1,4-disubstituted anthracene antitumor agents

Article abstract of DOI:10.1021/jm970308+

Three different types of 1,4-disubstituted anthracenes were synthesized, and their cytotoxicity in a panel of tumor cells was compared with that of the corresponding 9,10-disubstituted anthracenes. The panel contained human myeloma, melanoma, colon, and lung cancer cells and sensitive and multidrug- resistant murine L1210 leukemia cells. These compounds had [[(dimethylamino)ethyl]amino]methyl, N-[(dimethylamino)ethyl]carbamoyl, and carboxaldehyde (4,5-dihydro-1H-imidazol-2-yl)hydrazone side chains. The 1,4- diamide was more potent across the tumor panel than the corresponding 9,10- isomer, but the 1,4-diamine and the 1,4-hydrazone were less potent than their 9,10-isomers. Although the 1,4-hydrazone was active against P388 leukemia in mice, it was inactive against L1210 leukemia. Within each pair of compounds, the one with greater average potency against tumor cells gave a greater increase in the transition melt temperature of DNA.

Full text of DOI:10.1021/jm970308+

3
734
J . Med. Chem. 1997, 40, 3734-3738
Articles
1
,4-Disu bstitu ted An th r a cen e An titu m or Agen ts
†
‡
‡
†
‡
Bhashyam S. Iyengar, Robert T. Dorr, David S. Alberts, Anik o´ M. S o´ lyom, Mary Krutzsch, and
William A. Remers*
,
†
Department of Pharmacology and Toxicoclogy and Arizona Cancer Center, University of Arizona, Tucson, Arizona 85721
X
Received May 12, 1997
Three different types of 1,4-disubstituted anthracenes were synthesized, and their cytotoxicity
in a panel of tumor cells was compared with that of the corresponding 9,10-disubstituted
anthracenes. The panel contained human myeloma, melanoma, colon, and lung cancer cells
and sensitive and multidrug-resistant murine L1210 leukemia cells. These compounds had
[
(
[(dimethylamino)ethyl]amino]methyl, N-[(dimethylamino)ethyl]carbamoyl, and carboxaldehyde
4,5-dihydro-1H-imidazol-2-yl)hydrazone side chains. The 1,4-diamide was more potent across
the tumor panel than the corresponding 9,10-isomer, but the 1,4-diamine and the 1,4-hydrazone
were less potent than their 9,10-isomers. Although the 1,4-hydrazone was active against P388
leukemia in mice, it was inactive against L1210 leukemia. Within each pair of compounds,
the one with greater average potency against tumor cells gave a greater increase in the
transition melt temperature of DNA.
The anthracene nucleus is present in many com-
pounds that have activity against tumor cells. These
compounds typically are DNA-intercalating agents,
based on the ability of the large, flat anthracene chromo-
phore to bind strongly between the base pairs. They
usually have side chains or sugar substituents with bas-
ic nitrogens which, upon protonation, further strengthen
the DNA binding. Bisantrene (1) is one example of a
1
9
,10-disubstituted anthracene antitumor agent, and a
related compound (2) had good potency against tumor
cells in culture, although its activity was only marginal
in tumored mice.2 Examples of 1,4-disubstituted an-
thracenes with antitumor activity include mitoxantrone
3
,4
(
3) and 1,4-bis[[(dimethylamino)ethyl]amino]anthra-
4
cene-9,10-dione (4). Even some monosubstituted an-
thracenes, for example, amide derivative 5, have activity
against tumor cells.5 The very important anthracyclines
such as doxorubicin and daunorubicin also may be con-
sidered as anthracene derivatives.
