Synthesis and calculated properties of some 1,4-bis(amino)anthracene-9,10- diones

Article abstract of DOI:10.1039/b610625k

The synthesis of a number of 1,4-bis(amino)anthracene-9,10-diones containing chlorine or sulfur which are related to the anti-cancer drugs Ametantrone and Mitoxantrone are reported. 1,4-Dichloro-2,3-dihydro-5,8- dihydroxyanthracene-9,10-dione reacts readi

Full text of DOI:10.1039/b610625k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and calculated properties of some
1,4-bis(amino)anthracene-9,10-diones
John O. Morley* and Patrick J. Furlong
Received 24th July 2006, Accepted 12th September 2006
First published as an Advance Article on the web 2nd October 2006
DOI: 10.1039/b610625k
The synthesis of a number of 1,4-bis(amino)anthracene-9,10-diones containing chlorine or sulfur which
are related to the anti-cancer drugs Ametantrone and Mitoxantrone are reported.
1,4-Dichloro-2,3-dihydro-5,8-dihydroxyanthracene-9,10-dione reacts readily with a series of
alkylamines to yield the corresponding 1,4-bis(alkylamino)-5,8-dichloroanthracene-9,10-dione after
oxidation. The subsequent reaction of the products with ethanethiol or thiophenol gives the
corresponding 1,4-bis(alkylamino)-5,8-bis(sulfanyl)anthracene-9,10-dione in good yield. Theoretical
calculations at the RHF 6-31G** level indicate that the introduction of either chlorine or the
phenylsulfanyl group into the 5- and 8-positions of 1,4-bis(alkylamino)anthracene-9,10-diones results
in a lowering of the LUMO energies suggesting that related functionalised derivatives might have lower
cardiotoxicities than Mitoxantrone.
Introduction
For well over a century substituted anthraquinones or anthracene-
9,10-diones such as those based on 1,4-bis(amino)anthracene-
9,10-dione (1a) and 1,4-bis(amino)-5,8-dihydroxyanthracene-
9,10-dione (1b) (Fig. 1), have been used as dyes or pigments
because of their high chemical, photochemical and thermal
stability.1–5 In the 1970s, however, new applications emerged for
these derivatives and Murdock and Child were the first to show
that the N-alkyl derivatives of (1b) were chemotherapeutically
active as anti-cancer agents.6 Subsequently it was shown that
functionalised N-alkyl derivatives such as Ametantrone (1c)
and Mitoxantrone (1d) were highly effective anti-cancer drugs
with an efficacy and therapeutic index exceeding adriamycin,
methotrexate, or 5-fluorouracil.7–13 However, while the additional
hydroxyl groups present at the 5- and 8-positions of Mitoxantrone
(1d) lead to tenfold increase in its antineoplastic activity over
Ametantrone (1c), this beneficial enhancement is unfortunately
countered by a tenfold increase in its cardiotoxicity.14 As a
consequence, the effectiveness of Mitoxantrone and Ametantrone
is similar at the optimal dose with the most common dose-
limiting factor being myelosuppression though in most cases
it is not severe or life threatening. Mitoxantrone (1c) is now
used for the treatment of adult acute myeloid leukaemia, for
symptomatic hormone-refractory prostate cancer, and multiple
sclerosis (MS).15,16 Mitoxantrone (1d) appears to be effective in
reducing disease progression through a variety of different mech-
anisms of action. For example, it suppresses the proliferation of
T cells, B cells, and macrophages, it impairs antigen presentation,
Fig. 1 Structures of 1,4-bis(alkylamino)anthracene-9,10-diones.
decreases the secretion of proinflammatory cytokines and inhibits
macrophage-mediated myelin degradation.15,16
The initial antineoplastic mode of action of both Ametantrone
(1c) and Mitoxantrone (1d) almost certainly involves their inter-
calation into DNA which is facilitated by their planarity.17–23 This
factor alone however does not explain their high activity as other
planar derivatives, such as 1,4-diaminoanthracene-9,10-dione
(1a), are inactive and removal of the terminal hydroxyl groups on
the side chain of (1d) leads to reduced activity.9 Furthermore, the
distance between the two side chain nitrogen atoms of (1c) and (1d)
is an important factor, with two carbons providing the optimum
value. The insertion of additional ethylamino groups into the side
Chemistry Department, University of Wales Swansea, Singleton Park,
Swansea, UK SA2 8PP
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chains drastically reduces activity, indicating that additional basic
centres and lengthening of the side chain is undesirable. Finally
the nitrogen at the centre of the side chain plays an important role
in activity as no activity is found when it is replaced by a methylene
group or another atom such as sulfur.9,18
The structures of the DNA–anthracenedione intercalation
complexes14 have been explored and established using physical
techniques such as electron microscopy24 and high field NMR
spectroscopy,21,25 and modelled using computer graphics26–28 and
ab initio calculations.29 However, a second mode of action always
follows the initial binding of the drug to specific base pair
sites leading to the death of the cell. Historically, this final
process has been attributed to nucleic acid condensations,22,30 the
formation of free radicals,31–33 a disruption of normal DNA protein
interactions during cell replication particularly an interference
with the normal mode of action of topoisomerase,34–36 and possibly
reaction with glutathione via an enzyme-mediated process.37 The
formation of free radicals in liver microsomes from several
cytotoxic alkylaminoanthracenediones, which have been detected
by ESR, has suggested that the killing mode may involve radical
anion intermediates formed during metabolic activation but other
studies have strongly linked this behaviour to the cardiotoxicity of
the drug.38,39 In general, enzymatic reduction of anthracene-9,10-
diones can either lead to the formation of a semiquinone by a one-
electron reduction process or a hydroquinone by a two-electron
reduction. It is well established that the semiquinone radical is
capable of transferring its electron to molecular oxygen to form
superoxide, a radical anion, which is now widely accepted to be
the cause of the cardiotoxicity of most anthracene-9,10-diones.40,41
In the present studies we have attempted to synthesise a
number of new 1,4-bis(alkylamino)anthracene-9,10-diones related
to Ametantrone (1c) and Mitoxantrone (1d) but containing
either chlorine or sulfur on the ring in an attempt to restrict
the ability of the molecule to form superoxide from its radical
anion and hence reduce the cardiotoxicity of the drug. In this
approach we have explored two potential synthetic routes to both
1,4-bis(alkylamino)-5,8-dichloroanthracene-9,10-diones and 1,4-
bis(alkylamino)-5,8-bis(sulfanyl) anthracene-9,10-diones such as
(1e) and (1f) respectively starting from the readily accessible 1,4-
dihydroxy-5,8-dichloroanthracene-9,10-dione using simple alky-
lamines as reagents and precursors to the more complex side
chain present in both (1c) and (1d) (see later). In tandem we
have theoretically calculated the structures and properties of some
of these new 1,4-bis(alkylamino)-anthracene-9,10-diones to assess
the influence of both chlorine and sulfur on their likely reduction
potentials and binding characteristics.
