Novel 6,12-disubstituted chrysene as potent anticancer agent: Synthesis, in vitro and in vivo study

Article abstract of DOI:10.1016/j.ejmech.2010.07.033

We describe herein the synthesis of novel 6,12-distributed chrysene as potent anticancer agents. In vitro and in vivo studies are also reported here.

Full text of DOI:10.1016/j.ejmech.2010.07.033

European Journal of Medicinal Chemistry 45 (2010) 4687e4691
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Novel 6,12-disubstituted chrysene as potent anticancer agent: Synthesis, in vitro
and in vivo study
,
b
Bimal K. Banik a , Frederick F. Becker
*
a The University of Texas-Pan American, Department of Chemistry, 1201 West University Drive, Edinburg, TX 78539, USA
b The University of Texas, M.D. Anderson Cancer Center, Department of Molecular Pathology, Unit 951, 7435 Fannin Street, Houston, TX 77030, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein the synthesis of novel 6,12-distributed chrysene as potent anticancer agents. In vitro
and in vivo studies are also reported here.
Received 7 April 2010
Received in revised form
22 June 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Accepted 18 July 2010
Available online 24 July 2010
Keywords:
Substituted chrysenes
Anticancer agents
In vitro assay
In vivo test
1. Introduction
studies indicated the important roles of the nature and length of
the appended chain as well as the terminal moiety [13]. Despite the
Research on PAH and their derivatives has received significant
attention from organic and medicinal chemists as well as biologists
[1]. In parallel with these efforts there has been a persistent, but
relatively limited focus on the use of these molecules as anticancer
agents. For example, Bair et al. reported a close correlation between
their effectiveness against tumor lines and the configuration of the
polyaromatic molecule [2]. This group then developed benzylic
aminopropanediols that were predicted to be more effective based
on from SAR studies. These compounds were proposed to interact
with DNA by intercalation and also suggested to be inhibitors of
topoisomerase II. Intercalation has been confirmed for at least two
of the most active napthalimides, amonafide and mitonafide and
their antitumor activity has been suggested to result from this
interaction [3e6]. These interesting reports appeared to us to offer
significant opportunities to expand the investigation of PAH-
derived compounds to improve their antitumor activities, decrease
toxicity and to better identify their crucial targets [7e12].
significant activity of a number of these compounds against
a spectrum of human and animal lines in vitro their in vivo activity
was limited.
Therefore, to extend the previous studies of these biologically
active aromatic compounds this paper describes the synthesis of
a few of 6,12-disubstitued chrysene derivatives and their evaluation
in vitro and in vivo against a number of human and animal tumor
lines. At least one of these compounds demonstrated reasonable
activity in vivo and when examined by the NIH-Compare Program
was reported to have an “unidentified mode of action”.
2. Synthesis
It has been established that some disubstitued compounds were
more active than the compounds which had a single chain or
a single aromatic moiety 7c. The chemistry described in our earlier
study can be extended to prepare a new family of compounds of
these types by simple chemical manipulation. For example, two
amide derivatives 7a, and 7b were prepared as shown below
(Scheme 1). (1) On acetylation afforded 6-acetamidochrysene (2).
6-Acetamidochrysene (2) on nitration by nitric acid produced the
nitro amide 3 which on reduction (hydrazine hydrate and 10% Pd/C)
[14e15] and subsequent hydrolysis (20% sulfuric acid in aqueous
ethanol) afforded 6,12-diaminochrysene (5). A coupling reaction of
6 with 5 in the presence of isobutyl chloroformate afforded the
In prior studies we have reported that a series of mono-
substituted chrysene derivatives have demonstrated a structurally
related antitumor activity that suggested crucial interactions at the
tumor cell membrane as an alternate target for activity and SAR
* Corresponding author. Tel.: þ1 956 380 8741; fax: þ1 956 384 5006.