Thus far, the 1,4-disubstituted anthracenes studied
have been 9,10-anthraquinones. It was of interest to
investigate the potential antitumor activity of 1,4-disub-
stituted anthracenes without the quinone function,
1
,4-naphthoquinone with 2,4-hexadiene followed by air
7
oxidation in alkaline solution. We found it more
convenient to prepare 8 by Friedel-Crafts acylation of
1,4-xylene with phthalic anhydride followed by cycliza-
tion of the crude intermediate in sulfuric acid. The
overall yield was 57.5%. Oxidation of 8 to the corre-
sponding diacid 9 was effected by the known method of
particularly in view of the in vivo antitumor activity
reported for 5.5 Such compounds should not have the
toxicity associated with hydroxyl radicals generated by
quinone redox processes.6 Consequently, three different
types of 1,4-disubstituted anthracenes were synthesized
and evaluated for antitumor activity in comparison with
the corresponding 9,10-disubstituted anthracenes.
8
nitric acid oxidation at high temperature. Reduction
of the quinone carbonyls of 9 was accomplished by the
literature procedure involving zinc dust and ammonia,9
and the resulting anthracene-1,4-dicarboxlyate (11) was
converted into its dimethyl ester 12 by the known
procedure involving HCl in methanol. Diester 12 was
then heated with N,N-dimethylethylenediamine to af-
ford the desired diamide 13. The corresponding diamide
with anthraquinone functionality (10) was prepared by
converting 9 into a bis(acid chloride), which was then
heated with (N,N-dimethylamino)ethylamine.
Ch em istr y
The first compound prepared was 13, which corre-
sponds to 5 with two side chains. The first step in the
preparation of 13 was formation of 1,4-dimethylan-
thraquinone (8) (Scheme 1). This compound had been
prepared previously by a Diels-Alder condensation of
1
0
†
Department of Pharmacology and Toxicology.
Arizona Cancer Center.
Abstract published in Advance ACS Abstracts, October 15, 1997.
‡
The reduction of diester 12 to bis(hydroxymethyl)-
X
10
anthracene 14 by LAH was reported. We were unable
S0022-2623(97)00308-7 CCC: $14.00 © 1997 American Chemical Society

1
,4-Disubstituted Anthracene Antitumor Agents
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3735
Sch em e 1a
anthracene-1,4-dicarboxaldehyde (15), which was con-
verted into 17, an isomer of bisantrene (1), by condensa-
tion with two molecules of 2-hydrazino-2-imidazole
hydrobromide (Scheme 1).
Treatment of 1,4-bis(hydroxymethyl)anthracene (14)
with dibromotriphenylphosphorane in acetonitrile af-
forded the corresponding bis(bromomethyl)anthracene
1
6. This compound could be converted into either the
mono- or bis(dimethylamino)ethylamino derivatives 18
and 19, depending on the reaction conditions. Thus,
treatment with (dimethylamino)ethylamine for 1.5 h at
room temperature gave 18, whereas heating a mixture
of 16 with (dimethylamino)ethylamine in toluene at
reflux afforded 19 (Scheme 1). A better preparation of
1
9 was obtained by treating dialdehyde 15 with (di-
methylamino)ethylamine hydrochloride and sodium cy-
anoborohydride in ethanol.
Anthracene-9,10-bis[N-[(dimethylamino)ethyl]carbox-
amide] (21) was prepared from anthracene-1,9-dicar-
boxylic acid (20) by treatment with thionyl chloride
followed by (dimethylamino)ethylamine.
Biology
The potencies of new 1,4-disubstituted anthracenes
in a panel of tumor cell lines are compared with those
of related 1,9-disubstituted anthracenes in Table 1. The
human tumor cell lines include sensitive and 40-fold
multidrug-resistant multiple myeloma, two colon car-
cinomas, and a non-small-cell lung carcinoma. Fur-
thermore, it contains sensitive and 10-fold multidrug-
resistant (P-glycoprotein expressing) murine L1210
leukemia cell lines. Also listed in this table are the
inhibitory potency to neonatal rat heart myocytes and
the effect of drug concentration on increasing the melt
transition temperature (∆Tm) of calf thymus DNA.
It is apparent in Table 1 that the 1,4-diamide 13 is
considerably more potent than the corresponding 9,10-
diamide 21. 1,4-Diamide-9,10-dione 10 is active in some
tumor cell lines but not in others. Among the diami-
noanthracenes, 9,10-diamine 2 is more potent on aver-
age than 1,4-diamine 19 by a factor of approximately
2
. The corresponding monoamine 18 is less active than
diamine 19. The largest difference between members
of paired 1,9- and 1,4-isomers occurs with bisantrene
(1) and its 1,4-isomer 17, wherein bisantrene is consid-
erably more potent against most of the tumor cell lines,
although its potencies against the resistant strains of
8
226 myeloma and L1210 leukemia decrease to surpris-
ing degrees.