Fig.
2
Numbering convention adopted for calculations on
1,4-bis(alkylamino)anthracene-9,10-diones.
Results and discussion
The introduction of chlorine or sulfur into the aromatic ring of
anthracene-9,10-diones would be expected to alter their electronic
properties and exert a marked effect on their reduction potentials
and hence their ability to reduce oxygen to superoxide. Superoxide
can act in both an oxidising and reducing reaction by accepting or
donating electrons respectively depending on its environment,44,45
but it can only be formed if the reduction potential of the
anthracene-9,10-dione radical anion is smaller (more negative)
•
than the O2/O2 − couple at −325 mV.45 Mitoxantrone (1d, denoted
AQ) has a reduction potential of −527 mV46 for the couple
AQ/AQ•− and it is therefore able to reduce oxygen to superoxide
[eqn (1)]:
•
AQ•− + O2 = AQ + O2
(1)
−
In contrast, the O-acetylated derivative of Ametantrone (1c)
has a reduction potential of only −348 mV47 and is therefore
a less potent source of superoxide anion. A similar reduction
potential has been reported for the related anthracyclines such as
Adriamycin at −341 mV47 but that for Daunomycin is slightly less
at −305 mV.47 Structural and substituent effects therefore play an
important role, as expected, in the ability of the anthracene-9,10-
diones to facilitate the formation of superoxide, but the effect of
chlorine or sulfur is not known, though both 1,4-bis(alkylamino)-
5,8-dichloroanthracene-9,10-diones and 1,4-bis(alkylamino)-5,8-
bis(sulfanyl)anthracene-9,10-diones such as (1e) and (1f) would
be expected to have different electronic properties to the parent
drug which, could be potentially beneficial in terms of a reduced
ability to form radical anions while still showing good binding
characteristics to DNA.
Synthetic studies
In principle, 1,4-bis(alkylamino)-5,8-bis(sulfanyl)anthracene-
9,10-diones such as (1f) can be synthesised from 1,4-dihydroxy-
5,8-dichloroanthracene-9,10-dione by two routes (Fig. 3):
(1) displacement of both chlorine atoms with thiolate ions
to give 1,4-dihydroxy-5,8-bis(sulfanyl) anthracene-9,10-diones,
followed by subsequent reduction and amination with selected
amines;
(2) reduction and subsequent amination with alkylamines to
give 1,4-bis(alkylamino)-5,8-dichloroanthracene-9,10-diones fol-
lowed by displacement of both chlorine atoms with thiolate ions.
The starting material, 1,4-dihydroxy-5,8-dichloroanthracene-
9,10-dione (2), has been synthesised previously from the conden-
sation reaction of 3,6-dichlorophthalic anhydride with benzene-
1,4-diol in concentrated sulfuric acid with boric acid48 but in
Methods of calculation
Molecular orbital calculations were carried out on empirical
structures for the anthracene-9,10-diones at the ab initio RHF
level using the 6-31G** basis set of the GAMESS program42
(directives: runtype optxyz, scftype direct rhf). The fully optimised
structures and related crystal structures were displayed and
analysed using the SYBYL Molecular Modelling package.43 The
following numbering convention was adopted for each structure
(Fig. 2)
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Fig. 3 Potential synthetic routes to 1,4-bis(alkylamino)-5,8-bis(sulfanyl)anthracene-9,10-diones.
these studies it was prepared by the direct chlorination of 1,4-
dihydroxyanthracene-9,10-dione in 65% oleum using boric acid
and iodine as catalysts.49–52
material and facilitate the nucleophilic displacement reaction, the
hydroxyl groups were methylated with dimethyl sulfate and a base
of potassium carbonate in acetone using a standard procedure54 to
give 1,4-dimethoxy-5,8-dichloroanthracene-9,10-dione. However,
the attempted reaction of this product with thiophenol in either
ethanol, DMF or DMSO was also unsuccessful and only the
starting material was recovered.
1. Direct reaction of 1,4-dihydroxy-5,8-dichloroanthracene-
9,10-dione with thiols. Although 1,4-dichloroanthracene-
9,10-dione reacts with thiophenol to yield 1,4-bis(phenyl-
sulfanyl)anthracene-9,10-dione,53 the attempted displacement
of the chlorine atoms of 1,4-dihydroxy-5,8-dichloroanthracene-
9,10-dione (2) with various thiols was unsuccessful either in
air or under nitrogen. A reaction using sodium hydroxide and
thiophenol in ethanol led only to the formation of diphenyl
disulfide, and it is clear that the presence of the two electron
donating hydroxyl groups or their anions results in the molecule
being less reactive towards nucleophilic substitution. The use
of either potassium hydroxide, sodium carbonate or potassium
carbonate in place of sodium hydroxide as the base was also
unsuccessful and only the starting material was recovered. In
an attempt to modify the electronic properties of the starting
2. Reduction
and
amination
of
1,4-dihydroxy-5,8-
dichloroanthracene-9,10-dione. As the direct thiolation reactions
were not successful, another pathway was sought to bypass
the suspected deactivation of the molecule by the hydroxyl
groups using the reduced or leuco form (3) of 1,4-dihydroxy-
5,8-dichloroanthracene-9,10-dione (2). It is well established
that the leuco form (4a) of 1,4-dihydroxyanthracene-9,10-dione
reacts readily with a variety of amines, such as n-butylamine
to form 1,4-bis(n-butylamino)anthracene-9,10-dione via the
intermediate (4b).55,56 While the leuco derivative (4a) can exist
in several tautomeric forms (Fig. 4), in practice, only one
Fig. 4 Potential tautomers of the reduced forms of 1,4-disubstituted anthracene-9,10-diones.
