Structure-activity relationships for substituted bis(acridine-4- carboxamides): A new class of anticancer agents

Article abstract of DOI:10.1021/jm980687m

A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH₂)₃N(Me)(CH₂)₃ chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N

Full text of DOI:10.1021/jm980687m

J . Med. Chem. 1999, 42, 2383-2393
2383
Str u ctu r e-Activity Rela tion sh ip s for Su bstitu ted Bis(a cr id in e-4-ca r boxa m id es):
A New Cla ss of An tica n cer Agen ts
Swarna A. Gamage, J ulie A. Spicer, Graham J . Atwell, Graeme J . Finlay, Bruce C. Baguley, and
William A. Denny*
Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, The University of Auckland,
Private Bag 92019, Auckland 1000, New Zealand
Received December 7, 1998
A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3
chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-
4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the
mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA),
currently in clinical trial, show superior potencies to the corresponding monomeric DACA
analogues in a panel of cell lines, including wild-type (J LC) and mutant (J LA and J LD) forms
of human J urkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted
agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl)
at the acridine 5-position were clearly superior, with IC50’s as low as 2 nM against the Lewis
lung carcinoma and 11 nM against J LC. Larger substituents at any position caused a steady
decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues
of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the
1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while
the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl
group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against
the mutant J urkat lines than in the wild-type, consistent with a relatively greater effect on
topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found
to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average
10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the
wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell
line panel. Several analogues produced significant growth delays in the relatively refractory
subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis-
(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase
inhibitors.
In tr od u ction
Early structure-activity relationship (SAR) studies
with DNA-intercalating topoisomerase (topo) II inhibi-
tors suggested a positive correlation between cytotoxic
potency and the strength of reversible DNA binding.1-4
Because bis-intercalation would theoretically greatly
increase DNA binding, a number of reports have dis-
cussed various dimeric compounds, designed as poten-
tial bis-intercalating agents.5-7 While many of these
compounds did show increased affinity for DNA, their
biological activities were generally disappointing. The
bis(acridine) (1) was considered for clinical trial8 but had
significant central nervous system (CNS) toxicity,9 while
the bis(ellipticine) analogue ditercalinium (2) had unac-
ceptable mitochondrial toxicity.10 Until recently the only
dimeric, bis-intercalating agent to receive clinical evalu-
ation was the bis(quinoxaline) natural product echino-
mycin.11,12
However, a number of recent papers have reported
that lipophilic dimeric naphthalimides and imidazoacri-
dinones show broad-spectrum activity against a variety
of human solid tumor cell lines, both in culture and as
xenografts in nude mice. The monomeric naphthalimide
mitonafide (3) itself has undergone extensive clinical
trials, where it has shown activity but also severe CNS
toxicity.13 The bis(naphthalimide) analogue DMP 840
10.1021/jm980687m CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/15/1999

2384 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Gamage et al.
Sch em e 1a
Sch em e 2a
a
(i) Al/Hg/NaOH/H2O/EtOH/reflux, then FeCl3/H+/40 °C/2-20
h; (ii) CDI/DMF/12 h/50 °C; (iii) [H2N(CH2)3]2NMe/THF/20 °C/12
h.
(4) shows curative activity against a variety of human
solid tumor xenografts in nude mice14,15 and is presently
in clinical trial.16 The related compound LU 79553 (5)
is also reported to be under clinical development.17 The
monomeric imidazoacridinone C-1311 (6) is also a
candidate for clinical trial,18 and a series of bis-
analogues (e.g., WMC-26, 7) show highly selective
cytotoxicity toward human colon carcinoma cells both
in culture and in xenografts, although they appear not
to be bis-intercalating agents.19
a
(i) Cu/CuI/N-ethylmorpholine/butane-2,3-diol; (ii) Cu/CuI/
K2CO3/DMSO; (iii) PPA/100 °C; (iv) Al/Hg/NaOH/H2O/EtOH/
reflux, then FeCl3/H+.
Sch em e 3a
The acridinecarboxamide derivative N-[(2-dimethy-
lamino)ethyl]acridine-4-carboxamide (DACA, 8) is an-
other lipophilic mono-intercalator which entered phase
I clinical trial20 on the basis of its mixed inhibition of
both topo I and topo II21,22 and excellent activity in
experimental solid tumor models.20,23 DACA has been
shown to retain activity in cell lines resistant due to
alterations in topo I, topo II, and P-glycoprotein expres-
sion.24,25 In a recent study26 of a series of dimeric
tricyclic aromatic carboxamides, the bis(DACA) ana-
logue 9a showed a 5-fold increase in cytotoxic potency
over the monomer 8 and also showed significant growth
delay (ca. 6 days) in the colon 38 tumor model.
The activity profiles of 8 and 9a , and the work
reported above on the high solid tumor activity of
dimeric analogues of other lipophilic mono-intercalators,
prompted us to prepare and evaluate a series of bis-
(DACA) compounds (9a -9oo, Table 1), where the acri-
dine substituents were varied.
a
(i) Cu/CuI/N-ethylmorpholine/butane-2,3-diol; (ii) CDI/THF/
20 °C/18 h, then NaBH4/20 °C/0.5 h; (iii) MnO2/EtOAc/reflux/7 h;
(iv) TFA/40 °C/4 h.
examples) were prepared by reduction of the corre-
sponding acridone-4-carboxylic acids 10 with aluminum/
mercury amalgam, followed by FeCl3 reoxidation of the
resulting acridans23 (Scheme 2). Ullmann reaction of
anilines 13 and 14 with 2-iodoisophthalic acid (15), or
2-bromo-3-methylbenzoic acid (18) with anthranilic acid
(19) followed by cyclization of the resulting dipheny-
lamine diacids 16, 17, and 20 in PPA, gave the required
acridone-4-carboxylic acids 10ll, 10n n , and 10m m .
In cases where this was not compatible with the ring
substituent, the recently reported27,28 synthesis via ring
closure of a precursor aldehyde was employed (Scheme
3). Thus condensation of 3-methylanthranilic acid (21)
and methyl 4-chloro-2-iodobenzoate (22) gave acid 23,
which was reduced to 24 and reoxidized with MnO2 to
the aldehyde 25. Cyclization of this in TFA followed by
hydrolysis gave the required acridine-4-carboxylic acid
11oo.
Ch em istr y
The bis(acridines) 9 were prepared as shown in
Scheme 1. The acids 11 (prepared via the acridones 10
or by direct ring closure) were activated with 1,1′-
carbonyldiimidazole, and after isolation, the intermedi-
ate N-imidazolides 12 were reacted with a stoichiomet-
ric amount of the appropriate diamine. The bis(dimethyl-
amino) analogues 9q, 9x, and 9h h were prepared from
the corresponding fluoro analogues 9m , 9t, and 9ee by
prolonged treatment with excess dimethylamine in
aqueous MeOH under pressure at 100 °C.
Most of the ring-substituted acridine-4-carboxylic
acids 11 required were known, and these (and some new

SAR for Bis(acridine-4-carboxamides)
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2385
Ta ble 1. Cytotoxicity Data for Substituted Bis(acridine-4-carboxamides)
IC50 (nM)a
LLd
ratiosb
e
f
g
no.
R
mp (°C)
P388c
98
J LC
J LA/J LC
J LD/J LC
8
ref 27
189
30
14
42
67
5.9
2400
2980
1.8
27
1050
1085
170
35
8
6
39
670
56
20
20
13
18
160
320
73
770
2080
1400
610
20
32
46
35
183
16
580
110
41
127
255
46
1295
900
11
113
2080
2540
345
49
33
24
115
180
177
51
1.9
0.7
0.6
0.6
0.7
0.7
0.9
0.9
0.4
0.7
0.9
0.5
0.5
0.6
0.55
0.4
0.85
0.7
0.7
0.5
0.6
0.5
0.6
0.6
0.3
0.9
0.9
1.1
1.1
1.0
0.70
0.6
0.8
0.7
1.0
0.7
0.8
0.5
0.4
0.3
0.5
0.3
85
2.3
0.8
1.0
1.0
1.1
0.9
1.0
1.2
0.7
0.9
1.1
0.8
0.8
0.9
1.0
0.9
1.1
0.9
0.9
0.8
0.9
0.9
0.9
1.1
0.6
1.1
1.4
1.1
1.1
1.1
1.1
0.8
0.9
0.9
0.9
1.0
1.2
0.8
0.7
0.7
0.7
0.6
74
9a h
9b
H
168-170i
130
170
400
220
113
3500
>2 × 105
23
170
2760
1230
430
16
46
15
240
2130
345
76
1-Me
ncj
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
9s
1-Cl
94-96
nc
175.5-176.5
2-Me
2-Cl
3-Me
nc
3-Cl
117 dec
118-120
70-73
nc
5-Me
5-Et
5-iPr
5-Ph
5-OMe
5-F
nc
nc
134-136
89-93
172-174.5
231-233i
nc
5-Cl
5-Br
5-CF3
5-NMe2
6-Me
6-OMe
6-F
nc
180-181
165 deci
149-150
171-172
169-171
nc
9t
9u
9v
9w
9x
24
66
49
52
51
58
6-Cl
6-Br
6-CF3
6-NMe2
7-Me
9600
760
270
1080
1450
1760
710
132
140
170
225
970
180
750
210
24
355
225
275
1640
2080
1070
1020
147
96
136
226
760
71
9y
9z
nc
nc
nc
nc
7-Et
9a a
9bb
9cc
9d d
9ee
9ff
9gg
9h h
9ii
9jj
9k k
9ll
7-iPr
7-tBu
7-Ph
7-OMe
7-F
162-163
nc
128-133
183-185
201-202
nc
7-Cl
7-Br
7-NMe2
8-Me
nc
nc
nc
8-Cl
123
20
238
105
11
5,7-diMe
5,8-diMe
1,5-diMe
5-Me, 8-Cl
1-Cl, 5-Me
119-124
110-116
212-215
156-158.5
3.2
1.4
8.8
6.0
12
9m m
21
41
48
20
3.9
20
9n n
9oo
12
37
amsacrine
doxorubicin
31
22
9.6
4.4
13
a
IC50, concentration of drug (nM) to reduce cell number to 50% of control cultures (see text). The value is the average of at least two
independent determinations; the coefficient of variation was 12-18%. Ratios of IC50’s in the cell lines shown. c Murine P388 leukemia.
b
Murine Lewis lung carcinoma. e J LC, wild-type human J urkat leukemia. f J LA, amsacrine-resistant J urkat. J LD, doxorubicin-resistant
d
g
h
i
j
J urkat. Data from ref 26. HCl salt. Noncrystalline.