Compound 17, the 1,4-isomer of bisantrene, was
tested against P388 lymphocytic leukemia in DBA/2J
6
mice according to the standard NCI protocol (10 tumor
1
1
cells). At a dose of 50 mg/kg given on days 1, 5, and
, it showed an ILS of 32%, but it was toxic at higher
9
doses. It was inactive against L1210 leukemia in mice.
a
(
i) AlCl3; (ii) concd H2SO4; (iii) HNO3, 185-190 °C; (iv) SOCl2;
Str u ctu r e-Activity Rela tion sh ip s
(
(
v) H2N(CH2)2N(CH3)2, toluene; (vi) Zn, NH4OH; (vii) HCl, CH3OH;
viii) Red-Al, toluene; (ix) pyridine chlorochromate, CH2Cl2; (x)
dibromotriphenylphosphorane, CH3CN; (xi) 2-hydrazino-2-
imidazoline‚HBr; (xii) H2N(CH2)2N(CH3)2, H2N(CH2)2N(CH3)2‚HCl,
NaCNBH4, ethanol; (xiii) H2N(CH2)2N(CH3)2, CH2Cl2, rt; (xiv)
H2N(CH2)2N(CH3)2, toluene, reflux.
In a large set of DNA-intercalating anthracene deriv-
atives related to amonafide, it was found that within
series of compounds that are closely related structurally,
there are correlations between the strength of DNA
binding, as measured by transition melt temperature
1
2
to repeat this conversion, but we found that Red-Al in
toluene gave a 49% yield of 14. Oxidation of 14 with
pyridine chlorochromate in dichloromethane provided
(∆Tm), and the cytotoxicity to tumor cells. It is known
that bisantrene (1) and 9,10-diamine 2 both intercalate
1
3
DNA, and probably the other compounds in Table 1

3
736 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Iyengar et al.
Ta ble 1. Activity of Anthracene Derivatives against Human and Murine Tumor Cells in Culturea
potency against tumor cells: IC50 (µM)
myeloma 8226
Rb
5.0
5.0
>10
leukemia L1210
Rc
colon
lung
compd
S
S
SW 480
WiDr
A549
∆Tm (°C)d
1
1
2
1
0
3
1
9
2
8
7
1
>10
3.3
63
4.2
44
73
29
140
UAe
3.2
44
19
5.0
UA
0.72
0.09
4.5
1.4
26
17
4.0
15
UA
0.71
99
8.1
5.0
91
5.0
0.017
0.0
5.2
1.5
6.2
13.6
>10
7.0
3.0
4.0
3.0
4
2.8
3.3
8.3
3.6
188
13
3.2
1
1
12
52
5.6
0.018
6.7
9.1
2.6
0.049
1.6
0.79
17
18.9
a
The murine leukemia and human myeloma experiments utilized the MTT assay (Alley, M. C.; Scudiero, D. A.; Monks, A.; Hursey, M.
L.; Czerwinsky, M. J .; Fine, D. L.; Mayo, J . D.; Shoemaker, R. R.; Boyd, M. R. Feasibility of Drug Screening with Panels of Human Tumor
Cell Lines Using a Microculture Tetrazolium Assay. Cancer Res. 1988, 48, 589-601). Determination of cytotoxicity against colon and
lung tumors utilized the sulforhodamine B assay (Skehan, P.; Strong, R.; Scudiero, D.; Monks, A.; McMahon, J .; Vistica, D.; Warren, J .
T.; Bokesh, H.; Kenney, S.; Boyd, M. R. New Colorimetric Assay for Anticancer-Drug Screening. J . Natl. Cancer Inst. 1990, 82, 1107-
b
1
112). A human myeloma 40-fold resistant to doxorubicin (Dalton, W. S.; Durie, B. G. M.; Alberts, D. S.; Gerlach, J . H.; Cress, A.