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tautomer, 2,3-dihydro-9,10-dihydroxyanthracene-1,4-dione (A),
is found experimentally by NMR studies.56 In contrast, the
preferred tautomeric form of the corresponding intermediate
leuco 1,4-bis(butylamino)anthracene-9,10-dione (4b) is thought
to be 1,4-bis(butylamino)-2,3-dihydroanthracene-9,10-dione
2,3-dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione to
yield 1,4-bis(methylamino)-5,8-dichloroanthracene-9,10-dione
(1h) in 43% yield. Likewise, the reaction of 2-aminoethanol with
2,3-dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione in
ethanol gives 1,4-bis(2-hydroxyethylamino)-5,8-dichloroanthra-
cene-9,10-dione (1i) in 64% yield.
The corresponding reactions of 2,3-dihydro-9,10-dihydroxy-
5,8-dichloroanthracene-1,4-dione (3) with N,N-dimethylethyl-
enediamine and N,N-diethylethylenediamine also occur to give
1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dichloroanthracene-
9,10-dione (1j) and 1,4-bis{[2-(diethylamino)ethyl]amino}-
5,8-dichloroanthracene-9,10-dione (1k) in 29% and 22%
yield respectively. These reactions suggest that the side chain
could be easily functionalised to contain the same [2-(b-
hydroxyethylamino)ethylamino] substituents as those found in
Ametantrone (1c) and Mitoxantrone (1d) though this aspect was
not examined in the present studies.
(D) on the basis of 1H and 13C NMR data in CDCl3
56
(Fig. 4). However, 13C NMR studies on the reduced form
of 1,4-bis(hydrazino)anthracene-9,10-dione (4c) appears to
show only the diimine, 1,4-bis(aminoimino)-2,3-dihydro-9,10-
dihydroxyanthracene (A).57
The reduction of 1,4-dihydroxy-5,8-dichloroanthracene-9,10-
dione (2) using procedures which are known to reduce 1,4-
dihydroxyanthracene-9,10-dione, such as tin in acetic acid,58
or aqueous sodium dithionite under alkaline conditions (our
preferred route),59,60 gives the leuco derivative (3) in yields of 64%
and 96% respectively with no apparent loss of the chlorine atoms.
As before, this product can in principle exist in one of the four
tautomeric forms shown (see Fig. 4; R = Cl; X = O), but the 1H
NMR spectrum in CDCl3 only shows a sharp singlet consisting
of four protons at 3.0 ppm which is only consistent with 2,3-
dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione (3) and
structure type (A).
The 1H NMR data for all the 1,4-bis(alkylamino)-5,8-
dichloroanthracene-9,10-diones shows that NH proton split into a
triplet confirming that the molecules exists as tautomer (A) rather
than tautomer (B) (Fig. 6).
Although the corresponding reactions of 2,3-dihydro-9,10-
dihydroxy-5,8-dichloroanthracene-1,4-dione with amines might
be complicated by side reactions involving the ring chlorine atoms,
the reactions proceeded smoothly with a variety of alkylamines
and few by-products were detected.
Thus 2,3-dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-
dione (3) reacts readily with an excess of n-propylamine
(used as a solvent) in air to yield 1,4-bis(n-propylamino)-5,8-
dichloroanthracene-9,10-dione (1e) in 32% yield (Fig. 5). The
reaction also proceeds readily in ethanol to give the same product
48% yield.
Fig. 6 Potential tautomers of 1,4-bis(alkylamino)-5,8-dichloroanthracene-
9,10-diones.
The related amination of 2,3-dihydro-9,10-dihydroxy-5,8-
dichloroanthracene-1,4-dione (3) with aniline was unsuccessful
under similar conditions to those employed with alkylamines but
the reaction did occur in ethanol when boric acid was used as
a catalyst to give 1,4-bis(phenylamino)-5,8-dichloroanthracene-
9,10-dione (1l) in 51% yield.
3. Thiolation of 1,4-bis(alkylamino)-5,8-dichloroanthracene-
9,10-diones. Despite the expected deactivating effects of the
alkylamino groups, the reaction of 1,4-bis(n-propylamino)-5,8-
dichloroanthracene-9,10-dione (1e) with potassium thiophenox-
ide proceeded readily in refluxing ethanol during two hours to
give 1,4-bis(n-propylamino)-5,8-bis(phenylsulfanyl)anthracene-
9,10-dione (1m) in 41% yield (Fig. 7). The yield improves to 66%
when DMF is employed as the solvent.
A similar reaction occurs with 2-ethanethiol during 2 h
to yield 1,4-bis(n-propylamino)-5,8-bis(ethylsulfanyl)anthracene-
9,10-dione (1f) in 62% yield. 1,4-Bis(isobutylamino)-5,8-
dichloroanthracene-9,10-dione (1g) also under goes thiolation
with both thiophenol and 2-ethanethiol under similar con-
ditions to yield 1,4-bis(isobutylamino)-5,8-bis(phenylsulfanyl)-
anthracene-9,10-dione (1n) and 1,4-bis(isobutylamino)-5,8-
bis(ethylsulfanyl)-anthracene-9,10-dione (1o) in 37% and 41%
yield respectively.
Fig. 5
A similar reaction occurs with isobutylamine in ethanol to give
1,4-bis(isobutylamino)-5,8-dichloroanthracene-9,10-dione (1g) in
52% yield. Methylamine (20% in water) also reacts readily with
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hydrogen bonded as in the first case to the propylamino hydrogen
atoms H18 and H20 respectively (Fig. 2). In the second case, it
is possible that the attacking nucleophile, RS−, initially prefers to
remove the acidic proton from the hydroxyl group of (2) to generate
a much less reactive 1,4-substituted-5,8-dichloroanthracene-9,10-
dione oxyanion. In the last case, the oxygen atoms O15 and O16
do not form hydrogen bonds with the methoxyl groups and the
carbonyl groups are therefore less effective electron attractors.
Molecular modelling studies
The insertion of either chlorine or sulfur atoms into the 5 and 8-
positions of 1,4-bis(alkylamino) anthracene-9,10-diones (1) would
be expected to change both the electronic properties of the
resulting molecule and the energy levels of the frontier orbitals.
In these studies we have assessed the likely effect of these changes
by theoretical calculations at the ab initio level using the 6-31G**
basis set. Initially, calculations were carried out on 1,4-bis(n-
butylamino)anthracene-9,10-dione (1t) whose crystal structure is
known61 not only to verify that the method provides a reasonable
account of the geometry, but also to provide a simple model for
Ametantrone (1c). Although the side chain is a critical factor in
the antineoplastic activity of Ametantrone (see above) it is not
thought to markedly affect the ability of the molecule to form the
semiquinone and subsequently generate superoxide (see below).
