5,8-diacetoxy-3-(3-m eth oxyph en oxy)-1,4-n aph -
th oqu in on e (8i). A red-colored mixture of 0.15 g of 8d and 5
mL of CH3COCl was refluxed for 23 h. The reaction solution
was evaporated under reduced pressure to yield a red oily
syrup. To this was added 100 mL of Et2O with stirring. Soon
a yellow solid was formed. It was collected and recrystallized
from CCl4 to give 0.14 g (75% yield) of 8i as yellow crystals,
mp 148 °C. MS: m/ z 430 (M+). Anal. (C21H15ClO8) C, H, Cl.
2-Ch lor o-5,8-d ia cetoxy-3-(3,5-d im eth oxyp h en oxy)-1,4-
n a p h th oqu in on e (8j) was prepared in a manner similar to
that for preparing 8i from 0.2 g of 8e and 5 mL of CH3COCl.
After the product was recrystallized from CCl4, the yield of
yellow crystalline 8j was 80%, mp 173-174.5 °C. MS: m/ z
460 (M+). Anal. (C22H17ClO9) C, H, Cl.
1,3,7,10-Tet r a m et h oxyb en zo[b]n a p h t h o[2,3-d ]fu r a n -
6,11-d ion e (9a ). A mixture of 2.0 g of 8h , 0.5 g of Pd(OAc)2,
and 0.75 g of Na2CO3 in 60 mL of dimethylacetamide was
heated at 120-130 °C in an oil bath under N2 for 8 h and
cooled. The pH of the solution was adjusted to 3 with 2 N HCl,
and H2O was added to make the final volume 1 L. The
resulting precipitate was collected by filtration (1.5 g) and
purified via silica gel column chromatography (CH2Cl2:EtOAc,
IC50 (µM)
NCI
topo II-mediated DNA
compd
HL-60a
SCLCb
screenc
cleavage activitiesd
1
2
5a
5b
7
9a
9b
8a
8b
8c
8d
8e
8f
0.22
0.39
0.049
0.22
1.00
127.9
14.5
0.22
0.16
0.25
0.2
0.07
0.067
0.44
0.12
0.2
1.03
1.5
0.3
++
>100 000
2000
ND
200
10
+++
ND
1.0
ND
ND
+
ND
0.75
>10
1.0
2
2
0.25
0.45
0.5
0.5
0.75
0.3
2.0
2.0
5.0
1.1
+++
++e
++
4000
100
200
800
50
10
20
100
200
50
++
++
++
8g
8h
8i
++e
++e
++
8j
0.5
++
10a
10b
11
0.16
0.13
30.0
1.0
0.1
+++
+++
ND
0
500
0.5
>10.0
a
Inhibitory concentration for established anticancer agent
m-AMSA is 0.055 µM and for compound 12b is 0.22 µM. Cyto-
b
toxicity against SCLC for mitoxantrone4a is 0.02 µM, for adria-
mycin is 0.04 µM, and for VP-16 is 0.5 µM. c National Cancer
Institute preclinical 60-human tumor cell line drug discovery
screen:8 complete inhibition of cell growth detected [log IC50 (M)]
for at least one cell line at -7, +++; -6, ++; -5, +; inactive, -;
d
ND, not determined. Relative activity to induce mammalian DNA
topoisomerase II-mediated DNA cleavage is based on the effective
doses which caused 50% of topoisomerase II-mediated DNA
fragmentation of linearized 8.4-kb YEpTG DNA. The cleavage
activity of VP-16 (a potent topoisomerase II drug) to stimulate topo
II-mediated DNA cleavage is taken as 100 000. e Active in the in
vivo hollow fiber assays at the National Cancer Institute.7
Descriptions of all the assay tests were given in one of our previous
publications.2b
molten mass was added portionwise, with continuous and
vigorous stirring (with a large stirring rod and a thermometer),
an intimate mixture of 11.7 g (0.08 mol) of 99% 1,4-dimethoxy-
benzene and 28.2 g (0.16 mol) of 97% dichloromaleic anhydride
at 140-150 °C. After the addition was complete, the reaction
temperature was raised to 170-175 °C for 5 min with
continuous stirring. The hot melt was quickly but carefully
added, with stirring, to 1000 mL of cold water containing 700
mL of concentrated HCl. The resulting mixture was allowed
to stand overnight at room temperature to complete the
hydrolysis. The solid was collected by filtration under suction
and washed thoroughly with H2O and dried. The crude dark
brown solid was purified with heptane (using a Soxhlet
extractor, 3 days) as shining magenta crystals, mp 197-198
°C (lit. mp 195 °C5). The yield was 20.4 g (93.4%).