Characterization of a New Drug Resistant Human Myeloma Cell Line Which Expresses P-Glycoprotein. Cancer Res. 1986, 46, 5125-
c
5
130). A multidrug-resistant murine leukemia that expresses high levels of P-glycoprotein (Dorr, R. T.; Liddil, J . D.; Trent, J . M.; Dalton,
W. S. Mitomycin C Resistant L1210 Leukemia Cells: Association with Pleiotropic Drug Resistance. Biochem. Pharmacol. 1987, 20, 33-
d
-5
3
6). Transition melt temperature increases for calf thymus DNA were determined at 5 × 10 M (base pairs) in pH 7.0 buffer solution
e
of 0.01 M NaH2PO4 and 0.001 M EDTA. Potency was so low that the IC50 was unachievable.
also intercalate. Although it is unlikely that a correla-
tion between ∆Tm and antitumor potency can be found
for the compounds in Table 1 as a group, it is interesting
to compare the relative ∆Tm values and antitumor
potencies for the isomeric pairs. These pairs should be
nearly identical in lipophilicity and degree of ionization,
which should minimize potential differences in cellular
uptake and emphasize the effect of different DNA
binding strengths. Inspection of the table shows that
Exp er im en ta l Section
Melting points were recorded on a Mel-Temp apparatus and
are uncorrected. Infrared spectra were taken on a Beckman
IR 33 spectrophotometer with samples prepared as KBr
-
1
1
pellets, and absorbances are reported in cm
.
H NMR
spectra were recorded on either a Brucker WM-250 MHz or a
J EOL FXQ 90 MHz spectrometer using deuteriochloroform as
solvent (unless stated otherwise) and tetramethylsilane as the
internal standard. NMR shift values (δ) are expressed in ppm.
Mass spectra were obtained on a Varian-MAT311 spectrometer
in electron impact mode. Elemental analyses were performed
by Desert Analytics, Inc., Tucson, AZ.
P r ep a r a tion of 1,4-Dim eth yla n th r a cen e-9,10-d ion e (8).
To an ice-cooled mixture of phthalic anhydride (6; 18 g, 0.12
mol) and p-xylene (7; 125 mL) was added aluminum chloride
(36 g, 0.33 mol) in three portions over a period of 30 min
keeping the mixture well stirred. After another 30 min of stir-
ring at 0-5 °C the mixture was allowed to warm to room tem-
perature, and then the mixture was stirred at reflux overnight.
The dark brown residue was cooled and carefully poured onto
9
,10-diamine 2 has a higher ∆Tm value than 19, bis-
antrene (1) has a higher ∆Tm value than isobisantrene
1
9
7, and 1,4-diamide 13 has a higher ∆Tm value than
,10-diamide 21. Thus, there is agreement with the
concept that DNA binding strength correlates with
antitumor potency within pairs of isomers. It is unclear
why the 1,4-diamide 13 is more potent than its 9,10-
isomer whereas the opposite relationship occurs for the
other two isomer pairs. An attempt to include all of the
1
kg of crushed ice containing 50 mL of concentrated HCl. The
1
,4-disubstituted anthracenes into a correlation of an-
resulting mixture was stirred for 40 min and then filtered.
The yellow solid was washed with deionized water (2 × 100
mL) and dried under vacuum. It had mp 144-148 °C.
Without further purification, the yellow product was heated
titumor potency with ∆Tm was unsuccessful, probably
because of the wide diversity in structural types within
this family.