1. Geometries. The calculated results obtained on (1t) using
a starting conformation for the n-butyl groups which was based
on the crystal structure61 show a reasonably good correlation with
the crystallographic data (Table 1) with the anthracene ring system
essentially planar and calculated C1–N17/C4–N19 and O15–
Fig. 7
˚
H18/O16–H20 bond distances of 1.361 and 1.860 A versus average
61,62
˚
Similarly, thiolation of 1,4-bis[2-(hydroxyethyl)amino]-5,8-di-
chloroanthracene-9,10-dione (1i) with thiophenol and 2-ethan-
ethiol in DMF gives 1,4-bis[2-(hydroxyethyl)amino]-5,8-bis-
(phenylsulfanyl)anthracene-9,10-dione (1p) and 1,4-bis[2-(hydro-
xyethyl)amino]-5,8-bis(ethylsulfanyl)anthracene-9,10-dione (1q)
in 67% and 51% yield respectively. Likewise 1,4-bis(phenylamino)-
5,8-bis(phenylsulfanyl)anthracene-9,10-dione (1r) and 1,4-bis-
(phenylamino)-5,8-bis(ethylsulfanyl)anthracene-9,10-dione (1s)
were synthesised in yields of 60% and 52% respectively from 1,4-
bis(phenylamino)-5,8-dichloroanthracene-9,10-dione (1l) and the
appropriate thiols.
Under prolonged reaction times in DMF, however, de-
alkylation occurs and both 1,4-bis(n-propylamino)-5,8-dichloro-
anthracene-9,10-dione (1e) and 1,4-bis[2-(hydroxyethyl)amino]-
5,8-dichloroanthracene-9,10-dione (1i) react with ethanethiol and
potassium hydroxide during 24 h reflux to give 1,4-bis(amino)-5,8-
bis(ethylsulfanyl)anthracene-9,10-dione (1u) as a major product.
It is not entirely clear why the thiolation of 1,4-bis(n-
propylamino)-5,8-dichloroanthracene-9,10-dione (1e) proceeds
readily while the corresponding reaction of either 1,4-dihydroxy-
5,8-dichloroanthracene-9,10-dione (2) or 1,4-dimethoxy-5,8-
dichloroanthracene-9,10-dione does not. Both the n-propylamino
group, hydroxyl group and methoxyl group are electron donors
which would be expected to exert a deactivating effect on
nucleophilic substitution at the 5- and 8-positions. However, the
electron attracting carbonyl groups provide an opposite activating
effect especially when the oxygen atoms O15 and O16 are strongly
values of 1.353 and 1.840 A respectively in the crystal structure.
However, the correlation is less satisfactory for the C6–O16/C13–
˚
O15 bond lengths with calculated values of 1.210 A versus the
˚
average experimental value of 1.255 A in the crystal structure
(Table 1) possibly because the latter form intermolecular hydrogen
bonds with adjacent molecules in the crystalline state. Despite this
apparent anomaly, further calculations were carried out on a rep-
resentative set of molecules all of which had been synthesised, to
gauge the effect of both chlorine and sulfur on the molecular prop-
erties. Calculations were carried on 1,4-bis(n-propylamino)-5,8-
dichloroanthracene-9,10-dione (1e) and 1,4-bis(n-propylamino)-
5,8-bis(ethylsulfanyl)anthracene-9,10-dione (1f) and the results
compared with and contrasted to those obtained for the simpler
n-butylamino derivative (1t). The effect of changing the alkylsul-
fanyl group to a phenylsulfanyl group was examined by calcu-
lating 1,4-bis(n-propylamino)-5,8-bis(phenylsulfanyl)anthracene-
9,10-dione (1m) while the effect of the N-alkyl group on the
molecular properties was examined by calculating the simpler 1,4-
bis(amino)-5,8-bis(ethylsulfanyl)anthracene-9,10-dione (1u). The
calculated results show that the anthracene-9,10-dione ring system
is essentially planar in all cases with the nitrogen atoms N17 and
N18 adopting a mainly planar sp2 conformation with C1–N17
˚
and C14–N19 bond lengths of 1.36 A and C1–N17–H18 and C4–
◦
˚
N19–H20 angles of 116 . The C–S bond lengths of 1.77 to 1.80 A
˚
for (1f), (1m) and (1u), and C–Cl bond lengths of 1.74 A for (1e)
are all consistent with values found in the Cambridge Structural
Database for related molecules.62
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Table 1 Geometries and properties of 1,4-bis(amino)anthracene-9,10-diones calculated at the 6-31G** level versus crystallographic data (CSD)a
Structure
(1t) (CSD)b
(1t)
(1e)
(1u)
(1f)
(1m)
n-Pr
R
X
n-Bu
H
n-Bu
H
n-Pr
Cl
H
SEt
n-Pr
SEt
SC6H5
1.362
0.991
1.901
1.207
1.799
Distance
C1N17
1.359
1.347
0.805
0.930
1.781
1.899
1.254
1.255
1.361
0.991
1.860
1.210
1.361
0.990
1.871
1.203
1.738
1.361
0.991
1.860
1.210
1.770
1.363
0.991
1.880
1.207
1.788
C14N19
H18N17
H20N19
O15H18
O16H20
O15C13
O16C6
XC8/XC11
Angles
C1N17H18
C4N19H20
C14C13O15
C5C6O16
SC11C12
Charges
O15/O16
N17/N19
H18/H20
S
110.2
110.4
123.1
122.4
116.2
116.8
116.3
122.9
121.2
122.9
−0.630
−0.782
0.363
−0.603
−0.825
0.363
−0.627
−0.805
0.362
−0.629
−0.828
0.363
−0.629
−0.825
0.360
0.314
0.314
0.408
Cl
0.065
Total
energy/au
Dipole
−1946.6307
−1745.8344
−1980.0146
−2282.0211
2.004
3.0504
2.404
1.070
0.996
moment/D
HOMO/eV
LUMO/eV
−6.808
−6.867
−6.858
−6.634
−6.729
0.971
0.920
1.040
1.046
0.838
a Taken from the Cambridge Structural Database (Ref. 62). Bond lengths are in angstroms and angles are in degrees. b Ref. 61 (CSD code: CAMJOP).