E-mail address: banik@panam.edu (B.K. Banik).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.033

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B.K. Banik, F.F. Becker / European Journal of Medicinal Chemistry 45 (2010) 4687e4691
Scheme 1. Synthesis of anticancer agents derived from 6-aminochrysene. Synthesis of 6,12-disubstituted chrysene.
amide 7. The amide 7 was then reduced to produce the amine 8 and
the amine 8 was then converted to the hydrochloride salt 9
(Scheme 1).
the single chain amino derivative with a terminal piperidine moiety
demonstrated IC50 against all 7 cancer cell lines below 5 M. This
considerable enhancement of anticancer activity is commensurate
with the increase in activity that has been reported previously for
all related, single chain amino analogues regardless of the terminal
moiety.
m
2.1. In vitro cytotoxicity
Six human tumor lines of hematopoietic (HL-60) and five of
epithelial origin were tested, as well as one mouse lymphoma, P388
which is used as a standard in chemotherapy testing. As indicated
in Table 1 the activities of the monosubstituted compounds were
consistent with previously reported results (Fig. 1). While 10a, the
single chain amide with a terminal piperidine moiety failed to
The effect of substituting amino chains for the amides had an
even greater effect than it had for the single chain amino substi-
tution. Compound 8a with symmetrical piperidine rings had IC50 of
2
m
M or less against 5/7 lines and <1
a human prostate cancer cell line against which cisplatin demon-
strated an IC50 of 2.1 M. The amino compound 8b with terminal N-
methylpiperazine rings demonstrated an IC50 of <4 M against 1/7
cancer cell lines; <2 M against 4/7 cancer cell lines and <1
against 2/7 cancer cell lines including SKOV-3, an ovarian cancer
mM against 2/7 including PC-3,
m
produce an IC50 below 20
a terminal piperazine ring demonstrated an IC50 below 10
against 4 cancer cell lines of different derivation. Compound 11a,
mM against any cancer cell line, 10b with
m
mM
m
mM

B.K. Banik, F.F. Becker / European Journal of Medicinal Chemistry 45 (2010) 4687e4691
4689
Table 1
IC50 M) of compounds 7a, 7b, 8a, 8b, and 9b, against several cancer cell lines; MTT
assay (72 h continuous exposure).
Table 2
(
m
Effect of 9b on intraperitoneal growth of SKOV-3.
T/Ma
T/TBMb
Tvol/Mc
Tvol/TBMd
Compounds BRO
Cisplatin
HT-29 MCF-7 SKOV-3 PC-3
HL-60 P388
Controls (20)
40 mg/k (15)
6.5
4.2
10.8
5.8
1.1 cm3
1.9 cm3
5.66 16.99
10.05
24.5
7.1
5.99
21.0
11.1
4.4
2.1
50.4
18.4
3.7
1.66
18.8
9.5
1.1
11.0
29.5
6.0
0.6 cm3
0.7 cm3
10a (10)
10b (8)
11a (5)
11b (3)
7a (4)
>100
41.6
3.4
13.9
44.3
57.3
1.7
33.3
9.3
2.4
a
Average number of tumors per mouse.
Average number of tumors per tumor bearing mouse.
Total tumor volume per mouse.
b
c
2.3
2.2
14.3
41.1
66.6
1.2
6.4
8.4
10.02
24.4
15.5
0.8
5.3
19.5
37.8
98.0
2.0
d
Total tumor volume per tumor bearing mouse.
21.0
75.0
1.4
22.0
72.2
1.9
25.0
42.1
0.8
7b (5)
10 mm. Administration of 9b reduced the tumor number per tumor
8a (6)
8b (5)
9b (3)
3.8
0.6
2.1
1.6
1.7
1.2
0.9
1.0
1.2
2.1
0.9
0.9
1.7
0.8
bearing mouse by 35% and the tumor volume was reduced by 47%.
Data are provided as IC50 values (mM). Assays were conducted using 72 h of
3. Discussion
continuous exposure to drug; relative cell growth was determined using the MTT
method. The final concentration of solvent is <0.625%, which is not toxic to the cells.
All dilutions were made in RPMI 1640 with 10% FBS. The number of run indicates in
the brackets.