2-Ch lor o-3-p h en oxyn a p h th a za r in (8a ). A mixture of 2
g (7.7 mmol) of 5a , 2 g (21 mmol) of phenol (6c), and 2.5 g (24
mmol) of Na2CO3 in 120 mL of DMSO was stirred at 35-40
°C for 4 h. The reaction mixture was diluted with H2O, and
its pH was adjusted to 2-3 by means of 2 N HCl. The final
volume was 1000 mL. The crude product (2.3 g) was collected
by filtration and was purified by silica gel column chromatog-
raphy using CH2Cl2 as eluent to give pure 8a (1.95 g, 80%
yield) as brown crystals, mp 165-167 °C. MS: m/ z 316 (M+).
Anal. (C16H9ClO5) C, H, Cl.
2-Ch lor o-3-(3-h yd r oxyp h en oxy)n a p h th a za r in (8b) was
prepared by stirring a mixture of 4 g (15 mmol) of 5a , 5.6 g
(51 mmol) of resorcinol (6d ), and 6.4 g (60 mmol) of Na2CO3
in 200 mL of DMSO at room temperature for 3 h. After the
reaction mixture (which still contain some insoluble sodium
salt) was diluted with H2O and its pH adjusted to 2-3 with 2
N HCl, the isolated crude product was purified by silica gel
column chromatography (CH2Cl2:EtOAc, 5:1) to give 3.5 g (70%
yield) of pure 8b as dark red crystals, mp 198 °C. 1H NMR

408 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Chang et al.
3:1 then 2:1) to give 0.9 g of 9a , mp 265 °C. The crude product
could also be purified by recrystallization from 1-BuOH. MS:
m/ z 368 (M+). Anal. (C20H16O7) C, H.
1,3,7,10-Tet r a h yd r oxyb en zo[b]n a p h t h o[2,3-d ]fu r a n -
6,11-d ion e (2). A mixture of 0.4 g of 9a and 8 g of pyridine
research grant (N.S.), and NCI Grant CA 39662 (L.F.L.
and C.Y.). The authors also thank the National Cancer
Institute for conducting the in vitro disease-oriented
primary antitumor screen, M-H-W Laboratories, Phoe-
nix, AZ, for conducting the elemental analyses, The
University of Kansas Mass Spectrometry Laboratory for
performing the mass spectrometry analyses, and The
University of Kansas NMR Laboratory for providing the
1H and 13C NMR spectra determinations.
hydrochloride in
a round bottom flask, attached with a
condenser and a CaCl2 drying tube, was heated in an oil bath
at 190-195 °C, with stirring, for 30 min. The reaction mixture
was cooled to ca. 80 °C and acidified with 2 N HCl. After
standing overnight at room temperature, the crude product
was purified through a silica gel column (EtOAc:MeOH, 3:1)
to give 100 mg (27% yield) of 2 as a black solid, mp >300 °C.
MS: m/ z 312 (M+). Anal. (C16H8O7) C, H.
Refer en ces
(1) (a) Cheng, C. C. A Common Structural Pattern among Many
Biologically Active Compounds of Natural and Synthetic Origin.
Med. Hypoth. 1986, 20, 157-172. (b) Cheng, C. C. Structural
Aspects of Antineoplastic Agents - A New Approach. In Progress
in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.; Elsevier
Science Publishers, B.V.: Amsterdam, 1988; Vol. 25, pp 35-83.
(2) (a) Cheng, C. C.; Liu, D. F.; Chou, T. C. Design of Antineoplastic
Agents on the Basis of the “2-Phenylnaphthalene-type” Struc-
tural Pattern. I. Synthesis of Substituted 3-Phenylquinazolones,
Benzoxazolo[2,3-b]quinazolones and benzothiazolo[2,3-b]quinazo-
lones. Heterocycles 1993, 35, 775-789. (b) Cheng, C. C.; Dong,
Q.; Liu, D. F.; Luo, Y. L.; Liu, L. F.; Chen, A. Y.; Yu, C.; Savaraj,
N.; Chou, T. C. Design of Antineoplastic Agents on the Basis of
the “2-Phenylnaphthalene-type” Structural Pattern. 2. Synthesis
and Biological Activity Studies of Benzo[b]naphtho[2,3-d]furan-
6,11-dione Derivatives. J . Med. Chem. 1993, 36, 4108-4112. (c)
Luo, Y. L.; Chou, T. C.; Cheng, C. C. Design of Antineoplastic
Agents on the Basis of the “2-Phenylnaphthalene-type” Struc-
tural Pattern. 3. Synthesis and Biological Activity Evaluation
of 5H-Benzo[b]naphtho[2,3-d]pyrrole-6,11-dione Derivatives. J .