with 150 mL of concentrated H
C for 1 h. The dark product was cooled and carefully poured
2 4
SO in a sealed tube at 50-55
°
Con clu sion
into 1.75 L of crushed ice. After stirring for 45 min, the
mixture was filtered, and the yellow solid was washed with
deionized water and then dissolved in ethyl acetate. This
solution was washed with 5% sodium bicarbonate solution (2
Three different types of 1,4-disubstituted anthracenes
were synthesized and their activities against tumor cells
in culture were compared with those of the correspond-
ing 9,10-disubstituted anthracenes. The 1,4-disubsti-
tuted anthracenes had significant cytotoxicity in these
assays but showed no advantages in potency over the
×
200 mL) and water (2 × 200 mL), dried (Na
2 4
SO ), and
concentrated on a rotary evaporator. This procedure gave 16.5
7
g (57.5%) of 8 as a pale yellow solid: mp 138-140 °C (lit. mp
1
1
8
41-142 °C); H NMR 2.59 (s, 6), 7.40 (br s, 2), 7.73 (br s, 2),
-1
.13 (br s, 2); IR 3000-3600, 1650, 1310, 1240 cm ; MS 236
+
9
,10-disubstituted anthracenes. In particular, bisant-
(M ).
rene was much more potent than its 1,4-isomer. These
results are in contrast to the outstanding antitumor
potency shown by 1,4-disubstituted anthracene-9,10-
diones such as mitoxantrone. Within matched pairs of
P r ep a r a tion of 9,10-Dioxoa n th r a cen e-1,4-d ica r boxylic
Acid (9). This compound was prepared by the procedure
described in the literature, except that the reaction was run
in a Parr type T316 stainless steel pressure vessel at 185-
1
90 °C in an oil bath for 2 h. The yield of 9 was 8.0 g (80%):
8
1
1
,4- and 9,10-disubstituted anthracenes, the isomer with
mp 310-314 °C (lit. mp >300 °C); H NMR 7.88 (s, 2), 7.96
greater DNA binding strength had greater cytotoxicity
to tumor cells in culture; however, the large potency
differences among the types of pairs limit the ability of
transition melt increase studies to correlate or predict
structure-activity relationships for disubstituted an-
thracenes.
(2d, 2), 8.17 (2d, 2); IR 3000-3600, 1700, 1665, 1300, 1250
-
1
+
+
cm ; MS 252 (M - CO), 208 (M - 2 CO).
P r ep a r a t ion of 9,10-Dioxoa n t h r a cen e-1,4-b is[N-[2-
(
(
(
d im et h yla m in o)et h yl]ca r b oxa m id e] Dih yd r och lor id e
10). A solution of 9,10-dioxoanthracene-1,4-dicarboxylic acid
9; 1.0 g, 3.3 mmol) in 10 mL of thionyl chloride was heated at
2
reflux under N for 5 h, cooled, and concentrated on a rotary

1
,4-Disubstituted Anthracene Antitumor Agents
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3737
evaporator. The residue was dried by adding 10 mL of dry
toluene and concentrating on a rotary evaporator. It was then
pressure to give a crude solid that was chromatographed on
silica gel with dichloromethane as eluant. The fast-moving
pale yellow fraction was evaporated to give 300 mg (40%) of
16, which was recrystallized from toluene-petroleum ether:
mp >300 °C dec (lit.10 mp >300 °C); H NMR 5.06 (s, 4), 7.49
heated with 30 mL of dry toluene under N
N,N-dimethylethylenediamine (1 mL, 9 mmol) in dry toluene.
The dark red mixture was heated at reflux under N for 3 h,
2
and treated with
1
2
+
cooled, and stirred at room temperature overnight. The
solvent was then removed on a rotary evaporator, and the
residue was stirred with 50 mL of absolute ethanol and then
filtered. The residue was washed with ice-cold ethanol (2 × 5
mL) and dried under vacuum to give 471 mg (32%) of 10 as
(s, 2), 7.57 (2d, 2), 8.1 (2d, 2), 8.76 (s, 2); MS (EI) 3.64 (M ),
366 (M + 2).
P r ep a r a tion of An th r a cen e-1,4-d ica r boxa ld eh yd e Bis-
[(4,5-d ih yd r o-1H-im id a zol-2-yl)h yd r a zon e] (17). A mix-
ture of anthracene-1,4-dicarboxaldehyde (15; 50 mg, 0.213
mmol) and 2-hydrazino-2-imidazoline hydrobromide (105 mg,
0.058 mmol) in 5 mL of ethanol was heated at reflux for 5 h.