Resu lts a n d Discu ssion
tumor model. Absolute IC50 values are given for the
P388, LLTC, and J LC lines, together with ratios of IC50
values against J LC and the other two J urkat lines
(ratios J LA/J LC and J LD/J LC). Values of these ratios of
less than about 2-fold suggest a novel, non-topo II-
mediated mechanism of action. DACA itself (8), which
is a mixed topo I/II inhibitor,21 has ratios of 2.3 and 2.5,
respectively, while the 6-chloro derivative, which has
been shown to be a preferential topo I inhibitor,21 has
ratios of 1.2 and 1.3. The panel was designed to provide
an initial screen for selecting analogues of DACA with
greater absolute potency but similar or lower J LA/J LC
and J LD/J LC ratios, for advanced evaluation against
subcutaneous colon 38 tumors and human tumor xe-
IC50 values were determined for all the compounds
in a panel of cell lines in culture, and the results are
given in Table 1. The murine P388 leukemia was used
to provide comparison with previous data on related
compounds.23 The three human leukemia (J urkat) lines
have been described in detail previously.25,29 J LC is the
wild-type (sensitive) line, while J LA is resistant to the
DNA intercalator amsacrine and similar agents (85-fold
resistant to amsacrine) by virtue of a reduced level of
topo II enzyme. J LD is a doxorubicin-resistant line,
primarily by virtue of altered levels of topo II but
probably also by additional mechanisms. LLTC is a
murine Lewis lung carcinoma line,30 included as a solid

2386 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Gamage et al.
nografts in vivo. For quantitative structure-activity
relationships (QSAR), MR (molar refractivity) was used
as a measure of steric bulk because values were avail-
able for all substituents, and it correlated well (r ) 0.96)
with the Taft steric parameter Es in the cases where
these values were also available. Lipophilicity was
measured by π values, and electronic properties by σp
values for 5- and 7-substituents and σm values for 6-and
8-substituents (reflecting contributions to acridine pKa).31
Previous work26 showed the utility of the (CH2)3N-
(Me)(CH2)3 linker chain, and this was used for studying
the SAR of the acridine-substituted bis(DACA) ana-
logues. The parent (CH2)3N(Me)(CH2)3-linked compound
9a was 5-fold more cytotoxic than DACA in the J LC line
(IC50 110 versus 580 nM). A series of compounds (9a -
9oo) was prepared and evaluated in the cell line panel.
For the whole set, IC50 values against the different lines
correlated reasonably well (eqs 1 and 2), although not
as tightly as for the substituted monoDACA analogues.28
Importantly, these increases in potency do not appear
to be the result of a change in mechanism (as in the
monoDACA series).28 The compounds show even better
activity against the resistant J urkat lines (J LA/J LC and
J LD/J LC ratios < 1), suggesting retention of the desired
mixed topo I/II profile.
Most of the 6-substituted derivatives 9r -9x were also
slightly more potent than the parent compound, and all
retained ratios of <1, but there were insufficient num-
bers of compounds to carry out QSAR studies. The
7-substituted analogues 9y-9h h behaved broadly as the
5-substituted compounds but were less potent. The
cytotoxicity data were again fitted best by the steric
parameter MR alone (eq 4).
log(IC50)J LC ) 0.50((0.13)[0.1 MR] + 2.05((0.16)
n ) 11, r ) 0.79, F ) 15
(4)
Multiple linear regressions with MR and σ for both
the 5- and 7-substituted compounds provided negative
coefficients for the σ parameter, suggestive of electron-
withdrawing groups increasing cytotoxicity, but these
did not quite reach the 5% level.
log(IC50)LLTC ) 0.98((0.08) log(IC50)P388
0.52((0.21) (1)
n ) 40, r ) 0.88, F ) 135
-
Because the 5-methyl derivative 9h showed the
highest cytotoxicity, a small series of 5,x-disubstituted
compounds (9k k -9oo) was also evaluated. The 5,7-
dimethyl compound 9k k was prepared because studies
with 5,7-disubstituted monomeric compounds32 had
shown that such compounds retained both the high
potency of 5-substituted analogues and the mixed topo
I/II-type activity pattern of the 5-substituted com-
pounds. However, 9k k was less cytotoxic than the
corresponding 5-Me derivative 9h .
The other disubstituted analogues focused on Cl or
Me groups at the 1- or 8-position. These substituents
by themselves had resulted in compounds of enhanced
or equal potency to that of the parent compound 9a , and
the possible influence of steric bulk close to C-9, the site
of the major route of cellular metabolism of DACA by
aldehyde oxidase,33 was of interest.
The results for these compounds are listed in Table
1, together with background data for the respective
monosubstituted analogues. The 1,5- and 5,8-dimethyl
analogues 9m m and 9ll had similar potencies to the
5-Me derivative 9h (in fact 9m m was about 2-fold more
cytotoxic and was the most potent analogue studied).
The 5-Me, 8-Cl and 1-Cl, 5-Me, derivatives 9n n and 9oo
were slightly less effective but still had IC50’s broadly
similar to that of 9h (and were much superior to the
corresponding 1- and 8-Cl analogues 9c and 9jj). Thus,
while the above 1- and 8-substituents are acceptable, it
is the 5-methyl group that is largely responsible for the
greatly enhanced potencies of these compounds com-
pared to the unsubstituted parent 9a .
A subset of the compounds (the parent, all the methyl-
and chloro-substituted analogues, the 5-substituted
compounds, and two 5,8-disubstituted derivatives) was
evaluated in the NCI cell human line panel,34 and
results for six of those lines are presented in Table 2 as
GI50 values (the concentration of drug resulting in
inhibition of cell growth to 50% of controls; equivalent
to IC50), together with the mid-value (the average GI50
value for the drug over the whole cell line panel). A
comparison of the GI50(mid) value for each compound
log(IC50)J LC ) 0.77((0.07) log(IC50)P388
0.38((0.17) (2)
n ) 40, r ) 0.87, F ) 120
+
The dataset included two substituents (Me and Cl)
in all seven available positions. A comparative analysis
of the IC50’s of these compounds showed that the
positional effects fell into three categories. Substitution
at the 3-position dramatically decreased potency over
the parent unsubstituted compound 9a in all cell lines
(for example, 9-fold for the 3-Cl analogue 9g, 12-fold for
the 3-Me analogue 9f in the J LC line). Substitution at
this position, ortho to the CONH, is likely to interfere
with the conformation of the side chain. In the mono-
DACA series, 3-substitution led to a marked drop in
DNA binding (and cytotoxicity).23 In contrast, substitu-
tion at the 5-position markedly increased potency (for
example, 3-fold for the 5-Cl compound 9n , 10-fold for
the 5-Me analogue 9h in the J LC line). For the remain-
ing positions, there were no marked effects in potency
compared to the parent compound.
The 5-substituted analogues 9h -9q contained sub-
stituents possessing a wider range of electronic, steric,
and hydrophobic properties. For the 5-substituted com-
pounds 9h -9q (and 9a ), regression equations correlat-
ing IC50 values with electronic, hydrophobic, and steric
properties were developed, but only those with MR alone
(for example, eq 3) were significant.
log(IC50)J LC ) 0.78((0.24)[0.1 MR] + 1.51((0.28)
n ) 11, r ) 0.74, F ) 11
(3)
This overall equation suggests that larger groups lead
to a loss of activity (probably by lowering DNA binding
ability) but does not highlight the significant increase
in potency of analogues substituted with small groups
over the unsubstituted derivative 9a . For example, 9h
(5-Me) and 9n (5-Cl) have IC50’s of 11 and 33 nM,
respectively, against J LC, compared with 110 nM for 9a .

SAR for Bis(acridine-4-carboxamides)
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2387
Ta ble 2. Cytotoxicity of Selected Bis(acridine-4-carboxamides) in the NCI Cell Line Panel
GI50 (nM)a
no.
substituent
MCF7
NCI-ADR
CAK-1
14
42
247
SKOV3
HT29
HCT-116
midb
9a
9b
9d
9f
9g
9h
9i
H
24
54
408
77
657
8570
1170
<10c
<10
265
1430
727
<10
1390
1620
103
<10
31
<10
33
62
<10
34
60
120
<10
<10
<10
<10
446
171
<10
221
5060
330
<10
14
<10
32
130
<10
12
130
130
470
3800
2240
17
910
4070
600
40
290
26
175
930
80
1-Me
2-Me
3-Me
3-Cl
5-Me
5-Et
5-Ph
5-OMe
5-F
546
3030
488
<10
265
1020
394
<10
167
13
79
530
13
190
174
614
<10
460
1.6 × 104
3.7 × 104
116
6360
4580
<10
104
1.3 × 104
8380
87
1340
1790
1390
93
1200
110
1290
407
274
1.0 × 104
1.2 × 104
1.2 × 104
845
9k
9l
1.2 × 104
1490
34
9m
9n
9o
9p
9r
9u
9y
9ii
9jj
9ll
5-Cl
5-Br
95.9
<10
600
669
<10
268
58
450
<10
1.2 × 104
166
5-CF3
6-Me
6-Cl
7-Me
8-Me
8-Cl
1260
3040
1.1 × 104
480
1040
624
1180
220
165
480
32
594
1070
320
13
216
<10
5,8-diMe
172
a
b
GI50, concentration of drug (nM) resulting in inhibition of cell growth to 50% of controls. Mid: the average GI50 value for the drug
over the whole cell line panel. c Lowest dose tested.
with IC50 values in the J LC line shows a good correlation
(eq 5), indicating that the latter is a useful model for
broadly ranking the cytotoxicity of the compounds (in
this and other calculations, values of <10 nM in Table
2 were taken as 10 nM).
Con clu sion s
The parent bis(DACA) analogues 9, where the two
acridine-4-carboxamide chromophores are linked by a
(CH2)3N(Me)(CH2)3 chain, are significantly more cyto-
toxic than the corresponding monomeric analogues. This
phenomenon has been demonstrated previously with
other neutral DNA-binding chromophores such as the
naphthalimides (e.g., 3)14-17 and the imidazoacridinones
(e.g., 6).18,19
log(GI50)mid ) 0.98((0.10) log(IC50)J LC + 0.35((0.22)
(5)
n ) 19, r ) 0.92, F ) 89
The MCF7 and NCI/ADR lines were selected to
measure the degree to which the compounds are affected
by P-glycoprotein-mediated multidrug resistance (the
NCI/ADR line overexpresses P-glycoprotein). The degree
of resistance shown by the P-glycoprotein overproducing
line [measured as GI50(NCI-ADR)/GI50(MCF7)] varied
from 0.75 (for 9r ) to 75 (for 9g), with an average value
over all the compounds of 10-fold. This suggests a
moderate but significant degree of resistance for the
class, but no SARs were obvious.
The CAK-1 renal tumor line and the SKOV3 ovarian
carcinoma were selected as representative refractory
solid tumor lines. Overall, the compounds displayed
some selectivity toward colon cell lines, and HT29 and
HCT-116 were selected as representative of the colon
line subpanel. Selectivity for HT-116 [measured as GI50-
(mid)/GI50(HCT-116)] varied from 0.8 (for 9k ) to 47 (for
9d ), with an average of 11-fold, again with no obvious
SARs. Results for HT29 were broadly similar.
The 5-Me, 5-Br, and 6-Cl derivatives 9h , 9o, and 9u
were evaluated in vivo against subcutaneous colon 38
tumors. The unsubstituted bis(DACA) 9a provides a 5.5-
day growth delay in this assay when given on a 4d×3
schedule at its MTD of 65 mg/kg/day but only a 2-day
growth delay using a single-dose protocol (MTD of 90
mg/kg).26 The analogues were therefore evaluated using
the more stringent single-dose protocol (administered
in two halves 1 h apart, commencing when the tumors
were ca. 4 mm in diameter). The 6-Cl derivative 9u
showed modest growth delay (≈2 days), while the
5-bromo and 5-methyl compounds 9o and 9h were more
effective, with growth delays of 5 and 6 days, respec-
tively (Figure 1).
SARs for ring-substituted bis(DACA)s were broadly
similar to those of the monomeric analogues,28 with
small substituents (e.g., Me, Cl) at the 5-position
providing compounds of highest potency (IC50’s as low
as 2 nM against the Lewis lung carcinoma and 11 nM
against the wild-type human J urkat leukemia). Large
substituents at any position caused a decrease in
potency, likely due to lowering of DNA binding affinity.