2. Electronic properties. In the transition from 1,4-bis(n-
butylamino)anthracene-9,10-dione (1t) to either 1,4-bis(n-
propylamino)-5,8-dichloroanthracene-9,10-dione (1e), 1,4-bis(n-
propylamino)-5,8-bis(ethylsulfanyl)anthracene-9,10-dione (1f) or
1,4-bis(n-propylamino)-5,8-bis(phenylsulfanyl) anthracene-9,10-
dione (1m), although the substituent at the 5- and 8-positions
of the right hand ring of the anthracene-9,10-dione changes from
H to either Cl, SC2H5 or SC6H5, the calculated atomic charges at
the hydrogen atoms, H18 and H20, are largely unaffected and all
have a similar value of 0.36. However, the charges at the amino
nitrogen atoms, N17 and N18, differ and increase from −0.78 in
(1t) to −0.83 in the other cases (Table 1).
charged though they exert a much smaller effect than the sulfur
atom does. The N-alkyl group clearly exerts a significant effect at
the nitrogen atoms as the charge increases from −0.81 to −0.83 in
moving from (1u) to (1f). The close similarity between the positive
atomic charges at the intramolecularly bound hydrogens, H18 and
H20, and negatively charged oxygen and nitrogen and atoms, O15,
O16, N17 and N19 respectively, for all these molecules, coupled
with their planarity atoms suggest that all would intercalate into
DNA.
3. Frontier orbital energies. It is well established that the
calculated LUMO energies of many organic systems correlate
with the energies of formation of their radicals and radical
anions because this property is a reflection of their electron
affinity.63 For example, in a recent relevant theoretical and
experimental study on related benzocarbazolediones and anili-
nenaphthoquinones a good linear relationship was found be-
tween the measured first reduction potential and the calculated
LUMO energies.64 Furthermore, very recent work on substituent
effects in a number of quinones using density functional theory
has shown good correlations between the calculated electron
affinities based on the LUMO energies and the experimental
redox potentials.65 Similarly, the LUMO energies of the related
1,4-bis(amino)anthracene-9,10-diones (1) discussed here would
also be expected to reflect their likely reduction potentials to
form the radical anion or semiquinone. These values in turn
should also indicate the ability of the semiquinone (AQ•−) to
The carbonyl oxygen atoms, O15 and O16, which are in-
tramolecularly hydrogen bonded to H18 and H20, show different
trends with a smaller negative charge of −0.60 found in (1e)
versus the value of around −0.63 in (1t), (1f) and (1m) possibly
reflecting the electron attracting effect of the chlorine atoms in the
former case. The positive charge of 0.31 calculated at the sulfur
atoms in both (1u) and (1f) probably reflects electron donation
through the ring to the nitrogen atoms, N17 and N18, as these are
more negatively charged than those in (1t). However, the larger
atomic charge of 0.408 for the sulfur atoms of the phenylsulfanyl
derivative (1m) (Table 1) possibly arises because of additional
electron donation from sulfur into the conjugated phenyl groups.
Alternatively, this change may simply reflect the fact that the sulfur
is bonded to an sp3 carbon in (1f) but a more electronegative sp2
carbon in (1m). The chlorine atoms in (1e) are also positively
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reduce oxygen to superoxide [eqn (1)] and thus mirror the likely
trends in their cardiotoxicities. Using the calculated LUMO
energy of 1,4-bis(n-butylamino)anthracene-9,10-dione (1t) as a
reference point at 0.971 eV (Table 1), as this is thought to be
directly related to the reduction potential of the anti-cancer drug
Ametantrone (1c), the corresponding values for 1,4-bis(amino)-
5,8-bis(ethylsulfanyl)anthracene-9,10-dione (1u) and 1,4-bis(n-
propylamino)-5,8-bis(ethylsulfanyl)anthracene-9,10-dione (1f) at
1.040 and to 1.046 eV respectively are significantly larger than
(1t) and consequently the ethylsulfanyl groups would make the
reduction potential of the radical anion more negative. Although
it was originally anticipated that the vacant d orbitals on the
sulfur atoms would behave as electron attractors66 and stabilise
the radical anion, the overall effect of sulfur in (1u) and (1f)
appears to be similar to the effect of oxygen in Mitoxantrone (1d)
which has a reduction potential of −527 mV.46 It follows from the
calculations that both (1f) and (1u) would be expected to display
similar reduction potentials to Mitoxantrone (1d) and therefore
exhibit similar cardiotoxicities.
However, the LUMO energies of the other derivatives consid-
ered are more interesting and both 1,4-bis(n-propylamino)-5,8-
dichloroanthracene-9,10-dione (1e) and 1,4-bis(n-propylamino)-
5,8-bis (phenylsulfanyl)anthracene-9,10-dione (1m) possess values
of 0.920 or 0.838 eV respectively following substitution at the 5-
and 8-positions of the ring (Table 1). This reduction from the value
found in the reference molecule (1t) probably reflects the effect
of the two electron attracting chlorine atoms on the one hand
which would be expected to stabilise a derived radical anion,
and the increased stabilisation arising from the presence of the
two attached phenylsulfanyl rings on the other which would be
able to distribute and accommodate the negative charge on a
derived radical anion. It follows that the reduction potentials of
both these molecules would be expected to be less negative than
that of Ametantrone (1c) assuming that the complex side chain is
not involved in the reduction step. An analysis of the composition
of the 6-31G** LUMO wavefunction for all the calculated
molecules confirms that it is composed primarily of p atomic
orbitals which are located on the anthracene ring only. For
example, in 1,4-bis(n-propylamino)-5,8-dichloroanthracene-9,10-
dione (1e) the 204 electrons are accommodated in the first 102
bonding MOs and an analysis of the LUMO (MO 103) shows
that it is mainly composed from p atomic orbitals at the ring
carbons and oxygen, with smaller contributions from nitrogen
and chlorine. There is no contribution from the saturated n-butyl
side chain and it is highly unlikely that the corresponding side
chain of Ametantrone would contribute either, as is not conjugated
with the aromatic ring. It follows that the trends in the LUMOs
reported here for the simple n-alkyl derivatives would probably
equally apply to related molecules which contain the optimal side
chain necessary for antineoplastic activity.
5,8-dichloroanthracene-9,10-dione. The subsequent reaction of
the products with ethanethiol or thiophenol gives the corre-
sponding 1,4-bis(amino)-5,8-bis(sulfanyl)anthracene-9,10-dione
in good yield. Theoretical calculations at the RHF 6-31G** level
indicate that the presence of either chlorine or the phenylsulfanyl
group at the 5- and 8-positions of 1,4-bis(alkylamino)anthracene-
9,10-diones results in a lowering of the LUMO energies of (1e)
and (1m) suggesting that their reduction potentials would be
significantly different to the unsubstituted derivative (1t).