This study was aimed at extending our initial findings that
a number of newly synthesized compounds with amide or amine
linkers, having a chrysene nucleus, demonstrated an interesting
degree of in vitro antitumor activity against human and animal
tumor cell lines. Since even the most active of these compounds,
those with amino structure, demonstrated only modest activity
against these cancer cell lines when tested in vivo, we speculated
that bis-compounds bearing a variety of such chains and terminal
moieties might reveal important SAR, as well as having the
potential for greatly enhanced anticancer activity.
Several findings utilizing amide compounds (7a and 7b) were of
interest. While it did not appear surprising that 7a, the amide
variant of 10b was as inactive as was the latter, the lack of any
significant activity by 7b, the amide variant 11b was unexpected.
When comparing amides, those bearing a piperazine ring as the
terminal moiety demonstrated at least limited activity against
several tumor cell lines. While we could not determine the cause of
this lack of activity of a bis-piperazine it seemed reasonable to
suggest that some form of hindrance resulted from the dual binding
of the identical terminal moieties perhaps limiting membrane
transport.
line against which cisplatin demonstrated an IC50 of 5.99 mM. The
hydrochloride salt 9b of the amino compound 8b might be
considered to be the most active of all of these compounds with
IC50 of <2 mM against 3/7 cancer cell lines and <1 mM against 4/7. In
this latter group was BRO, a human melanoma cancer cell line
against which no other compound demonstrated a comparable
activity and against which cisplatin demonstrated an IC50 of
5.66
mM; and <1 mM with P388 against which cisplatin’s IC50 was
11.0 (Table 1).
2.2. In vivo studies
The effectiveness of 9b was tested in vivo against the human
ovarian cancer cell line SKOV-3. The agent was dissolved in PBS, pH
7.4 just prior to injection. The cells were harvested at 80% conflu-
ence and viability was tested by trypan blue exclusion. Cells were
used only if viability was judged to be in excess of 90%. 6e10 week
old nu/nu females were used. The tumor cells were washed in PBS,
re-suspended in PBS and injected intra-peritoneally at 0.65 ꢀ106
per mouse. All mices were sacrificed at seven weeks after injection.
Administration of 9b was begun 72 h after the injection of the
tumor at 40 mg/k i.p. The regimen consisted of administration of
this dose administered for 5 days at 10:00 a.m. each morning of the
first and second weeks. Relative to control mice a weight loss of
between 5% and 7% was detected in the treated mice with complete
restoration of the weights to those of control mice by the end of the
third week.
Compounds 9a, and 9b demonstrated a typical effect of the
conversion of the amide to amino components of the linker
regardless of the nature of the terminal moiety. The amino
compound demonstrated activity against almost every cancer cell
line tested, regardless of its derivation. Thus, it was of interest that
each of the bis-amino compounds 9a and 9b demonstrated such
antitumor activities ranging from IC50 of 1.0e2.5
instances to <1.0 M in several. In evaluation of potential clinical
agents, compounds with <1.0 M activities are considered to be of
mM in a few
m
m
interest, while recognizing that their toxicity must be taken into
account. While one might conclude that the greatly increased
basicity of such compounds becomes the overriding element in
their activity we must admit that the exact mechanism is uncertain.
Further, we have demonstrated that for one of these amino
compounds, 9b, the salt of 8b demonstrated activity in vivo against
the human ovarian cancer cell line SKOV-3. Although clearly not
curative in the limited regimen used, this tumor is notoriously
resistant to many standard antitumor agents suggesting that
further study with variants of the regimen may be warranted.
Finally, as a caveat against presupposing that any of these agents
has a universal effect against all tumor cell lines, we have demon-
strated in a previous publication using human leukemic Jurkat T
cells in vitro, we demonstrated that while 11a caused extensive
cytotoxicity, 8b was far less active. This relatively lesser activity of
8b was also reflected in a greatly diminished degree of apoptotic
damage, the apparent mechanism of cell death imparted in this cell
line by these compounds [16]. However, selectivity of effect against
different tumors is more the rule than the exception for many
antitumor compounds.