An important difference between the substituted mono-
(DACA) and bis(DACA) series is that the J LA and J LD
lines, which express low amounts of topo II as the cause
of resistance to doxorubicin and amsacrine, are cross-
resistant to some DACA derivatives but to none of the
bis(DACA) derivatives. In the latter series, some mem-
bers are up to 4-fold cytotoxic toward the J LA and J LD
lines as compared to the wild-type J LC (IC50 ratios e 1,
Table 1). The bis(5-methylDACA) compound 9h was
found to inhibit the action of purified topo I in a cell-
free assay system (D. J . A. Bridewell, personal com-
munication) in a manner similar to that shown by
aclarubicin,35 consistent with the hypothesis that topo
I is involved in its cytotoxicity. The compounds were on
average about 10-fold less potent toward a cell line that
overexpresses P-glycoprotein and had some selectivity
toward colon lines in the NCI human tumor panel. Of
the four compounds evaluated in vivo, the two 5-sub-
stituted analogues 9o and 9h were the most effective,
giving growth delays in the subcutaneous colon 38
tumor model of 5-6 days, the latter at 30 mg/kg. These
results show that substituted bis(DACA)s are an inter-
esting new class of topoisomerase inhibitors, worthy of
further development.

2388 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Gamage et al.
Exp er im en ta l Section
Ch em istr y. Analyses were carried out in the Microchemical
Laboratory, University of Otago, Dunedin, New Zealand.
Melting points were determined on an Electrothermal 2300
melting point apparatus. NMR spectra were obtained on a
Bruker DRX-400 spectrometer and are referenced to Me4Si for
organic solutions and 3-(trimethylsilyl)propanesulfonic acid,
sodium salt for D2O solutions. Thin-layer chromatography was
carried out on aluminum-backed silica gel (Merck 60 F254) or
alumina plates. Flash column chromatography was carried out
on Merck silica gel (230-400 mesh) or alumina. Petroleum
ether refers to the fraction boiling at 40-60 °C. Satisfactory
high-resolution mass spectral data were obtained for these
compounds, using a VG 7070 spectrometer at nominal 5000
resolution. All of the bis(acridinecarboxamides) 9 were judged
to be >98% pure by reverse-phase HPLC analysis with diode
array detection. While the free bases of these compounds were
stable, the hydrochloride salts were difficult to obtain free of
water, and these hygroscopic forms decomposed slowly to give
a mixture of compounds, primarily acridones.
N,N-Bis[3-(5-m eth yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9h ) by th e Meth od of Sch em e 3: Gen er a l
Exa m p le. A suspension of 5-methylacridine-4-carboxylic acid23
(11h ) (5.30 g, 22.4 mmol) in DMF (60 mL) was treated with
CDI (7.25 g, 44.7 mmol) and stirred at 40 °C until a clear
solution was obtained. After cooling, the mixture was diluted
with CH2Cl2 (50 mL) followed by petroleum ether (200 mL) to
complete precipitation of product, which was collected, washed
with petroleum ether/CH2Cl2 (4:1), and dried to give the
moisture-sensitive imidazolide 12h . This was dissolved in dry
THF (100 mL), and the solution was cooled to 0 °C and treated
with N,N-bis(3-aminopropyl)methylamine (1. 80 mL, 0.5 equiv).
The mixture was stirred at 20 °C for 8 h, the THF was removed
under reduced pressure, and the residue was dissolved in CH2-
Cl2 (250 mL). The organic layer was washed with 1 M Na2-
CO3 (250 mL) and dried over Na2SO4, and the solvent was
removed under reduced pressure. The product was purified
by chromatography on alumina-90, eluting with CH2Cl2/MeOH
(200:1) to give 9h (4.64 g, 66%): mp (CH2Cl2/hexane) 118-
120 °C; 1H NMR (CDCl3) δ 1.97-2.00 (m, 4 H, 2×CH2CH2-
CH2), 2.30 (s, 3 H, NCH3), 2.58 (t, J ) 7.5 Hz, 4 H,
CH2N(CH3)CH2), 2.79 (s, 6 H, 2×CH3), 3.70 (q, J ) 6.7 Hz, 4
H, 2×CH2NH), 7.37 (dd, J ) 8.5, 6.8 Hz, 2 H, H-7), 7.57 (br d,
J ) 6.7 Hz, 2 H, H-8), 7.61 (dd, J ) 8.3, 7.2 Hz, 2 H, H-2),
7.74 (br d, J ) 8.6 Hz, 2 H, H-6), 8.03 (dd, J ) 8.4, 1.5 Hz, 2
H, H-1), 8.69 (s, 2 H, H-9), 8.94 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3),
11.79 (br t, J ) 5.1 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z
calcd for C37H38N5O2 584.3026 (MH+), found 584.3044. Anal.
(C37H37N5O2‚1.5H2O) C, H, N.
N,N-Bis[3-(1-m eth yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9b). From similar reaction of 1-methylacri-
dine-4-carboxylic acid23 (11b) (91% yield): oil; 1H NMR (CDCl3)
δ 2.02-2.09 (m, 4 H, 2×CH2CH2CH2), 2.38 (s, 3 H, NCH3),
2.75 (t, J ) 7.5 Hz, 4 H, CH2N(CH3)CH2), 2.80 (d, J ) 0.7 Hz,
6 H, 2×CH3), 3.73 (q, J ) 6.3 Hz, 4 H, 2×CH2NH), 7.36 (ddd,
J ) 8.2, 6.7, 0.9 Hz, 2 H, H-6 or H-7), 7.43 (dd, J ) 7.6, 0.8
Hz, 2 H, H-2), 7.66 (ddd, J ) 8.7, 6.7, 1.4 Hz, 2 H, H-7 or H-6),
7.80 (d, J ) 8.0 Hz, 2 H, H-5 or H-8), 7.99 (dd, J ) 8.7, 0.8 Hz,
2 H, H-8 or H-5), 8.78 (s, 2 H, H-9), 8.80 (d, J ) 7.3 Hz, 2 H,
H-3), 11.77 (br t, J ) 5.1 Hz, 2 H, 2×CONH); HRMS (FAB+)
m/z calcd for C37H38N5O2 584.3026 (MH+), found 584.3041.
Anal. (C37H37N5O2) C, H, N.
N ,N -Bis[(1-ch lor oa cr id in e -4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9c). From similar reaction of 1-chloroacridine-
4-carboxylic acid23 (11c) (83% yield): mp (CH2Cl2/n-hexane)
94-96 °C; 1H NMR (CDCl3) δ 2.02-2.09 (m, 4 H, 2×CH2CH2-
CH2), 2.39 (s, 3 H, NCH3), 2.79 (t, J ) 7.4 Hz, 4 H, CH2N-
(CH3)CH2), 3.72 (q, J ) 6.2 Hz, 4 H, 2×CH2NH), 7.31 (ddd,
J ) 8.2, 6.7, 0.8 Hz, 2 H, H-6 or H-7), 7.63 (ddd, J ) 8.7, 6.7,
1.3 Hz, 2 H, H-7 or H-6), 7.67 (d, J ) 7.9 Hz, 2 H, H-2), 7.74
(br d, J ) 8.0 Hz, 2 H, H-5 or H-8), 7.91 (br d, J ) 8.7 Hz, 2
H, H-8 or H-5), 8.75 (d, J ) 8.0 Hz, 2 H, H-3), 8.98 (s, 2 H,
F igu r e 1. Averaged growth delay data for control (b) and
treatment groups of five mice bearing advanced subcutaneous
colon 38 tumors (see text), using a single drug dose (given in
halves, 1 h apart): A, 9u at 60 (4) and 90 (O) mg/kg; B, 9o at
40 (9) and 60 (3) mg/kg; C, 9h at 20 (9) and 30 (2) mg/kg.
Higher doses than those indicated were toxic.
H-9), 11.45 (br t, J ) 4.8 Hz, 2 H, 2×CONH). Anal. (C35H31
-
Cl2N5O2‚0.5H2O) C, N; H: calcd, 5.8; found, 5.1.

SAR for Bis(acridine-4-carboxamides)
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2389
N,N-Bis[3-(2-m eth yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9d ). From similar reaction of 2-methylacri-
dine-4-carboxylic acid23 (11d ) (90% yield): foam; 1H NMR
(CDCl3) δ 2.01-2.08 (m, 4 H, 2×CH2CH2CH2), 2.38 (s, 3 H,
NCH3), 2.60 (s, 6 H, 2×CH3), 2.73 (t, J ) 7.4 Hz, 4 H, CH2N-
(CH3)CH2), 3.74 (q, J ) 6.3 Hz, 4 H, 2×CH2NH), 7.38 (ddd, J
) 8.6, 6.7, 0.9 Hz, 2 H, H-6 or H-7) 7.64 (ddd, J ) 8.7, 6.7, 1.4
Hz, 2 H, H-7 or H-6), 7.76 (br s, 2 H, H-1), 7.79 (d, J ) 8.8 Hz,
2H, H-5 or H-8), 8.00 (dd, J ) 8.7, 0.7 Hz, 2 H, H-8 or H-5),
8.55 (s, 2 H, H-9), 8.76 (d, J ) 2.1 Hz, 2 H, H-3), 11.79 (br t,
J ) 5.0 Hz, 2 H, 2×CONH). Anal. (C37H37N5O2) C, H, N.
Hz, 2×CONH); HRMS (FAB+) m/z calcd for C39H42N5O2
612.3339 (MH+), found 612.3343. Anal. (C39H41N5O2‚H2O) C,
H, N.
N,N-Bis[3-(5-isopr opylacr idin e-4-car boxam ido)pr opyl]-
m eth yla m in e (9j). From similar reaction of 5-isopropylacri-
dine-4-carboxylic acid28 (11j) (70% yield): oil; 1H NMR (CDCl3)
δ 1.47 (d, J ) 7.0 Hz, 12 H, 4CH3), 1.96-2.03 (m, 4 H,
2×CH2CH2CH2), 2.32 (s, 3 H, NCH3), 2.59 (t, J ) 7.4 Hz, 4 H,
CH2N(CH3)CH2), 3.70 (q, J ) 6.8 Hz, 4 H, 2×CH2NH), 4.15-
4.18 (m, 2 H, 2×CH), 7.53 (dd, J ) 8.4, 6.9 Hz, 2 H, H-7), 7.63
(dd, J ) 8.3, 7.2 Hz, 2 H, H-2), 7.67 (br d, J ) 6.6 Hz, 2 H,
H-6), 7.83 (dd, J ) 8.4, 1.1 Hz, 2 H, H-8), 8.07 (dd, J ) 8.3, 1.5
Hz, 2 H, H-1), 8.80 (s, 2 H, H-9), 8.95 (dd, J ) 7.1, 1.6 Hz, 2
H, H-3), 11.80 (br t, J ) 5.6 Hz, 2×CONH); HRMS (FAB+)
m/z calcd for C41H46N5O2 640.3652 (MH+), found 640.3655.