Experimental
All the reagents described including 1,4-dihydroxyanthracene-
9,10-dione were supplied by Sigma-Aldrich Chemicals. 1H NMR
spectra were recorded on a Bruker AC spectrometer at 400 MHz.
Chemical shifts are recorded in parts per million (d) relative
to tetramethylsilane in deuterated dimethyl sulfoxide (DMSO)
or chloroform (CDCl3). Mass spectra were recorded using the
EPSRC Mass spectrometry centre at Swansea using a VG ana-
lytical Quatro II triple quadrupole mass spectrometer. Accurate
masses were obtained on a Finngan MAT 900 XL using a
perfluorotributylamine as the reference compound for electron
ionisation and polyethyleneimine for chemical ionisations. Melting
points were recorded on an electrothermal digital melting point
apparatus. Most of the known products were synthesised using
literature procedures which are described in the text (above).
However, where the experimental procedure differed significantly
from that published, or the derivatives have not previously been
described, full details have been included.
2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione (3)
This was prepared using modified literature procedures.58–60 (a) 1,4-
Dihydroxy-5,8-dichloroanthracene-9,10-dione (1.00 g, 3.3 mmol)
was added to a solution of sodium carbonate (1.4 g, 13.2 mmol)
and water (125 ml). The solution was heated until boiling and
sodium dithionite (1.7 g, 9.8 mmol) was added. Because of
incomplete reduction, it was necessary to add a further quantity
of sodium dithionite (0.50 g, 2.9 mmol) after 15 min to complete
the reduction. The precipitate was filtered off, washed with dilute
acetic acid until alkali free and d◦ried in vacuo to yield the title
compound (0.90 g, 96%), mp 145 C, (lit.,60 150 ◦C), dH (CDCl3)
3.0 (4H, s), 7.6 (2H, s), 14.5 (2H, OH,s). (b) 1,4-Dihydroxy-5,8-
dichloroanthracene-9,10-dione (1.00 g, 3.3 mmol) was added to a
mixture of tin (3.00 g, 24.4 mmol) and HCl (70 ml) in acetic acid
(50 ml). The mixture was heated to 90–95 ◦C for 24 h. The solution
was allowed to cool and the precipitate was filtered off, the solid
was washed with water and dried in vacuo to yield 2,3-dihydro-
9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione (0.65, 64%), mp
147 ◦C, dH (CDCl3) 3.0 (4H, s), 7.6 (2H, s), 14.5 (2H, OH, s).
1,4-Bis(n-propylamino)-5,8-dichloroanthracene-9,10-dione (1e)
Conclusions
2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione
(1.00 g, 3.2 mmol) was added to a solution of n-propylamine
(1.00 g, 17 mmol) in ethanol (25 ml) and the mixture was heated
for 1 h at 50–55 ◦C. The solution was allowed to cool, petroleum
ether 40–60 (25 ml) was added and the mixture stirred overnight.
The resulting solid was filtered off and purified via column
chromatography using an eluant of toluene 95% and chloroform
1,4-Bis(alkylamino)-5,8-dichloroanthracene-9,10-diones are read-
ily synthesised from the reaction of 1,4-dichloro-2,3-dihydro-
5,8-dihydroxyanthracene-9,10-dione with alkylamines such as n-
propylamine, isobutylamine, methylamine, 2-aminoethanol and
N,N-dimethylethylenediamine. A related reaction with ani-
line in the presence of boric acid gives 1,4-bis(phenylamino)-
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5% to yield the title compound (0.60 g, 48%), mp 150 ◦C, dH
(CDCl3) 1.00 (6H, t), 1.50 (4H, m) 3.30 (4H, q), 7.10 (2H, s)
7.40 (2H, s), 10.30 (2H, NH t); m/z (EI) 390.0901, C20H20Cl2N2O2
requires 390.0902.
dH (DMSO-d6) 1.25 (12H, t), 3.20 (8H, q), 3.40 (4H, t), 3.90 (4H,
q), 7.60 (2H, s), 7.80 (2H, s), 9.90 (2H, NH, t), 10.90 (2H, HCl),
dC 180.51, 144.04, 136.61, 132.54, 132.26, 124.20, 111.04, 49.94,
46.75, 37.36, 8.69.
1,4-Bis(isobutylamino)-5,8-dichloroanthracene-9,10-dione (1g)
1,4-Bis(phenylamino)-5,8-dichloroanthracene-9,10-dione (1l)
A similar procedure using isobutylamine (1.24 g, 17 mmol) in
place of n-propylamine gave the title compound (0.70 g, 52%), mp
154 ◦C, dH (CDCl3) 1.00 (12H, d), 2.00 (2H, m) 3.10 (4H, t), 7.10
(2H, s), 7.50 (2H, s), 10.40 (2H, NH, t), dC 180.80, 145.75, 135.69,
133.44, 123.70, 113.30, 110.68, 61.55, 29.09, 20.92.
A mixture of 2,3-dihydro-9,10-dihydroxy-5,8-dichloroanthracene-
1,4-dione (1.00 g, 3.2 mmol), aniline (3.00 g, 32 mmol) and boric
acid (0.40 g, 6.4 mmol) was heated for 4 h at 90–95 ◦C. The solution
was allowed to cool, the precipitate was filtered off, and purified
by column chromatography using an eluant of toluene 95% and
chlo◦roform 5% to yield the title compound (0.35 g, 24%), mp
◦
230 C (lit., 234–235 C58), dH (CDCl3) 7.00–7.30 (10H, m), 7.40
1,4-Bis(methylamino)-5,8-dichloroanthracene-9,10-dione (1h)
(2H, s), 7.50 (2H, s), 11.40 (2H, NH, s), dC 182.26, 142.77, 139.97,
136.43, 133.60, 133.26, 129.92, 126.51, 125.30, 123.92, 113.42.
2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione
(1.00 g, 3.2 mmol) was added to a solution of 20% methylamine in
water (4.96 g, 32 mmol) and the mixture was heated for 1 h at 50–
55 ◦C. The solution was allowed to cool, the resulting precipitate
filtered off, washed with water (50 ml) and purified by column
chromatography using an eluant of toluene 95% and chloroform
5% to yield the title compound (0.50 g, 47%), mp 145 ◦C, dH
(CDCl3) 3.00 (6H, d), 7.15 (2H, s), 7.45 (2H, s), 10.10 (2H, NH).