2.3. In vivo results
The results of two in vivo runs are summarized in Table 2. In the
typical untreated mouse multiple nodules were detected throughout
the abdominal cavity and varied in diameter generally from 1 to
Fig. 1. Anticancer diamide derived from chrysene. Example of anticancer diamide and
diamine.

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B.K. Banik, F.F. Becker / European Journal of Medicinal Chemistry 45 (2010) 4687e4691
4. Experimental section
NaHCO3 solution (25 mL). The organic layer was then dried over
anhydrous Na2SO4 and concentrated under reduced pressure to
produce the amide. This was purified by column chromatography
over silica gel (methanol/ethyl acetate ¼ 1:4); Yield: 230 mg (53%);
mp 260e262 ꢂC; IR (film): 3252, 2934, 2855, 1650, 1538, 1470, 1441,
1225, 1218, 1138, 1013, 978; 1H NMR (CDCl3): 1.6 (bs, 12H), 2.95 (m,
8H), 3.45(dd, J ¼ 5.2 Hz, J ¼ 4.3 Hz, 2H), 3.7 (dd, J ¼ 5.8 Hz,
J ¼ 4.6 Hz, 2H), 7.6 (m, 4H), 8.15 (m, 2H), 8.6 (m, 2H), 9.1(s, 1H), 9.45
(s, 1H); Mass: 593, 569, 525, 481, 437, 393, 297, 122; Anal. Calcd for
C36H40O4N4: C, 72.9, H, 6.8, N, 9.5. Found: C, 72.31, H, 6.68, N, 9.19.
4.1. General methods
All solvents and reagents were obtained from commercial
sources and used without purification. Reactions were monitored
by TLC using pre-coated silica gel aluminum plates containing
a fluorescence indicator. Chemical shifts of 1H NMR spectra were
given in parts per million with respect to TMS, and the coupling
constant J was measured in Hz. Data are reported as follows:
chemical shifts, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet). 1H NMR spectra were recorded in CDCl3
using tetramethylsilane as an internal standard. IR spectra of neat
compounds were expressed as wave numbers (cmꢁ1).
4.1.6. N,N-(6,12-Chrysenyl)-bis(4-(4N-methylpiperazinyl)-butane)-
1,4-dicarboximide (7b)
To acid 6 (434 mg, 2.3 mmol) in dry dichloromethane (50 mL) at
0 ꢂC was added triethylamine (0.32 mL, 1.45 mmol) followed by
isobutyl chloroformate (0.290 mL, 1.4 mmol) and the mixture
allowed to stir at 0 ꢂC for 10 min. To this mixture was added 6,12-
diaminochrysene (180 mg, 0.7 mmol) and the reaction was allowed
to stir overnight at room temperature. On completion of the
reaction dilute HCl (10%, 50 mL) was added and the organic layer
was washed with saturated NaHCO3 solution (25 mL). The organic
layer was then dried over anhydrous Na2SO4 and concentrated
under reduced pressure to furnish the amide. This was purified
by column chromatography over silica gel (methanol/ethyl
acetate ¼ 1:4) Yield: 198 mg (48%); mp 246e248 ꢂC; IR (cmꢁ1):