N,N-Bis[3-(5-p h en yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9k ). From similar reaction of 5-phenylacridine-
4-carboxylic acid (11k )23 (64% yield): mp (CH2Cl2/hexane)
162-163 °C; 1H NMR (CDCl3) δ 1.24-1.26 (m, 4 H, 2×CH2CH2-
CH2), 2.04 (s, 3 H, NCH3), 2.06-2.10 (br t, J ) 7.7 Hz, 4 H,
CH2N(CH3)CH2), 3.13 (q, J ) 6.9 Hz, 4 H, 2×CH2NH), 7.43-
7.45 (m, 2 H, H-4’), 7.49-7.53 (m, 4 H, H-3′,5′), 7.59-7.67 (m,
8 H, H-2,2′,6′,7), 7.75 (dd, J ) 6.7, 1.4 Hz, 2 H, H-6), 7.99 (dd,
J ) 8.5, 1.3 Hz, 2 H, H-8), 8.09 (dd, J ) 8.4, 1.5 Hz, 2 H, H-1),
8.88 (s, 2 H, H-9), 8.94 (dd, J ) 7.2, 1.5 Hz, 2 H, H-3), 11.06
(br t, J ) 6.0 Hz, 2×CONH); HRMS (FAB+) m/z calcd for
C47H42N5O2 708.3339 (MH+), found 708.3345. Anal. (C47H41N5O2‚
0.5H2O) C, H, N.
N,N-Bis[3-(5-m eth oxya cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9l). From similar reaction of 5-methoxyacri-
dine-4-carboxylic acid23 (11l) (71% yield): oil; 1H NMR (CDCl3)
δ 1.99-2.06 (m, 4 H, 2×CH2CH2CH2), 2.38 (s, 3 H, NCH3),
2.72 (t, J ) 7.6 Hz, 4 H, CH2N(CH3)CH2), 3.65 (q, J ) 6.4 Hz,
4 H, 2×CH2NH), 3.87 (s, 6 H, 2×OCH3), 6.67 (dd, J ) 6.5, 2.0
Hz, 2 H, H-6), 7.10-7.16 (m, 4 H, H-7,8), 7.54 (dd, J ) 8.2,
7.2 Hz, 2 H, H-2), 7.86 (dd, J ) 8.4, 1.3 Hz, 2 H, H-1), 8.36 (s,
2 H, H-9), 8.82 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 12.04 (br t, J )
4.6 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z calcd for C37H38N5O4
616.2924 (MH+), found 616.2943.
N ,N -Bis[(2-ch lor oa cr id in e -4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9e). From similar reaction of 2-chloroacridine-
4-carboxylic acid23 (11e) (54% yield): mp (CH2Cl2/hexane)
175.5-176.5 °C; 1H NMR (CDCl3) δ 2.00-2.07 (m, 4 H,
2×CH2CH2CH2), 2.38 (s, 3 H, NCH3), 2.75 (t, J ) 7.4 Hz, 4 H,
CH2N(CH3)CH2), 3.71 (q, J ) 6.3 Hz, 4 H, 2×CH2NH), 7.42
(ddd, J ) 8.3, 6.6, 0.9 Hz, 2 H, H-6 or H-7), 7.68 (ddd, J ) 8.7,
6.6, 1.3 Hz, 2 H, H-7 or H-6), 7.74 (br d, J ) 7.9 Hz, 2 H, H-5
or H-8), 7.93-7.96 (m, 4 H, H-1 and H-8 or H-5), 8.49 (s, 2 H,
H-9), 8.74 (d, J ) 2.5 Hz, 2 H, H-3), 11.52 (br t, J ) 5.0 Hz,
2×CONH); HRMS (FAB+) m/z calcd for C35H3235Cl2N5O2
624.1933 (MH+), found 624.1900. Anal. (C35H21Cl2N5O2) C, H,
N.
N,N-Bis[3-(3-m eth yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9f). From similar reaction of 3-methylacridine-
4-carboxylic acid23 (11f), followed by purification using se-
quential chromatography on alumina followed by silica gel
(15% yield): gum; 1H NMR (CDCl3) δ 1.78-1.84 (m, 4 H,
2×CH2CH2CH2), 2.18 (s, 3 H, NCH3), 2.48 (s, 6 H, 2×CH3),
2.67 (t, J ) 6.5 Hz, 4 H, CH2N(CH3)CH2), 3.56 (q, J ) 6.1 Hz,
4 H, 2×CH2NH), 7.19 (d, J ) 8.6 Hz, 2 H, H-1 or H-2), 7.33
(ddd, J ) 8.4, 6.6, 1.0 Hz, 2 H, H-6 or H-7), 7.39 (br t, J ) 5.3
Hz, 2 H, 2×CONH), 7.58 (ddd, J ) 8.8, 6.6, 1.4 Hz, 2 H, H-7
or H-6), 7.66 (d, J ) 8.7 Hz, H-2 or H-1), 7.70 (br d, J ) 7.9
Hz, 2 H, H-5 or H-8), 7.94 (d, J ) 8.6 Hz, 2 H, H-8 or H-5),
8.37 (s, 2 H, H-9); HRMS (FAB+) m/z calcd for C37H38N5O2
584.3026, found 584.3016.
N,N-Bis[3-(3-ch lor oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9g). A suspension of 3-chloroacridine-4-car-
boxylic acid23 (11g) (540 mg, 2.10 mmol) in SOCl2 (30 mL) was
heated under reflux for 15 min, and excess reagent was then
evaporated under reduced pressure. The residue was azeo-
troped with dry benzene (30 mL) to give crude 3-chloroacridine-
4-carbonyl chloride. This was cooled, dissolved in THF (50 mL)
containing triethylamine (5% v/v), and then treated with bis-
(3-aminopropyl)methylamine (150 mg, 1.05 mmol). The mix-
ture was stirred at room temperature overnight, the THF was
removed under reduced pressure, and the residue was parti-
tioned between aqueous Na2CO3/CH2Cl2. Evaporation of the
organic layer and chromatography of the residue on alumina,
eluting with 0.5% MeOH/CH2Cl2, gave 9g (73%): mp (CH2-
N,N-Bis[3-(5-flu or oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9m ). From similar reaction of 5-fluoroacridine-
4-carboxylic acid28 (11m ) (96% yield): mp (CH2Cl2/hexane)
1
134-136 °C; H NMR (free base in CDCl3) δ 2.06 (quin, J )
7.2 Hz, 4 H, 2×CH2CH2CH2), 2.38 (s, 3 H, NCH3), 2.73 (t, J )
7.6 Hz, 4 H, CH2N(CH3)CH2), 3.72 (q, J ) 6.3 Hz, 4 H, 2×CH2-
NH), 7.26 (m, 4 H, ArH), 7.56 (m, 2 H, ArH), 7.59 (dd, J ) 8.4,
7.2 Hz, 2 H, H-2), 7.99 (dd, J ) 8.5, 1.4 Hz, 2 H, ArH), 8.64 (d,
J ) 0.6 Hz, 2 H, H-9), 8.93 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3),
11.61 (t, J ) 4.6 Hz, 2 H, CONH). Anal. (C35H31F2N5O2‚H2O)
C, H, N, F. Trihydrochloride salt: mp (MeOH/EtOAc) 188 °C
dec. Anal. (C35H31F2N5O2‚3HCl) C, H, N.
N,N-Bis[3-(5-ch lor oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9n ). From similar reaction of 5-chloroacridine-
4-carboxylic acid23 (11n ) (62% yield): mp (CH2Cl2/hexane) 89-
93 °C; 1H NMR (CDCl3) δ 2.01-2.05 (m, 4 H, 2×CH2CH2CH2),
2.33 (s, 3 H, NCH3), 2.64 (t, J ) 7.5 Hz, 4 H, CH2N(CH3)CH2),
3.72 (q, J ) 6.6 Hz, 4 H, 2×CH2NH), 7.33 (dd, J ) 8.4, 7.3 Hz,
2 H, H-7), 7.58 (dd, J ) 8.2, 7.2 Hz, 2 H, H-2), 7.74-7.77 (m,
4 H, H-6 and H-8), 7.96 (dd, J ) 8.4, 1.5 Hz, 2 H, H-1), 8.64 (s,
2 H, H-9), 8.91 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 11.74 (br t, J )
1
Cl2/hexane) 117 °C dec; H NMR (400 MHz, CDCl3) δ 1.74-
1.83 (m, 4 H, 2CH2CH2CH2), 2.16 (s, 3 H, NCH3), 2.65 (t, J )
6.4 Hz, 4 H, CH2N(CH3)CH2), 3.57 (q, J ) 6.1 Hz, 4 H, 2CH2-
NH), 6.90 (br t, J ) 5.4 Hz, 2 H, 2xCONH), 7.32 (d, J ) 8.9
Hz, 2 H, ArH), 7.40 (ddd, J ) 8.3, 6.6, 0.9 Hz, 2 H, ArH), 7.63
(ddd, J ) 8.9, 6.6, 1.3 Hz, 2 H, ArH), 7.71 (d, J ) 9.0 Hz, 2 H,
ArH), 7.75 (d, J ) 8.9 Hz, 2 H, ArH), 8.00 (d, J ) 9.0 Hz, 2H,
ArH), 8.44 (s, 2H, H-9); HRMS (FAB+) m/z calcd for C35H32
35Cl2N5O2 624.1933 (MH+), found 624.1945. Anal. (C35H31
Cl2N5O2‚3H2O) C, N; H: found, 4.7; calcd 5.5.
-
-
5.3 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z calcd for C35H32
35Cl2N5O2 624.1933 (MH+), found 624.1940. Anal. (C35H31
Cl2N5O2‚1.5H2O) C, H, N.
-
-
N ,N -Bis[3-(5-e t h yla cr id in e -4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9i). From similar reaction of 5-ethylacridine-
4-carboxylic acid28 (11i) (57% yield): mp (CH2Cl2/hexane) 70-
N,N-Bis[3-(5-b r om oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9o). From similar reaction of 5-bromoacridine-
4-carboxylic acid28 (11o) (80% yield): mp (CH2Cl2/hexane)
172-174.5 °C; 1H NMR (CDCl3) δ 2.05 (quin, J ) 7.3 Hz, 4 H,
2×CH2CH2CH2), 2.33 (s, 3 H, NCH3), 2.63 (t, J ) 7.6 Hz, 4 H,
CH2N(CH3)CH2), 3.73 (q, J ) 6.7 Hz, 4 H, 2×CH2NH), 7.28
(dd, J ) 8.2, 7.2 Hz, 2 H, H-2), 7.57 (dd, J ) 8.4, 7.2 Hz, 2 H,
H-7), 7.81 (dd, J ) 8.5, 0.9 Hz, 2 H, H-1), 7.91 (m, 4 H, ArH),
8.64 (s, 2 H, H-9), 8.90 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 11.72
(t, J ) 5.6 Hz, 2 H, CONH). Anal. (C35H31Br2N5O2‚H2O) C, H,
N, Br.
1
73 °C; H NMR (CDCl3) δ 1.42 (t, J ) 7.5 Hz, 6 H, 2×CH3),
1.97-2.04 (m, 4 H, 2×CH2CH2CH2), 2.32 (s, 3 H, NCH3), 2.61
(t, J ) 7.4 Hz, 4 H, CH2N(CH3)CH2), 3.24 (q, J ) 7.5 Hz, 4 H,
2×CH2CH3), 3.69 (q, J ) 6.2 Hz, 4 H, 2×CH2NH), 7.40 (dd, J
) 8.4, 6.8 Hz, 2 H, H-7), 7.53 (dd, J ) 6.7 Hz, 1.0, 2 H, H-6),
7.60 (dd, J ) 8.3, 7.1 Hz, 2 H, H-2), 7.74 (dd, J ) 8.2, 1.0 Hz,
2 H, H-8), 8.02 (dd, J ) 8.4, 1.5 Hz, 2 H, H-1), 8.69 (s, 2 H,
H-9), 8.93 (dd, J ) 7.1, 1.6 Hz, 2 H, H-3), 11.77 (br t, J ) 5.5

2390 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Gamage et al.