1,4-Bis(n-propylamino)-5,8-bis(ethylsulfanyl)anthracene-9,10-
dione (1f)
1,4-Bis(n-propylamino)-5,8-dichloroanthracene-9,10-dione (0.43 g,
1.1 mmol) was added to a solution of ethanethiol (0.68 g, 11 mmol)
and potassium hydroxide (0.62 g, 11 mmol) in DMF (25 ml) and
the solution was heated under reflux for 2 h. The DMF was
removed under vacuum distillation and the resulting solid was
washed with 10% potassium hydroxide solution (50 ml) and then
methanol. The crude product was purified by column chromatog-
raphy using an eluant of 90% toluene and 10% chloroform to yield
the title compound (0.30 g, 62%), mp 235 ◦C, dH (CDCl3) 1.00 (6H,
t), 1.30 (6H, t), 1.70 (4H, m), 2.80 (4H, q), 3.20 (4H, q), 6.90 (2H,
s), 7.25 (2H, s), 10.30 (2H, NH, t).
1,4-Bis[2-(hydroxyethyl)amino]-5,8-dichloroanthracene-9,10-dione
(1i)
2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione
(1.00 g, 3.2 mmol) was added to a solution of 2-aminoethanol
(1.00 g, 16 mmol) in ethanol (25 ml) and was heated for 1 h at 50–
◦
55 C. The solution was allowed to cool, petroleum ether 40–60
(25 ml) was added and the mixture was stirred for overnight. The
resulting solid was filtered off and recrystallised from ethanol to
yield the title compound (0.80 g, 64%), mp 197 ◦C, dH (CDCl3)
3.40 (2H, t), 3.60 (2H, q) 4.90 (2H, OH, s), 7.35 (4H, s) 7.60 (4H,
s), 10.30 (2H, NH, t).
1,4-Bis(isobutylamino)-5,8-bis(ethylsulfanyl)anthracene-9,10-
dione (1o)
A
similar procedure using 1,4-bis(isobutylamino)-5,8-di-
chloroanthracene-9,10-dione (0.43 g, 1.1 mmol) in place of the
n-propyl derivative gave the title compound (0.20 g 41%), mp
230 ◦C, dH 0.95 (12H, d), 1.30 (6H, t), 1.90 (2H, m), 2.80 (4H,
q), 3.05 (4H, t), 6.95 (2H, s), 7.30 (2H, s), 10.40 (2H, t, NH),
dC 182.17, 137.02, 131.11, 128.23, 127.34, 124.48, 108.4, 49.63,
29.79, 28.79, 19.53, 11.80.
1,4-Bis{[2-(dimethylamino)ethyl]amino}-5,8-dichloroanthracene-
9,10-dione (1j)67
2,3-Dihydro-9,10-dihydroxy-5,8-dichloroanthracene-1,4-dione
(1.00 g, 3.2 mmol) was added to
a solution of N,N-
dimethylethylenediamine (2.8 g, 32 mmol) in ethanol (25 ml)
and the mixture was heated for 2 h at 50–55 ◦C. The solution
was allowed to cool, petroleum ether 40–60 (25 ml) was added
and the mixture further cooled with ice. The resulting precipitate
was filtered off, added to a solution of diethyl ether (25 ml)
and methanol (25 ml) saturated with hydrogen chloride gas and
stirred for 15 min. The product was filtered off and purified by
column chromatography using an eluant of 10% methanol and
90% chloroform to yield the title compound (0.40 g, 29%), mp
255 ◦C, dH (DMSO-d6) 3.20 (12H, s), 3.30 (4H, t), 3.50 (4H, q), 7.35
(2H, s), 7.65 (2H, s), 10.10 (2H, NH, t), dC 179.91, 144.45,136.03,
132.23, 132.09, 124.66, 109.78, 55.55, 51.74, 46.79.
1,4-Bis[2-(hydroxyethyl)amino]-5,8-bis(ethylsulfanyl)anthracene-
9,10-dione (1q)
A similar procedure using 1,4-bis[2-(hydroxyethyl)amino]-5,8-di-
chloroanthracene-9,10-dione (0.43 g, 1.1 mmol) in place of the n-
propyl derivative gave the title compound (0.25 g, 51%), mp 254 ◦C,
dH (CDCl3) 1.10 (6H, t), 2.70 (4H, q), 3.30 (4H, q), 3.50 (4H, t),
7.20 (2H, s), 7.4 (2H, s), 10.10 (2H, NH); m/z (EI) 446.1336,
C22H26N2O4S2 requires 446.1334.
1,4-Bis(phenylamino)-5,8-bis(ethylsulfanyl)anthracene-9,10-dione
(1s)
1,4-Bis{[2-(diethylamino)ethyl]amino}-5,8-dichloroanthracene-
A
similar procedure using 1,4-bis(phenylamino)-5,8-di-
9,10-dione hydrochloride (1k)
chloroanthracene-9,10-dione (0.50 g, 1.1 mmol) in place of
the n-propyl derivative gave the title compound (0.30 g, 52%), mp
215 ◦C, dH (CDCl3), 1.35 (6H, t), 2.90 (4H, q), 7.00–7.50 (14H,
m), 11.75 (2H, NH, s), dC 184.74, 140.26, 139.77, 132.77, 132.22,
A similar procedure using N,N-diethylethylenediamine (2.80 g,
24 mmol) place of N,N-dimethylethylenediamine (2.80 g,
28 mmol) gave the title compound (0.30 g, 22%), mp 265 ◦C,
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129.89, 129.79, 128.50, 124.85, 124.79, 112.43, 26.79, 13.23; m/z
(EI) 510.1434, C30H26N2O2S2 requires 510.1436.
(2H, s), 8.20 (4H, s); m/z (EI) 358.0813, C18H18N2O2S2 requires
358.0810. The same product (0.01 g, 22%) was isolated also from
the same procedure and work up to that described for (1e) but
with an extended reaction time of 24 h.