The resulting orange precipitate was filtered hot, washed with
hot ethanol (2 × 5 mL), and dried to give 52.5 mg (44%) of 17:
1
the dihydrochloride: mp 240-245 °C dec; H NMR 3.15 (s,
1
2), 3.63 (t, 4), 3.93 (t, 4), 7.7-7.8 (m, 2), 7.9 (s, 2), 8.1-8.2
(m, 2). Anal. (C24
H
28
N
4
O
4
2
‚2HCl‚0.5H O) C, H; N: calcd, 10.80;
found, 10.35.
1
Syn th esis of An th r a cen e-1,4-bis[N-[2-(d im eth yla m i-
n o)eth yl]ca r boxa m id e] (13). Meth od A. A mixture of
mp 330-340 °C dec; H NMR 3.8 (s, 8), 6.7 (br s, 2), 8.24 (s,
+
4), 8.5-9.0 (br s, NH), 9.16 (s, 2), 9.26 (s, 2); MS (EI) 398 (M ),
1
0
dimethyl anthracene-1,4-dicarboxylate (12; 500 mg, 1.7
mmol) and N,N-dimethylethylenediamine (5 mL, 4.5 mmol)
in 20 mL of p-xylene was heated at reflux for 24 h, cooled,
and concentrated on a rotary evaporator. The oily residue was
stirred with 125 mL of diethyl ether and filtered, and the solids
were washed with diethyl ether (2 × 10 mL) and dried. This
313 (M - aminoimidazole), 228 (M - 2 aminoimidazole). Anal.
(C22
H
22
N
8
2
‚2HBr‚0.5H O) C, H, N.
P r ep a r a tion of 4-(Br om om eth yl)-1-[[[2-(d im eth yla m i-
n o)eth yl]a m in o]m eth yl]a n th r a cen e (18). A solution of 1,4-
bis(bromomethyl)anthracene (16; 100 mg, 0.27 mmol) and N,N-
dimethylethylenediamine (0.8 mL, excess) in 15 mL of dry
dichloromethane was stirred for 1.5 h at room temperature.
The yellow precipitate that formed was collected, washed with
dichloromethane, and dried under vacuum. This procedure
1
procedure gave 67 mg (9%) of 13: mp 190-195 °C; H NMR
2
.29 (s, 12), 2.6 (t, 4), 3.67 (q, 4), 6.76 (t, 2, NH), 7.5 (dd, 2, J
)
6.5, 3.5 Hz), 7.6 (s, 2), 8.0 (dd, 2, J ) 6.5, 3.5 Hz), 8.9 (s, 2);
1
HRMS calcd for C24 406.236 850, found 406.234 600.
H
30
N
4
O
2
gave 50 mg (41%) of 18: mp 195-205 °C dec; H NMR 3.06
9
Meth od B. A mixture of anthracene-1,4-dicarboxylic acid
11; 0.5 g) and 5 mL of thionyl chloride was heated at reflux
(s, 6), 3.01-3.36 (m, 2), 3.49 (t, 2), 4.02 (s, 2), 5.2 (s, 2), 7.65
(
(br s, 2), 7.9 (br s, 1), 8.15 (d, 2), 8.25 (br s, 1), 9.15 (s, 1), 9.30
under N
2
for 5 h, cooled, and concentrated on a rotary
23 2
(s, 1). Anal. (C20H N Br‚HBr) C, H, N.