N,N-Bis[3-(5-(tr iflu or om eth yl)acr idin e-4-car boxam ido)-
p r op yl]m eth yla m in e (9p ). From similar reaction of 5-(trif-
luoromethyl)acridine-4-carboxylic acid28 (11p ) (52% yield): oil;
1H NMR [free base in (CD3)2SO] δ 1.81 (quin, J ) 7.1 Hz, 4 H,
2×CH2CH2CH2), 2.42 (s, 3 H, NCH3), 2.44 (t, J ) 7.1 Hz, 4 H,
CH2N(CH3)CH2), 3.51 (q, J ) 6.8 Hz, 4 H, 2×CH2NH), 7.73
(q, J ) 7.4 Hz, 4 H, ArH), 8.24-8.29 (m, 4 H, ArH), 8.42 (d, J
) 8.1 Hz, 2 H, ArH), 8.78 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 9.30
(s, 2 H, 2×H-9), 10.92 (t, J ) 5.8 Hz, 2 H, 2×CONH). Anal.
(C37H31F6N5O2‚3HCl‚2H2O) C, H, N.
(dd, J ) 7.2, 1.5 Hz, 2 H, H-3), 9.13 (s, 2 H, H-9), 10.78 (t, J
) 5.5 Hz, 2 H, CONH). Anal. (C37H31F6N5O2‚0.5H2O) C, H, N.
N,N-Bis[3-(7-m eth yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9y). From similar reaction of 7-methylacri-
dine-4-carboxylic acid23 (11y) (73% yield): oil; 1H NMR (CDCl3)
δ 2.03-2.10 (m, 4 H, 2×CH2CH2CH2), 2.34 (s, 6 H, 2×CH3),
2.39 (s, 3 H, NCH3), 2.80 (t, J ) 7.6 Hz, 4 H, CH2N(CH3)CH2),
3.73 (q, J ) 6.2 Hz, 4 H, 2×CH2NH), 7.30 (br s, 2 H, H-8),
7.35 (dd, J ) 8.8, 1.9 Hz, 2 H, H-6), 7.55 (dd, J ) 8.4, 7.1 Hz,
2 H, H-2), 7.77 (d, J ) 8.9 Hz, 2 H, H-5), 7.92 (dd, J ) 8.4,
1.5 Hz, 2 H, H-1), 8.36 (s, 2 H, H-9), 8.84 (dd, J ) 7.1, 1.5 Hz,
2 H, H-3), 11.74 (br t, J ) 5.0 Hz, 2 H, 2×CONH); HRMS
(FAB+) m/z calcd for C37H38N5O2 584.3026 (MH+), found
584.3043. Anal. (C37H37N5O2‚0.5H2O) C, H, N.
N,N-Bis[3-(6-m eth yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9r ). From similar reaction of 6-methylacridine-
1
4-carboxylic acid23 (11r ) (89% yield): foam; H NMR (CDCl3)
δ 2.08 (quin, J ) 7.0 Hz, 4 H, 2×CH2CH2CH2), 2.42 (s, 3 H,
NCH3), 2.44 (d, J ) 0.7 Hz, 6 H, 2×CH3), 2.82 (t, J ) 7.5 Hz,
4 H, CH2N(CH3)CH2), 3.75 (q, J ) 6.2 Hz, 4 H, 2×CH2NH),
7.07 (dd, J ) 8.6, 1.5 Hz, 2 H, H-7), 7.54-7.59 (m, 4 H, H-2,8),
7.70 (br s, 2 H, H-5), 7.99 (dd, J ) 8.4, 1.5 Hz, 2 H, H-1), 8.52
(s, 2 H, H-9), 8.89 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 11.83 (t, J
) 5.0 Hz, 2 H, 2×CONH). Anal. (C37H37N5O2) C, H, N.
N ,N -Bis[3-(7-e t h yla cr id in e -4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9z). From similar reaction of 7-ethylacridine-
1
4-carboxylic acid28 (11z) (47% yield): oil; H NMR (CDCl3) δ
1.28 (t, J ) 7.5 Hz, 6 H, 2×CH3), 2.03-2.11 (m, 4 H,
2×CH2CH2CH2), 2.40 (s, 3 H, NCH3), 2.70 (q, J ) 7.6 Hz, 4 H,
2×CH2CH3), 2.79 (t, J ) 7.4 Hz, 4 H, CH2N(CH3)CH2), 3.74
(q, J ) 6.3 Hz, 4 H, 2×CH2NH), 7.46 (br s, 2 H, H-8), 7.48 (dd,
J ) 8.9, 1.8 Hz, 2 H, H-6), 7.56 (dd, J ) 8.3, 7.2 Hz, 2 H, H-2),
7.89 (d, J ) 8.8 Hz, 2 H, H-5), 7.98 (dd, J ) 8.3, 1.5 Hz, 2 H,
H-1), 8.51 (s, 2 H, H-9), 8.86 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3),
11.80 (br t, J ) 5.0 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z
calcd for C39H42N5O2 612.3339 (MH+), found 612.3333.
N,N-Bis[3-(6-m eth oxya cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9s). From similar reaction of 6-methoxyacri-
dine-4-carboxylic acid23 (11s) (68% yield): mp (CH2Cl2/hexane)
180-181 °C dec; 1H NMR [free base in (CD3)2SO] δ 2.07 (m, 4
H, 2×CH2CH2CH2), 2.41 (s, 3 H, NCH3), 2.78 (m, 4 H, CH2N-
(CH3)CH2), 3.74 (q, J ) 6.3 Hz, 4 H, 2×CH2NH), 3.89 (s, 6 H,
2×OCH3), 6.98 (d, J ) 9.0 Hz, 2 H, H-7), 7.08 (br s, 2 H, H-5),
7.54 (dd, J ) 8.1, 7.3 Hz, 2 H, H-2), 7.60 (d, J ) 9.1 Hz, 2 H,
H-8), 7.96 (dd, J ) 8.3, 1.3 Hz, 2 H, H-1), 8.50 (s, 2 H, H-9),
8.88 (dd, J ) 7.2, 1.5 Hz, 2 H, H-3), 11.77 (br s, 2 H, 2×CONH).
Anal. (C37H37N5O4) C, H, N. Dihydrochloride salt: mp (MeOH/
EtOAc) mp 204-206 °C.
N,N-Bis[3-(7-isopr opylacr idin e-4-car boxam ido)pr opyl]-
m eth yla m in e (9a a ). From similar reaction of 7-isopropylacri-
dine-4-carboxylic acid28 (11a a ) (73% yield): oil; 1H NMR
(CDCl3) δ 1.33 (d, J ) 6.9 Hz, 12 H, 4CH3), 2.04-2.08 (m, 4
H, 2×CH2CH2CH2), 2.38 (s, 3 H, NCH3), 2.74 (t, J ) 7.4 Hz, 4
H, CH2N(CH3)CH2), 3.03-3.06 (m, 2 H, 2×CH), 3.74 (q, J )
6.4 Hz, 4 H, 2×CH2NH), 7.58 (dd, J ) 8.3, 7.2 Hz, 2 H, H-2),
7.60-7.66 (m, 4 H, H-6 and H-8), 8.01 (d, J ) 9.5 Hz, 2 H,
H-5), 8.03 (dd, J ) 8.3, 1.5 Hz, 2 H, H-1), 8.66 (s, 2 H, H-9),
8.88 (dd, J ) 7.2, 1.5 Hz, 2 H, H-3), 11.85 (br t, J ) 5.1 Hz, 2
H, 2×CONH); HRMS (FAB+) m/z calcd for C41H46N5O2 640.3652
(MH+), found 640.3657.
N,N-Bis[3-(7-ter t-bu tylacr idin e-4-car boxam ido)pr opyl]-
m eth yla m in e (9bb). From similar reaction of 7-tert-buty-
lacridine-4-carboxylic acid28 (11bb) (82% yield): oil; 1H NMR
(CDCl3) δ 1.43 (s, 18 H, 6CH3), 2.04-2.07 (m, 4 H, 2×CH2CH2-
CH2), 2.38 (s, 3 H, NCH3), 2.72 (t, J ) 7.4 Hz, 4 H, CH2N-
(CH3)CH2), 3.74 (q, J ) 6.4 Hz, 4 H, 2×CH2NH), 7.59 (dd, J )
8.3, 7.2 Hz, 2 H, H-2), 7.81 (d, J ) 2.1 Hz, 2 H, H-8), 7.88 (dd,
J ) 9.2, 2.1 Hz, 2 H, H-6), 8.05 (dd, J ) 8.3, 1.4 Hz, 2 H, H-1),
8.07 (d, J ) 9.3 Hz, 2 H, H-5), 8.73 (s, 2 H, H-9), 8.89 (dd, J )
7.2, 1.5 Hz, 2 H, H-3), 11.87 (br t, J ) 5.1 Hz, 2 H, 2×CONH);
HRMS (FAB+) m/z calcd for C43H50N5O2 668.3965 (MH+), found
668.3963.
N,N-Bis[3-(7-p h en yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9cc). From similar reaction of 7-phenylacri-
dine-4-carboxylic acid28 (11cc) (90% yield): mp (CH2Cl2/MeOH)
162-163 °C; 1H NMR (CDCl3) δ 2.07-2.14 (m, 4 H, 2×CH2CH2-
CH2), 2.42 (s, 3 H, NCH3), 2.82 (t, J ) 7.4 Hz, 4 H, CH2N-
(CH3)CH2), 3.77 (q, J ) 6.2 Hz, 4 H, 2×CH2NH), 7.40-7.52
(m, 4 H, ArH), 7.48-7.52 (m, 4 H, ArH), 7.63-7.65 (m, 4 H,
ArH), 7.82-7.84 (m, 4 H, ArH), 7.87 (dd, J ) 8.4, 1.4 Hz, 2 H,
H-1), 7.97 (d, J ) 9.5 Hz, 2 H, H-5), 8.54 (s, 2 H, H-9), 8.80
(dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 11.69 (br t, J ) 5.2 Hz, 2 H,
2×CONH); HRMS (FAB+) m/z calcd for C47H42N5O2 708.3339
(MH+), found 708.3351. Anal. (C47H41N5O2‚0.5H2O) C, H, N.
N,N-Bis[3-(6-flu or oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9t). From similar reaction of 6-fluoroacridine-
1
4-carboxylic acid28 (11t) (57% yield): oil; H NMR (free base
in CDCl3) δ 2.04 (quin, J ) 7.1 Hz, 4 H, 2×CH2CH2CH2), 2.39
(s, 3 H, NCH3) 2.72 (t, J ) 7.4 Hz, 4 H, CH2N(CH3)CH2), 3.45
(q, J ) 6.4 Hz, 4 H, 2×CH2NH), 7.28 (ddd, J ) 9.2, 8.0, 2.4
Hz, 2 H, H-7), 7.62 (dd, J ) 8.4, 7.2 Hz, 2 H, H-2), 7.69 (dd, J
) 7.6, 2.4 Hz, 2 H, H-1), 7.89 (dd, J ) 9.2, 6.1 Hz, 2 H, H-8),
8.05 (dd, J ) 8.3, 1.5 Hz, 2 H, H-5), 8.74 (s, 2 H, H-9), 8.95
(dd, J ) 7.2, 1.5 Hz, 2 H, H-3), 11.57 (t, J ) 4.9 Hz, 2 H,
CONH). Hydrochloride salt: mp (MeOH/EtOAc) 165.5 °C dec;
Anal. (C35H31F2N5O2‚HCl‚4H2O) C, H, N.