1,4-Bis(n-propylamino)-5,8-bis(phenylsulfanyl)anthracene-9,10-
dione (1m)
1,4 - Bis(n - propylamino) - 5,8 - dichloroanthracene - 9,10 - dione
(0.43 g, 1.1 mmol) was added to a solution of thiophenol (1.20 g,
11 mmol) and potassium hydroxide (0.62 g, 11 mmol) in DMF
(25 ml). The solution was heated under reflux for 2 h and
the solvent was removed by vacuum distillation. The solid was
washed with 10% potassium hydroxide solution (50 ml) and then
methanol. The crude solid was purified via column chromatogra-
phy using an eluant of 90% toluene and 10% chloroform to yield
the title compound (0.40 g, 66%), mp 240 ◦C, dH (CDCl3) 1.00
(6H, t), 1.8 (4H, m), 3.30 (4H, q), 6.60 (2H, s) 7.40 (12H, m), 10.50
(2H, NH, t); m/z (EI) 538.1747, C32H30N2O2S2 requires 538.1749.
In an alternative procedure, the same reactants were refluxed in
ethanol (25 ml) for 2 h rather than DMF. The solvent was removed
under vacuum distillation, the residual solid was treated as before
and purified via column chromatography using an eluant of 90%
toluene and 10% chloroform to yield the title compound (0.25 g,
41%), mp 240 ◦C.
References
1 J. Houben, Das Anthracen aund der Anthrachinonen, Thieme, Liepzig,
1929.
2 F. B. Stilmar and M. A. Perkins, The Chemistry of Synthetic Dyes and
Pigments, ed. H. A. Lubs, Reinhold, New York, 1955, pp. 335–390.
3 Encyclopedia of Chemical Technology, ed. R. E. Kirk and D. F. Othmer,
Interscience, New York, 2nd edn, 1963, vol. 2, pp. 431–500.
4 P. F. Gordon and P. Gregory, Organic Chemistry in Colour, Springer-
Verlag, Heidelberg, 1983.
5 J. Fabian and H. Hartmann, Light Absorption of Organic Colorants,
Springer-Verlag, Heidelberg, 1980, ch. 7, and references cited therein.
6 K. C. Murdock and R. G. Child, US Patent 4138415/1979 (to American
Cyanamid).
7 R. K. Y. Zee-Cheng and C. C. Cheng, J. Med. Chem., 1978, 21, 291.
8 R. K. Y. Zee-Cheng, E. G. Podrebarac, C. S. Menon and C. C. Cheng,
J. Med. Chem., 1979, 22, 501.
9 K. C. Murdock, R. G. Child, P. F. Fabio, R. B. Angier, R. E. Wallace,
F. E. Durr and R. V. Citarella, J. Med. Chem., 1979, 22, 1024.
10 C. C. Cheng and R. K. Y. Zee-Cheng, Prog. Med. Chem., 1983, 20, 83.
11 T. D. Shenkenberg and D. D. Von Hoff, Ann. Intern. Med., 1986, 105,
67.
12 D. Faulds, J. A. Balfour, P. Chrisp and H. D. Lantry, Drugs, 1991, 41,
1,4-Bis(isobutylamino)-5,8-bis(phenylsulfanyl)anthracene-9,10-
dione (1n)
400.
13 J. Koeller and M. Eble, Clin. Pharm., 1988, 7, 574.
14 A. P. Krapcho, J. J. Landi, K. J. Shaw, D. G. Phinney, M. P. Hacker and
J. J. McCormack, J. Med. Chem., 1986, 29, 1370.
15 E. J. Fox, Neurology, 2004, 63, S15.
16 Dorland’s Illustrated Medical Dictionary, ed. W. B. Saunders, Elsevier,
Philadelphia, 2004 (www.dorlands.com).
A
similar procedure using 1,4-bis(isobutylamino)-5,8-di-
chloroanthracene-9,10-dione (0.43 g, 1.1 mmol) in place of the
n-propyl derivative in DMF yielded the title compound (0.22 g,
◦
17 X. L. Yang, H. Robinson, Y. G. Gao and A. H. Wang, Biochemistry,
37%), mp 240 C, dH (CDCl3) 1.00 (12H, d), 2.10 (2H, m), 3.30
2000, 39, 10950.
(4H, t), 6.60 (2H, s), 7.50 (12H, m), 10.60 (2H, NH, t).
18 ed. J. W. Lown, Bioactive Molecules. Anthracyclines and
Anthracenedione-Based Anticancer Agents, Elsevier, New York,
1988, vol. 6.
1,4-Bis[2-(hydroxyethyl)amino]-5,8-bis(phenylsulfanyl)anthracene-
9,10-dione (1p)
19 W. A. Denny, Anti-Cancer Drug Des., 1989, 4, 241.
20 W. A. Denny and L. P. G. Wakelin, Anti-Cancer Drug Des., 1990, 5,
189.
A similar procedure using 1,4-bis[2-(hydroxyethyl)amino]-5,8-di-
chloroanthracene-9,10-dione (0.43 g, 1.1 mmol) in place of the
n-propyl derivative in DMF gave the title compound (0.40 g,
67%), mp 260 ◦C, dH (DMSO) 3.40 (4H, q), 3.75 (4H, t), 5.10
(2H, OH, s), 6.70 (2H, s), 7.50 (12H, m), 10.50 (2H, NH, s),
dC 181.64, 145.64, 139.88, 135.95,133.33, 130.50, 130.45, 129.87,
129.17, 124.56, 108.77, 60.27, 45.19.
21 G. Kotovych, J. W. Lown and J. P. K. Tong, J. Biomol. Struct. Dyn.,
1986, 4, 111.
22 J. Kapuscinski and A. Darzynkiewicz, Proc. Natl. Acad. Sci. U. S. A.,
1986, 83, 6302.
23 N. Chegini and A. R. Safa, Cancer Lett. (Shannon, Irel.), 1987, 37,
327.
24 J. W. Lown, C. C. Hanstock, R. D. Bradley and D. G. Scraba, Mol.
Pharmacol., 1984, 25, 178.
25 J. W. Lown and C. C. Hanstock, J. Biomol. Struct. Dyn., 1985, 2, 1097.
26 D. A. Collier and S. Neidle, J. Med. Chem., 1988, 31, 847.
27 S. Neidle, Chem. Br., 2000, 36, 27.
1,4-Bis(phenylamino)-5,8-bis(phenylsulfanyl)anthracene-
9,10-dione (1r)68
28 D. Cairns, E. Michalitsi, T. Jenkins and S. Mackay, Bioorg. Med. Chem.,
2002, 10, 803.
A
similar
procedure
using
1,4-bis(phenylamino)-5,8-
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(22H, m), 11.85 (2H, NH, s), dC 184.56, 143.46, 141.60, 137.44,
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4014 | Org. Biomol. Chem., 2006, 4, 4005–4014
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