evaporator. The residue was dried by treatment with 5 mL
of dry toluene and concentrated on a rotary evaporator, and
then the yellow residue was heated with 15 mL of dry toluene
P r ep a r a tion of 1,4-Bis[[[2-(d im eth yla m in o)eth yl]a m i-
n o]m eth yl]a n th r a cen e (19). Meth od A. A solution of
anthracene-1,4-dicarboxaldehyde (15; 80 mg, 0.34 mmol), N,N-
dimethylethylenediamine (185 mg, 2.09 mmol), and N,N-
dimethylethylenediamine hydrochloride (240 mg, 1.5 mmol)
in 20 mL of absolute ethanol was stirred for 3 h at room
temperature and then treated with 50 mg of sodium cy-
anoborohydride. The mixture was stirred at room temperature
for 24 h, cooled to 0 °C, and treated with 5 mL of 1 N HCl,
and the ethanol was removed on a rotary evaporator. The
residue was made basic with 5% NaOH and extracted with
under N
diethylethylenediamine. The resulting mixture was heated at
reflux for 3 h under N , cooled, and stirred overnight at room
2
and treated with a solution of 0.45 mL of N,N-
2
temperature. It was then concentrated on a rotary evaporator,
and the residue was stirred with 15 mL of absolute ethanol
for 1 h. The solid was washed with absolute ethanol (2 × 5
mL) and dried to give 66 mg (8%) of 13 as the dihydrochloride
with mp 235-240 °C. A small sample of this product was
converted into the free base by treatment with NaOH in CH
3
-
CHCl
dried (Na
give 47 mg (37%) of 19 as a dark brown crystalline solid:
NMR 2.2 (s, 6), 2.5 (t, 2, J ) 6.0 Hz), 2.88 (t, 2, J ) 6 Hz,
NCH ), 4.4 (s, 4, CH ), 7.42 (s, 2, H2, H3), 7.45-7.50 (m, 2,
3
. The organic layer was washed with water (2 × 5 mL),
OH. The free base was identical with 13 prepared by method
A according to TLC.
2
SO ), and concentrated on a rotary evaporator to
4
1
H
P r epar ation of 1,4-Bis(h ydr oxym eth yl)an th r acen e (14).
A solution of dimethyl anthracene-1,4-dicarboxylate (12; 5.0
g, 0.017 mol) in 120 mL of freshly distilled toluene was cooled
in an ice bath and treated with 12 mL of a 3.4 M solution of
Red-Al in toluene under a nitrogen atmosphere. The mixture
was stirred well for 1 h, and then excess reducing agent was
destroyed by adding 10 mL of ice-cold 10% HCl. After being
stirred for 30 min, the mixture was filtered, and the solid was
washed with ice-cold water (2 × 100 mL) and dried under
vacuum. This procedure gave 2.0 g (49%) of 14: mp 155-158
2
2
H6, H7), 8.03 (2d, 2, J ) 6.3, 3.3 Hz), 8.69 (s, 2, H9, H10). The
hydrochloride salt of 19, prepared with dry HCl gas in
methanol, had mp >300 °C. Anal. (C24
34 4
H N ‚2HCl) C, H.
Meth od B. A solution of 1,4-bis(bromomethyl)anthracene
(16; 50 mg, 0.14 mmol) and N,N-dimethylethylenediamine (20
mg, 0.34 mmol) in 15 mL of dry toluene was heated at reflux
temperature for 6 h, cooled, and concentrated to dryness. The
residue was extracted with 15 mL of diethyl ether, filtered,
and dried. This procedure gave 8.9 mg (12%) of 19 as the
9
1
°
6
C (lit. mp 160 °C); H NMR (DMSO-d ) 4.5 (d, 4), 4.7 (t, 2);
+
+
+
+
MS 238 (M ), 220 (M - H
2
O), 202 (M - 2 H
2
O).
dihydrobromide salt: MS (CI) 379 (MH ). A small sample of
P r ep a r a tion of An th r a cen e-1,4-d ica r boxa ld eh yd e (15).
A solution of 1,4- bis(hydroxymethyl)anthracene (14; 200 mg,
this product was converted into the free base, which was
identical in TLC with a sample prepared by method A.
P r ep a r a tion of An th r a cen e-9,10-bis[N-[(d im eth yla m i-
n o)eth yl]ca r boxa m id e] Hyd r och lor id e (21). A solution of
anthracene-9,10-dicarboxylic acid (20; 514.7 mg) in 15 mL of
0
.84 mmol) in 250 mL of dry dichloromethane was treated with
pyridine chlorochromate (500 mg, 2.32 mmol) at room tem-
perature for 2 h. The mixture was filtered through a Florisil
bed which was washed with dichloromethane until the wash-
ings became colorless. The combined filtrate and washings
were concentrated to dryness under reduced pressure and the
residue was chromatographed on a silica gel column with
dichloromethane as eluant. The fast moving pale yellow
fraction was collected and evaporated under reduced pressure
2
toluene was stirred under N and treated with 3 mL of thionyl
chloride. The mixture was stirred for 3 days at room temper-
ature and concentrated on a rotary evaporator. The residue
was treated with 18 mL of (N,N-dimethylamino)ethylamine,
and the mixture was stirred overnight at room temperature.