N,N-Bis[3-(6-ch lor oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9u ). From similar reaction of 6-chloroacridine-
4-carboxylic acid23 (11u ) (76% yield): mp (MeOH/EtOAc) 149-
150 °C; 1H NMR (CDCl3) δ 2.06 (quin, J ) 7.1 Hz, 4 H,
2×CH2CH2CH2), 2.40 (s, 3 H, NCH3), 2.75 (t, J ) 7.2 Hz, 4 H,
CH2NCH3), 3.74 (q, J ) 6.3 Hz, 4 H, CH2N(CH3)CH2), 7.32
(dd, J ) 8.9, 2.0 Hz, 2 H, H-7), 7.64 (dd, J ) 8.2, 7.2 Hz, 2 H,
H-2), 7.75 (d, J ) 8.9 Hz, 2 H, H-8), 8.03 (dd, J ) 8.4, 1.5 Hz,
2 H, H-1), 8.05 (d, J ) 2.0 Hz, 2 H, H-5), 8.67 (s, 2 H, H-9),
8.95 (dd, J ) 7.1, 1.6 Hz, 2 H, H-3), 11.50 (t, J ) 5.1 Hz, 2 H,
2×CONH). Anal. (C35H31Cl2N5O2) C, H, N, Cl.
N,N-Bis[3-(6-b r om oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9v). From similar reaction of 6-bromoacridine-
4-carboxylic acid28 (11v) (91% yield): mp (CH2Cl2/hexane)
1
171-172 °C; H NMR (CDCl3) δ 2.07 (quin, J ) 7.0 Hz, 4 H,
2×CH2CH2CH2), 2.41 (s, 3 H, CH3), 2.76 (t, J ) 7.4 Hz, 4 H,
CH2N(CH3)CH2), 3.75 (q, J ) 6.4 Hz, 4 H, 2×CH2NH), 7.42
(dd, J ) 9.0, 1.8 Hz, 2 H, H-7), 7.65 (m, 4 H, H-2,8), 8.03 (dd,
J ) 8.4, 1.5 Hz, 2 H, H-1), 8.25 (d, J ) 0.9 Hz, 2 H, H-5), 8.67
(s, 2 H, H-9), 8.95 (dd, J ) 7.2, 1.5 Hz, 2 H, H-3), 11.45 (t, J
) 5.0 Hz, 2 H, CONH). Anal. (C35H31Br2N5O2) C, H, N, Br.
N,N-Bis[3-(7-m eth oxya cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9d d ). From similar reaction of 7-methoxy-
1
acridine-4-carboxylic acid23 (11d d ) (93% yield): oil; H NMR
N,N-Bis[3-(6-(tr iflu or om eth yl)acr idin e-4-car boxam ido)-
p r op yl]m eth yla m in e (9w ). From similar reaction of 6-(tri-
fluoromethyl)acridine-4-carboxylic acid28 (11w ) (60% yield):
(CDCl3) δ 2.02-2.06 (m, 4 H, 2×CH2CH2CH2), 2.37 (s, 3 H,
NCH3), 2.74 (t, J ) 7.4 Hz, 4 H, CH2N(CH3)CH2), 3.72 (q, J )
6.3 Hz, 4 H, 2×CH2NH), 3.88 (s, 6 H, 2×OCH3), 6.89 (d, J )
2.7 Hz, 2 H, H-8), 7.32 (dd, J ) 9.3, 2.7 Hz, 2 H, H-6), 7.54
(dd, J ) 8.2, 7.2 Hz, 2 H, H-2), 7.85 (d, J ) 9.3 Hz, 2 H, H-5),
7.94 (dd, J ) 8.4, 1.5 Hz, 2 H, H-1), 8.44 (s, 2 H, H-9), 8.82
(dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 11.69 (br t, J ) 5.1 Hz,
2×CONH); HRMS (FAB+) m/z calcd for C37H38N5O4 616.2924
(MH+), found 616.2927.
1
mp (CH2Cl2/hexane) 169-171 °C; H NMR [(CD3)2SO] δ 1.89
(quin, J ) 6.6 Hz, 4 H, 2×CH2CH2CH2), 2.28 (s, 3 H, NCH3),
2.66 (t, J ) 6.8 Hz, 4 H, CH2N(CH3)CH2), 3.56 (q, J ) 6.1 Hz,
4 H, 2×CH2NH), 7.60 (dd, J ) 8.8, 1.5 Hz, 2 H, H-7), 7.68 (dd,
J ) 8.3, 7.2 Hz, 2 H, H-2), 8.14 (d, J ) 8.8 Hz, 2 H, H- 8),
8.23 (dd, J ) 8.4, 1.4 Hz, 2 H, H-1), 8.38 (s, 2 H, H-5), 8.55

SAR for Bis(acridine-4-carboxamides)
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2391
N,N-Bis[3-(7-flu or oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9ee). From similar reaction of 7-fluoroacri-
dine-4-carboxylic acid28 (11ee) (57% yield): mp (CH2Cl2/
hexane) 128-133 °C; 1H NMR (CDCl3) δ 2.04 (quin, J ) 7.17
Hz, 4 H, 2×CH2CH2CH2), 2.38 (s, 3 H, NCH3), 2.73 (t, J ) 7.4
Hz, 4 H, CH2N(CH3)CH2), 3.73 (q, J ) 6.3 Hz, 4 H, 2×CH2-
NH), 7.32 (dd, J ) 8.6, 2.7 Hz, 2 H, H-8), 7.42 (ddd, J ) 9.4,
8.1, 2.8 Hz, 2 H, H-6), 7.63 (dd, J ) 7.7, 7.2 Hz, 2 H, H-2),
7.96 (dd, J ) 9.1, 4.9 Hz, 2 H, H-5), 7.99 (dd, J ) 7.7, 1.5 Hz,
2 H, H-1), 8.56 (s, 2 H, H-9), 8.89 (dd, J ) 7.0, 1.5 Hz, 2 H,
H-3), 11.50 (t, J ) 5.0 Hz, 2 H, 2×CONH). Anal. (C35H31F2N5O2)
C, H, N, F.
acid (16). This was cyclized directly with PPA to give 5,8-
dimethylacridone-4-carboxylic acid (10ll) (46% overall): mp
(MeOH/H2O) 343-346 °C; 1H NMR [(CD3)2SO] δ 2.87 (s, 6 H,
2×CH3), 6.98 (d, J ) 7.3 Hz, 1 H, H-6), 7.33 (t, J ) 7.7 Hz, 1
H, H- 2), 7.51 (d, J ) 7.5 Hz, 1 H, H-7), 8.41 (dd, J ) 7.6, 1.6
Hz, 1 H, H-1), 8.46 (dd, J ) 7.9, 1.6 Hz, 1 H, H-3), 12.00 (br s,
1 H, NH), 13.93 (br s, 1 H, COOH). Anal. (C16H13NO3) C, H,
N.
Reduction of 10ll as above gave 5,8-dimethylacridine-4-
carboxylic acid (11ll) (82%): mp (MeOH/H2O) 239-241 °C; 1H
NMR [(CD3)2SO] δ 2.78 (s, 3 H, CH3), 2.83 (s, 3 H, CH3), 7.50
(d, J ) 6.7 Hz, 1 H, H-6), 7.81 (d, J ) 7.0 Hz, 1 H, H-7), 7.88
(dd, J ) 8.3, 7.2 Hz, 1 H, H-2), 8.62 (dd, J ) 8.4, 1.4 Hz, 1 H,
H-1), 8.76 (dd, J ) 7.0, 1.4 Hz, 1 H, H-3), 8.61 (s, 1 H, H-9),
17.48 (s, 1 H, COOH). Anal. (C16H13NO2) C, H, N.
N,N-Bis[3-(7-ch lor oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9ff). From similar reaction of 7-chloroacridine-
4-carboxylic acid23 (11ff) (75% yield): mp (CH2Cl2/hexane)
183-185 °C; 1H NMR (CDCl3) δ 2.03-2.07 (m, 4 H, 2×CH2CH2-
CH2), 2.38 (s, 3 H, NCH3), 2.75 (t, J ) 7.4 Hz, 4 H, CH2N-
(CH3)CH2), 3.73 (q, J ) 6.3 Hz, 4 H, 2×CH2NH), 7.45 (dd, J )
9.2, 2.3 Hz, 2 H, H-6), 7.63-7.67 (m, 4 H, H-2 and H-8), 7.84
(d, J ) 9.2 Hz, 2 H, H-5), 7.99 (dd, J ) 8.4, 1.5 Hz, 2 H, H-1),
8.48 (s, 2 H, H-9), 8.93 (dd, J ) 7.2, 1.5 Hz, 2 H, H-3), 11.42
(br t, J ) 5.0 Hz, 2×CONH); HRMS (FAB+) m/z calcd for
Reaction of 11ll as above gave 9ll (79%): mp (CH2Cl2/
1
hexane) 119-124 °C; H NMR (CDCl3) δ 2.00 (quin, J ) 7.3
Hz, 4 H, 2×CH2CH2CH2), 2.31 (s, 3 H, NCH3), 2.60 (t, J ) 7.4
Hz, 4 H, CH2N(CH3)CH2), 2.70 (s, 6 H, 2×CH3), 2.73 (s, 6 H,
2×CH3), 3.70 (q, J ) 6.7 Hz, 4 H, 2×CH2NH),7.16 (d, J ) 7.1
Hz, 2 H, H-6), 7.40 (d, J ) 6.8 Hz, 2 H, H-7), 7.61 (dd, J ) 8.1,
7.3 Hz, 2 H, H-2), 8.06 (dd, J ) 8.3, 1.4 Hz, 2 H, H-1), 8.81 (s,
2 H, H-9), 8.93 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3), 11.81 (br s, 2 H,
2×CONH). Anal. (C39H41N5O2) C, H, N.
(MH+) C35H3235Cl2N5O2 624.1933, found 624.1923. Anal. (C35H31
Cl2N5O2) C, H, N.
-
N,N-Bis[3-(1,5-dim eth ylacr idin e-4-car boxam ido)pr opyl]-
m eth yla m in e (9m m ). Reaction of 3-methylanthranilic acid
(19) and 2-bromo-3-methylbenzoic acid (18) as reported gave
crude 5,6′-dimethyl-2,2′-iminodibenzoic acid (20), which was
cyclized as above to give 1,5-dimethylacridone-4-carboxylic acid
(10m m ) (49% overall): mp (MeOH) 317-318 °C; 1H NMR
[(CD3)2SO] δ 2.51 (s, 3 H, CH3), 2.91 (s, 3 H, CH3), 8.08 (d, J
) 7.1 Hz, 1 H, H-2), 7.20 (t, J ) 7.0 Hz, 1 H, H-7), 7.51 (d, J
) 7.0 Hz, 1 H, H-6), 8.05 (d, J ) 7.7 Hz, 1 H, H-3), 8.26 (d, J
) 7.8 Hz, 1 H, H-8). Anal. (C16H13NO3) C, H, N.