Heterocycl. Chem. 1996, 33, 113-117.
(3) Tarasiuk, J .; Kolodziejczyk, P.; Borowski, E. Enzymatic Studies
of the Effect of Cu(II) on Oxygen Radical Production Stimulated
by Daunorubicin and Ametantrone. Biochem. Pharmacol. 1990,
39, 1405-1410 and references cited therein.
(4) (a) Zee-Cheng, R. K. Y.; Cheng, C. C. Antineoplastic Agents.
Structure-Activity Relationship Study of Bis(substituted ami-
noalkylamino)anthraquinones. J . Med. Chem. 1978, 21, 291-
294. (b) Cheng, C. C.; Zee-Cheng, R. K. Y.; Narayanan, V. L.;
Ing, R. B.; Paull, K. D. The Collaborative Development of a New
Family of Antineoplastic Drugs. Trends Pharmacol. Sci. 1981,
2, 223-224.
(5) Huot, R.; Brassard, P. Friedel-Crafts Condensations with Maleic
Anhydrides. III. The Synthesis of Polyhydroxylated Naphtho-
quinones. Can. J . Chem. 1974, 52, 838-842.
3,7,10-Tr im et h oxyb en zo[b]n a p h t h o[2,3-d ]fu r a n -6,11-
d ion e (9b) was prepared and isolated in a manner similar as
that for the preparation of 9a from 0.9 g of 8g, 0.2 g of Pd-
(OAc)2, 0.3 g of Na2CO3, and 30 mL of dimethylacetamide. The
crude product was purified through a silica gel column (CH2-
Cl2:EtOAc, 3:1) to give 0.1 g (12% yield) of dark brown solid,
mp 260-263 °C. Purification of the crude product could also
be conducted by stirring it in 50 mL of CH2Cl2 and the
insoluble solid recrystallized from DMF, with similar yield.
MS: m/ z 338 (M+). Anal. (C19H14O6) C, H.
2,3-Bis(3-m et h oxyp h en oxy)-5,8-d im et h oxyn a p h t h o-
qu in on e (10a ). A mixture of 1 g (3.4 mmol) of 5b, 1 g (8 mmol)
of 3-methoxyphenol (6e), and 0.9 g (8.6 mmol) of Na2CO3 in
50 mL of DMSO was heated at 105-115 °C for 5 h. The
reaction mixture was cooled and diluted with 600 mL of H2O.
It was then acidified with 2 N HCl to pH 2. The crude solid
was isolated by filtration and recrystallized from 1-BuOH to
give 1.4 g (88% yield) of pure product as orange needles, mp
180 °C. MS: m/ z 462 (M+). Anal. (C26H22O8) C, H.
2,3-Dip h en oxyn a p h th a za r in (10b). A mixture of 2 g (7.7
mmol) of 5a , 2 g (21 mmol) of phenol (6c), and 2.5 g (24 mmol)
of Na2CO3 in 120 mL of DMSO was heated at 80-85 °C for
3.5 h. The reaction mixture was cooled and diluted with H2O
to a total volume of 1000 mL. It was then acidified to pH 3
with 2 N HCl. The crude product was collected by filtration
and purified by silica gel column chromatography using CH2-
Cl2 as the eluent to give 2 g (70% yield) of pure product as red
crystals, mp 219-220 °C. MS: m/z 374 (M+). Anal. (C22H14O6)
C, H.
(6) Chang, H. X.; Cheng, C. C. Formation of Naphthoquinone Oxo-
pyridinium Inner Salts. Synth. Commun. 1998, 28, 1079-1085.
(7) Hollingshead, M. G.; Alley, M. C.; Camalier, R. F.; Abbott, B.
J .; Mayo, J . G.; Malspeis, L.; Grever, M. R. In Vivo Cultivation
of Tumer Cells in Hollow Fibers. Life Sci. 1995, 57, 131-141.
(8) Boyd, M. R. Status of the NCI Preclinical Antitumor Drug
Discovery Screen. Princ. Pract. Oncol. 1989, 3, 1-12.
Ack n ow led gm en t . This investigation was sup-
ported by the Kansas Health Foundation Fund #411606,
the Shawnee Mission La Sertoma Club Cancer Research
Fund and Dr. K. L. Cheng Research Trust Fund
#15383354 (H.X.C. and C.C.C.), NCI Grant CA 18856
and the Elsa U. Pardee Foundation (T.C.C.), a V.A.
J M9804679