After removal of excess amine on a rotary evaporator, the
residue was treated with a small amount of toluene and
reconcentrated. The residue was dissolved in methanol and
treated with sodium bicarbonate solution. The resulting
solution was concentrated on a rotary evaporator, and the
1
to afford 96 mg (49%) of 15: mp 166-169 °C; H NMR 7.63-
7
2
.66 (m, 2), 8.14-8.18 (m, 2), 8.15 (s, 2), 9.92 (s, 2), 10.56 (s,
-
1
+
); IR 3010 (very weak), 1690 cm ; MS 234 (M ). Anal.
‚0.0.1H O) C, H.
P r ep a r a tion of 1,4-Bis(br om om eth yl)a n th r a cen e (16).
A solution of 1,4-bis(hydroxymethyl)anthracene (14; 500 mg,
.1 mmol) in 150 mL of dry acetonitrile was treated with
(C
10
H
10
O
2
2
residue was purified by chromatography on silica gel with CH
3
-
OH-CHCl (6:10) as solvent. Four bands appeared, and the
3
2
slowest-moving one was collected, concentrated on a rotary
evaporator, and dried under high vacuum to afford 302 mg
(38.4%) of 21 as the free base. A 139-mg portion of this product
was dissolved in 9 mL of absolute ethanol into which HCl gas
dibromotriphenylphosphorane (1.8 g, 4.3 mmol), and the
mixture was heated at reflux overnight and then filtered
through Florisil. The filtrate was evaporated under reduced

3
738 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Iyengar et al.
had been bubbled. Dilution of the resulting solution with ether
gave the hydrochloride salt, which was collected and dried
(5) Palmer, B. D.; Rewcastle, G. W.; Atwell, G. J .; Baguley, B. C.;
Denny, W. A. Potential Antitumor Agents. 54. Chromophore
Requirements for in Vivo Antitumor Activity among the General
Class of Linear Tricyclic Carboxamides. J . Med. Chem. 1988,
under vacuum to furnish 228 mg of 21 as a cream-colored
1
solid: mp 296-301 °C; H NMR (DMSO-d
6
+ TFA) 3.0 (s, 12),
3
1, 707-712.
3
9
.6 (br s, 4), 4.1 (br s, 4), 7.65-7.80 (m, 4), 8.05-8.2 (m, 4),
.25 (br s, 2), 10.6 (br s, 2). Anal. (C24 ‚1.70HCl) C,
H; N: calcd, 11.23; found, 11.86.
(
6) Powis, G. Free Radical Formation by Antitumor Quinones. Free
Radical Biol. Med. 1989, 6, 63-101.
7) Alder, K.; Kurth, R. The Configuration of R- and â-Elaostearic
Acid Liebigs Ann. 1957, 609, 19-39.
30 4 4
H N O
(
Ack n ow led gm en t. This project was supported by
Grant CA 37798 awarded by the National Cancer
Institute, DHHS. We thank Dr. G. Craig Hill for
preparing compound 21.
(8) Arient, J .; Podstata, J . Nitration and Oxidation of Anthraquinine
Dimethyl Derivatives Collect. Czech. Chem. Commun. 1974, 39,
3
117-3123.
(9) Elbs, K. Contribution to Knowledge of Homologs of Anthracene
and Anthraquinone. J . Prakt. Chem. 1890, 41, 7-32.
(
10) Gundermann, K.-D.; Roker, K.-D. Chemiluminescent Paracy-
clophanes, II: Intramolecular Sensitized Chemiluminescence.
Liebigs Ann. 1976, 140-152.
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(
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