N,N-Bis[3-(7-b r om oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9gg). From similar reaction of 7-bromoacri-
dine-4-carboxylic acid28 (11gg) (55% yield): mp (CH2Cl2/
1
hexane) 201-202 °C; H NMR (CDCl3) δ 2.04 (quin, J ) 7.0
Hz, 4 H, 2×CH2CH2CH2), 2.38 (s, 3 H, NCH3), 2.75 (t, J ) 7.4
Hz, 4 H, CH2N(CH3)CH2), 3.73 (q, J ) 6.3 Hz, 4 H, 2×CH2-
NH), 7.55 (dd, J ) 9.1, 2.1 Hz, 2 H, H-6), 7.66 (dd, J ) 8.3, 7.2
Hz, 2 H, H-2), 7.76 (d, J ) 9.2 Hz, 2 H, H-5), 7.83 (d, J ) 2.1
Hz, 2 H, H-8), 7.99 (dd, J ) 8.2, 1.4 Hz, 2 H, H-1), 8.46 (s, 2
H, H-9), 8.94 (dd, J ) 7.0, 1.5 Hz, 2 H, H-3), 11.41 (t, J ) 4.9
Hz, 2 H, 2×CONH). Anal. (C35H31Br2N5O2) C, H, N, Br.
Reduction of 10m m as above gave 1,5-dimethylacridine-4-
carboxylic acid (11m m ) (98%): mp (MeOH) 267 °C dec; 1H
NMR [(CD3)2SO] δ 2.83 (s, 3 H, CH3), 2.93 (s, 3 H, CH3), 7.70
(m, 2 H, H-2 and H-7), 7.95 (d, J ) 6.7 Hz, 1 H, H-6), 8.25 (d,
J ) 8.4 Hz, 1 H, H-8), 8.67 (d, J ) 7.3 Hz, 1-H, H-3), 9.63 (s,
1 H, H-9), 17.55 (s, 1 H, CO2H). Anal. (C16H13NO2) C, H, N.
Reaction of 11m m as above gave 9m m (82%): mp (CH2Cl2/
N,N-Bis[3-(8-m eth yla cr id in e-4-ca r boxa m id o)p r op yl]-
m eth yla m in e (9ii). From similar reaction of 8-methylacri-
dine-4-carboxylic acid23 (11ii) (61% yield): oil; 1H NMR (CDCl3)
δ 2.03-2.10 (m, 4 H, 2×CH2CH2CH2), 2.39 (s, 3 H, NCH3),
2.66 (s, 6 H, 2×CH3), 2.79 (t, J ) 7.5 Hz, 4 H, CH2N(CH3)-
CH2), 3.74 (q, J ) 6.2 Hz, 4 H, 2×CH2NH), 7.09 (d, J ) 6.9
Hz, 2 H, H-5 or H-7), 7.49 (dd, J ) 8.8, 6.8 Hz, 2 H, H-6), 7.62
(dd, J ) 8.4, 7.1 Hz, 2H, H-2), 7.83 (d, J ) 8.7 Hz, 2 H, H-7 or
H-5), 8.04 (dd, J ) 8.3, 1.5 Hz, 2 H, H-1), 8.74 (s, 2 H, H-9),
8.91 (dd, J ) 7.1, 1.5 Hz, 2H, H-3), 11.78 (br t, J ) 4.8 Hz, 2
H, 2×CONH). Anal. (C37H37N5O2‚0.5H2O) C, H, N.
1
hexane) 110-116 °C dec; H NMR (CDCl3) δ 2.01 (quin, J )
6.9 Hz, 4 H, 2×CH2CH2CH2), 2.34 (s, 3 H, NCH3), 2.64 (br t,
4 H, 2×CH2NCH3), 2.77 (s, 6 H, 2×CH3), 3.69 (q, J ) 6.7 Hz,
4 H, 2×CH2NH), 7.36 (dd, J ) 8.4, 6.9 Hz, 2 H, H-7), 7.42 (dd,
J ) 7.2, 0.8 Hz, 2 H, H-6), 7.52 (d, J ) 6.8 Hz, 2 H, H-8), 7.75
(d, J ) 8.4 Hz, 2 H, H-2), 8.80 (s, 2 H, H-9), 8.8 (d, J ) 8.6 Hz,
2 H, H-3), 11.80 (br s, 2 H, 2×CONH). Anal. (C39H41N5O2‚
2H2O) C, H, N.
N,N-Bis[3-(8-ch lor oa cr id in e-4-ca r b oxa m id o)p r op yl]-
m eth yla m in e (9jj). From similar reaction of 8-chloroacridine-
1
4-carboxylic acid23 (11jj) (88% yield): oil; H NMR (CDCl3) δ
N,N-Bis[3-(8-ch lor o-5-m eth yla cr id in e-4-ca r boxa m id o)-
p r op yl]m eth yla m in e (9n n ). Reaction of 2-methyl-5-chloroa-
niline (14) and 2-iodo-1,3-dibenzoic acid (15) by the reported
method28 gave crude 2-[(5-chloro-2-methylphenyl)amino]ben-
zene-1,3-dicarboxylic acid (17). This was cyclized directly with
PPA to give 8-chloro-5-methylacridone-4-carboxylic acid (10n n )
2.04-2.10 (m, 4 H, 2×CH2CH2CH2), 2.40 (s, 3 H, NCH3), 2.84
(t, J ) 7.4 Hz, 4 H, CH2N(CH3)CH2), 3.74 (q, J ) 6.1 Hz, 4 H,
2×CH2NH), 7.10 (dd, J ) 7.3, 0.8 Hz, 2 H, H-5 or H-7), 7.33
(dd, J ) 8.8, 7.3 Hz, 2 H, H-2 or H-6), 7.65 (dd, J ) 8.3, 7.2
Hz, 2H, H-6 or H-2), 7.73 (d, J ) 8.7 Hz, 2H, H-7 or H-5), 8.06
(dd, J ) 8.8, 1.5 Hz, 2 H, H-1), 8.86 (s, 2H, H-9), 8.90 (dd, J )
7.2, 1.5 Hz, 2 H, H-3), 11.36 (br t, J ) 5.0 Hz, 2 H, 2×CONH);
HRMS (FAB+) m/z calcd for C35H3235Cl2N5O2 624.1933 (MH+),
found 624.1939. Anal. (C35H31Cl2N5O2) C, H, N.
1
(51% overall): mp (MeOH) 325-330 °C; H NMR [(CD3)2SO]
δ 2.50 (s, 3 H, CH3; overlapped with DMSO peak), 7.81 (d, J
) 7.2 Hz, 1 H, H-6), 7.38 (t, J ) 7.8 Hz, 1 H, H-2), 7.61 (d, J
) 7.7 Hz, 1 H, H-7), 8.43-8.48 (m, 2 H, H-1,3). Anal. (C15H10
ClNO3) C, H, N.
-
N,N-Bis[3-(5,7-dim eth ylacr idin e-4-car boxam ido)pr opyl]-
m eth yla m in e (9k k ). From similar reaction of 5,7-dimethy-
lacridine-4-carboxylic acid32 (11k k ) (56% yield): oil; 1H NMR
(CDCl3) δ 1.94-2.05 (m, 4 H, 2×CH2CH2CH2), 2.31 (s, 3 H,
NCH3), 2.45 (s, 6 H, 2×CH3), 2.58 (t, J ) 7.4 Hz, 4 H, CH2N-
(CH3)CH2), 2.70 (s, 6 H, 2CH3), 3.68 (dd, J ) 7.2, 5.7 Hz, 4 H,
2×CH2NH),7.32 (br s, 2 H, H-6 or H-8) 7.41 (br s, 2 H, H-8 or
H-6), 7.57 (dd, J ) 8.3, 7.2 Hz, 2 H, H-2), 7.96 (dd, J ) 8.4, 1.4
Hz, 2 H, H-1), 8.49 (s, 2 H, H-9), 8.89 (dd, J ) 7.2, 1.5 Hz, 2
H, H-3), 11.75 (br t, J ) 5.3 Hz, 2 H, 2×CONH); HRMS (FAB+)
m/z calcd for C39H42N5O2 612.3339 (MH+), found 612.3330.
Anal. (C39H41N5O2‚0.5H2O) C, H, N.
Reduction of 10n n as above gave 8-chloro-5-methylacridine-
1
4-carboxylic acid (11n n ) (84%): mp (MeOH) 259-260 °C; H
NMR [(CD3)2SO] δ 2.81 (s, 3 H, CH3), 7.86-7.95 (m, 3 H,
H-1,2,3), 8.74 (d, J ) 8.4 Hz, 1 H, H-6), 8.80 (d, J ) 7.0 Hz, 1
H, H-7), 9.70 (s, 1 H, H-9), 16.83 (br s, 1 H, CO2H). Anal.
(C15H10ClNO2) C, H, N.
Reaction of 11n n as above gave 9n n (81%): mp (CH2Cl2/
1
hexane) 212-215 °C; H NMR (CDCl3) δ 1.98 (quin, J ) 7.3
Hz, 4 H, 2×CH2CH2CH2), 2.02 (s, 3 H, NCH3), 2.60 (t, J ) 7.4
Hz, 4 H, CH2N(CH3)CH2), 2.67 (s, 6 H, 2×CH3), 3.70 (q, 4 H,
2×CH2NH),7.28 (dd, J ) 7.7, 0.9 Hz, 2 H, H-7), 7.32 (d, J )
7.4 Hz, 2 H, H-6), 7.65 (dd, J ) 8.3, 7.2 Hz, 2 H, H-2), 8.07
(dd, J ) 8.6, 1.5 Hz, 2 H, H-1), 8.96 (dd, J ) 7.2, 1.5 Hz, 2 H,
H-3), 9.01 (s, 2 H, H-9), 11.41 (t, J ) 5.3 Hz, 2 H, 2×CONH).
Anal. (C37H35Cl2N2O5‚0.5H2O) C, H, N, Cl.
N,N-Bis[3-(5,8-dim eth ylacr idin e-4-car boxam ido)pr opyl]-
m eth yla m in e (9ll). Reaction of 2,5-dimethylaniline (13) and
2-iodobenzene-1,3-dicarboxylic acid (15) as reported28 gave
crude 2-[(2,5-dimethylphenyl)amino]benzene-1,3-dicarboxylic

2392 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Gamage et al.
N,N-Bis[3-(1-ch lor o-5-m eth yla cr id in e-4-ca r boxa m id o)-
p r op yl]m eth yla m in e (9oo). A mixture of 3-methylanthra-
nilic acid (21) (7.6 g, 50 mmol), methyl 4-chloro-2-iodobenzoate
(22) (19.2 g, 65 mmol), Cu, and CuI (catalytic) in 2,3-butanediol
(20 mL) was heated with benzene (30 mL) in an oil bath. After
the benzene had distilled off, N-ethylmorpholine (50 mL) was
added, and the stirred mixture was heated at 110 °C for 18 h,
then diluted with dilute HCl, extracted into EtOAc, and
filtered to remove Cu salts. The organic layer was separated
and extracted into dilute NH4OH, when the ammonium salt
of the product crystallized. This was collected and stirred in
dilute HCl, and the mixture was filtered and washed with
water to give 2-[[5-chloro-2-(methoxycarbonyl)phenyl]amino]-
3-methylbenzoic acid (23) (6.6 g, 41%): mp (MeOH) 187-188.5
°C; 1H NMR [(CD3)2SO] δ 2.10 (s, 3 H, CH3), 3.87 (s, 3 H,
OCH3), 6.12 (d, J ) 2.0 Hz, 1 H, H-6′), 6.79 (dd, J ) 8.6, 2.0
Hz, 1 H, H-4′), 7.29 (t, J ) 7.6 Hz, 1 H, H-5), 7.52 (d, J ) 7.4
Hz, 1 H, H-4), 7.74 (d, J ) 7.4 Hz, 1 H, H-6), 7.89 (d, J ) 8.5
Hz, 1 H, H-3′), 9.9 (br s, 1 H, NH). Anal. (C16H14ClNO4) C, H,
N, Cl.
A solution of 23 (6.0 g, 18.8 mmol) in dry THF (100 mL)
was treated with CDI (6.0 g, 37.6 mmol) at 20 °C for 18 h,
and the solution was then added dropwise to a suspension of
NaBH4 (0.69 g, 5 equiv) in H2O (50 mL). When the reaction
was complete (30 min, as monitored by TLC), the mixture was
quenched with dilute HCl and extracted with CH2Cl2. The CH2-
Cl2 layer was dried (Na2SO4) and evaporated to give a crude
product that was chromatographed on silica gel, eluting with
a gradient of MeOH in CH2Cl2, to give methyl 4-chloro-2-[[2-
(hydroxymethyl)-6-methylphenyl]amino]benzoate (24) (1.0 g,
17%): mp (CH2Cl2/hexane) 114-115 °C; 1H NMR (CDCl3) δ
1.78 (br s, 1 H, OH), 2.18 (s, 3 H, CH3), 3.92 (s, 3 H, CO2CH3),
4.54 (dd, J ) 12.8, 4.3 Hz, 1 H, CHOH), 4.67 (dd, J ) 12.8, 4.3
Hz, 1 H, CHOH), 6.01 (d, J ) 2.0 Hz, 1 H, H-3), 6.63 (dd, J )
8.3, 2.0 Hz, 1 H, H-5), 7.24-7.29 (m, 2 H, 2×ArH), 7.35-7.39
(m, 1 H, ArH), 7.89 (d, J ) 8.6 Hz, 1 H, H-6), 9.22 (s, 1 H,
NH). Anal. (C16H16ClNO3) C, H, N. Unreacted starting material
(2 g) was also recovered.
fluoroacridine) 9t (0.52 g, 0.7 mmol) was heated with 40%
aqueous dimethylamine (10 mL) in MeOH (10 mL) in a
pressure vessel at 100 °C for 1 week. Solvent and excess
reagent were evaporated under reduced pressure, ammonia
was added, and the mixture was extracted with CH2Cl2.
Evaporation and chromatography of the residue on alumina,
eluting with a gradient of MeOH in CH2Cl2, gave 9× (84%
yield). Hydrochloride salt: mp (MeOH/EtOAc) 100 °C; 1H NMR
(free base in CDCl3) δ 2.03 (quin, J ) 7.0 Hz, 4 H, 2×CH2CH2-
CH2), 2.37 (s, 3 H, NCH3), 2.82 (t, J ) 7.6 Hz, 4 H, CH2N-
(CH3)CH2), 2.85 (s, 12 H, 2×N(CH3)2), 3.73 (q, J ) 6.1 Hz, 4
H, 2×CH2NH), 6.54 (d, J ) 2.2 Hz, 2 H, H-5), 6.67 (dd, J )
9.2, 2.4 Hz, 2 H, H-7), 7.31 (d, J ) 9.2 Hz, 2 H, H-8), 7.37 (t,
J ) 7.6 Hz, 2 H, H-2), 7.86 (dd, J ) 8.2, 1.6 Hz, 2 H, H-1),
8.21 (s, 2 H, H-9), 8.81 (dd, J ) 7.2, 1.6 Hz, 2 H, H-3), 12.15
(t, J ) 5.0 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z calcd for
C
39H44N7O2 642.3556 (MH+), found 642.3557.
N,N-Bis[3-(5-(dim eth ylam in o)acr idin e-4-car boxam ido)-
p r op yl]m eth yla m in e (9q). From similar reaction of the bis-
(5-fluoroacridine) analogue 9m in excess 40% aqueous dime-
thylamine/MeOH for 8 weeks in a pressure vessel (60%
1
yield): foam; H NMR (CDCl3) δ 1.97 (quin, J ) 7.3 Hz, 4 H,
2×CH2CH2CH2), 2.30 (s, 3 H, NCH3), 2.59 (t, J ) 7.3 Hz, 4 H,
CH2N(CH3)CH2), 3.01 (s, 12 H, 2×N(CH3)2), 3.68 (q, J ) 6.7
Hz, 4 H, 2×CH2NH), 7.12 (dd, J ) 7.2, 0.9 Hz, 2 H, H-6), 7.39
(dd, J ) 8.4, 7.3 Hz, 2 H, H-7), 7.51 (dd, J ) 8.2, 0.8 Hz, 2 H,
H-8), 7.62 (dd, J ) 8.3, 7.2 Hz, 2 H, H-2), 8.04 (dd, J ) 8.4, 1.4
Hz, 2 H, H-1), 8.70 (s, 2 H, H-9), 8.91 (dd, J ) 7.1, 1.5 Hz, 2
H, H-3), 11.94 (br s, 2 H, 2×CONH). Anal. (C39H43N7O2‚H2O)
C, H.
Bis[3-(7-(d im eth yla m in o)a cr id in e-4-ca r boxa m id o)p r o-
p yl]m eth yla m in e (9h h ). From similar reaction of the bis(7-
fluoroacridine) analogue 9ee in excess 40% aqueous dimeth-
ylamine/MeOH for 6 weeks in a pressure vessel (89% yield):
foam; 1H NMR (CDCl3) δ 2.08 (quin, J ) 7.0 Hz, 4 H,
2×CH2CH2CH2), 2.40 (s, 3 H, NCH3), 2.86 (t, J ) 7.6 Hz, 4 H,
CH2N(CH3)CH2), 2.99 (s, 12 H, 2×N(CH3)2), 3.75 (q, J ) 6.1
Hz, 4 H, 2×CH2NH), 6.30 (d, J ) 2.8 Hz, 2 H, H-8), 7.18 (dd,
J ) 9.5, 2.8 Hz, 2 H, H-6), 7.44 (dd, J ) 8.2, 7.2 Hz, 2 H, H-2),
7.67 (d, J ) 9.5 Hz, 2 H, H-5), 7.82 (dd, J ) 8.5, 1.4 Hz, 2 H,
H-1), 8.13 (s, 2 H, H-9), 8.69 (dd, J ) 7.1, 1.5 Hz, 2 H, H-3),
11.84 (t, J ) 5.0 Hz, 2 H, 2×CONH). Anal. (C39H43N7O2‚H2O)
C, H, N.
In Vitr o Gr ow th Dela y Assa ys. Murine P388 leukemia
cells, Lewis lung carcinoma cells (LLTC), and human J urkat
leukemia cells (J LC), together with their amsacrine- and
doxorubicin-resistant derivatives (J LA and J LD, respectively),
were obtained and cultured as described.21,30 Growth inhibition
assays were performed by culturing cells at 4.5 × 103 (P388),
103 (LLTC), and 3.75 × 103 (J urkat lines) cells/well in microc-
ulture plates (150 mL/well) for 3 (P388) or 4 days in the
presence of drug. Cell growth was determined by [3H]TdR
uptake (P388)36 or the sulforhodamine assay.37 Independent
assays were performed in duplicate, and coefficients of varia-
tion were ca. 25%.
In Vivo Colon 38 Tu m or Assa y. Colon 38 tumors were
grown subcutaneously from 1-mm3 fragments implanted in one
flank of mice (anesthetized with pentobarbitone 90 mg/kg).
When tumors reached a diameter of approximately 4 mm (7-8
days), mice were divided into control and drug treatment
groups (5 mice/group), with similar average tumor volumes
in each group. Drugs were administered as solutions of the
hydrochloride salts in distilled water and were injected in a
volume of 0.01 mL/g of body weight in two equal injections
administered 1 h apart. The mice were monitored closely, and
tumor diameters were measured with callipers three times a
week. Tumor volumes were calculated as 0.52×a2×b, where a
and b are the minor and major tumor axes, and data plotted
on a semilogarithmic plot as mean tumor volumes ((SEM)
versus time after treatment. The growth delay was calculated
as the time taken for tumors to reach a mean volume 4-fold
higher than their pretreatment volume.
A solution of 24 (0.72 g, 2.35 mmol) in EtOAc (100 mL) was
heated under reflux for 7 h with MnO2 (1 g). The mixture was
filtered through Celite to remove Mn residues, and the solvent
was evaporated and the residue filtered through a column of
silica gel in CH2Cl2 to give methyl 4-chloro-2-[(2-formyl-6-
methylphenyl)amino]benzoate (25) (0.7 g, 98%): mp (MeOH/
H2O) 81-82 °C; 1H NMR (CDCl3) δ 2.23 (s, 3 H, CH3), 3.95 (s,
1 H, CO2CH3), 6.27 (d, J ) 2.0 Hz,1 H, H-3), 6.70 (dd, J ) 8.7,
2.0 Hz, 1 H, H-5), 7.37 (t, J ) 7.6 Hz, 1 H, H-4′), 7.58 (d, J )
7.9 Hz, 1 H, H-5′), 7.81(dd, J ) 7.7, 1.3 Hz, 1 H, H-3′), 7.92 (d,
J ) 8.6 Hz, 1 H, H-6), 9.68 (br s, 1 H, NH), 10.15 (s, 1 H, CHO).
Anal. (C16H14ClNO3) C, H, N.
A solution of 25 (0.65 g, 2.1 mmol) in trifluoroacetic acid (8
mL) was stirred at 40 °C for 4 h under nitrogen. Excess reagent
was removed under reduced pressure at 40 °C, and the residue
was suspended in 2 N NaOH (25 mL) and EtOH (18 mL) and
heated for 1 h until a clear solution was obtained. The cooled
reaction mixture was neutralized with AcOH, and the resulting
precipitate was collected, washed with water, and dried to give
1-chloro-5-methylacridine-4-carboxylic acid (11oo) (0.6 g,
1
100%): mp (MeOH/H2O) 260 °C dec; H NMR (CDCl3) δ 2.93
(s, 3 H, CH3), 7.64 (dd, J ) 8.4, 7.9 Hz, 1 H, H-7), 7.83-7.86
(m, 2 H, H-2 & H-6 or H-8), 8.08 (d, J ) 8.6 Hz, 1 H, H-8 or
H-6), 8.84 (d, J ) 7.8 Hz, 1 H, H-3), 9.4 (s, 1 H, H-9), 17.26 (s,
1 H, CO2H). Anal. (C15H10ClNO2) C, H, N.
Reaction of 11oo as above gave 9oo (84%): mp (CH2Cl2/
hexane) 156-158.5 °C; 1H NMR (CDCl3) δ 1.85 (quin, J ) 7.2
Hz, 4 H, 2×CH2CH2CH2), 2.32 (s, 3 H, NCH3), 2.60 (t, 4 H,
2×CH2NCH3), 2.74 (s, 6 H, 2×CH3), 3.68 (q, J ) 6.7 Hz, 4 H,
2×CH2NH), 7.38 (dd, J ) 8.3, 6.8 Hz, 2 H, H-7), 7.52 (d, J )
6.8 Hz, 2 H, H-6), 7.65 (d, J ) 8.0 Hz, 2 H, H-2), 7.76 (d, J )
8.5 Hz, 2 H, H-8), 8.80 (d, J ) 8.0 Hz, 2 H, H-3), 9.04 (s, 2 H,
H-9), 11.50 (br s, 2 H, 2×CONH). Anal. (C37H35Cl2N5O2) C, H,
N, Cl.
Ack n ow led gm en t. This work was supported by
Xenova Ltd. and the Auckland Division of the Cancer
N,N-Bis[3-(6-(dim eth ylam in o)acr idin e-4-car boxam ido)-
p r op yl]m eth yla m in e (9x): Gen er a l Exa m p le. The bis(6-

SAR for Bis(acridine-4-carboxamides)
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