3252, 2920, 2850, 1650, 1537, 1442, 1372, 1293, 1255, 1220, 1146,
1022, 1001, 871, 750; 1H NMR (CDCl3) 2.3 (s, 6H), 2.4 (m, 8H), 2.9
(m, 8H), 3.6 (dd, J ¼ 5.4 Hz, J ¼ 4.6 Hz, 2H), 3.8 (dd, J ¼ 5.2 Hz,
J ¼ 4.3 Hz, 2H), 7.55 (m, 8H), 8.1 (m, 4H), 8.5 (m, 4H), 8.9 (s, 2H), 9.2
(s, 2H); Mass: 624.28, 623.22, 483.2, 441.2, 423.1, 341.2, 312.3,
183.2, 155.1, 101.17; Anal. Calcd for C36H42O4N6: C, 69.4, H, 6.8, N,
13.5. Found C, 68.37, H, 6.78, N, 11.33.
4.1.1. 6-Acetamidochrysene (2)
To 6-aminochrysene (1 g, 4 mmol) in pyridine (8 mL) at 0 ꢂC was
added acetylchloride (326 ml, 4.2 mmol) dropwise with vigorous
stirring and the mixture was allowed to stir for further 10 min. The
resultant mixture was poured into dilute HCl (10%, 100 mL). The
precipitated solid was filtered, washed with dilute HCl (10%) fol-
lowed by water and dried to furnish of 6-acetamidochrysene
(1.160 g, 98%).
4.1.2. 12-Nitro-6-acetamidochrysene (3)
To 6-acetamidochrysene (0.5 g, 1.7 mmol) in dry dichloro-
methane (5 mL), cooled to 0 ꢂC with ice bath was added concen-
trated nitric acid (1 mL) and the mixture was allowed to stir
overnight at room temperature. On completion of the reaction as
indicated by TLC, the mixture was diluted with dichloromethane
(50 mL), washed with saturated NaHCO3 (25 mL) and water
(25 mL). The solvent was then removed and the crude nitro
compound was crystallized (dichloromethane/hexane) to yield 12-
nitro-6-acetamidochrysene (330 mg, 58%).
4.1.7. General procedure for the reduction of the tetramide 7
To a cooled suspension of tetra-amide (0.5 mmol) in dry THF
(150 mL) was added lithium aluminum hydride (3 mmol, 1 M
solution in THF) under argon and the mixture heated to reflux for
21 h under argon. At the end of this time the mixture was cooled
and quenched with saturated solution of sodium sulfate. The
precipitated aluminum hydroxide was filtered and washed with
ethyl acetate. The ethyl acetate layer was washed with water dried
and evaporated under vacuum. Purification by column chroma-
tography over silica gel or alumina gave the tetra-amine.
4.1.3. 12-Amino-6-acetamidochrysene (4)
To a stirred suspension of 12-nitro-6-acetamidochrysene (0.3 g,
0.9 mmol) in ethanol (50 mL) was added 10% Pd/C (133 mg) fol-
lowed by hydrazine monohydrate (0.85 mL) and the mixture was
heated to reflux for 2 h. The mixture was then filtered and the Pd/C
was washed with hot ethanol. After evaporation of the solvent the
residue was extracted with dichloromethane (50 mL) and washed
with water (20 mL). The organic layer was separated, dried over
anhydrous Na2SO4 and evaporated to provide 12-amino-6-acet-
amidochrysene (265 mg, 97% yield).
4.1.8. N,N-(6,12-Chrysenyl)-bis-(4-(1-piperidinyl)-butane)-1,4-
diamine (8a)
4.1.4. 6,12-Diaminochrysene (5)
mp 186e188 ꢂC; IR (film): 3415, 3032, 2930, 2857, 2801, 2763,
2359, 1595, 1521, 1449, 1354, 1274, 1217, 1110, 1042; 1H NMR
(CDCl3): 1.4 (m, 4H), 1.6 (m, 8H),1.8 (m, 8H), 2.4 (m, 12H), 3.4 (t, 4H),
7.6 (m, 6H), 7.9 (d, 2H, J ¼ 8 Hz), 8.65 (d, 2H, J ¼ 8 Hz); Mass: 537,
475, 398, 313, 269, 226, 206, 199, 193, 179, 139; Anal. Calcd for
C36H48N4: C, 80.54, H, 8.9, N, 10.4. Found: C, 80.31, H, 8.80, N, 10.21.
To
a stirred suspension of 12-amino-6-acetamidochrysene
(0.24 g, 0.8 mmol) in absolute ethanol (50 mL) was added conc.
H2SO4 (15 mL) dropwise and the mixture heated to reflux for 1.5 h.
The resulting mixture was poured into ice and neutralized with 50%
NaOH solution. The precipitated diamine was extracted with ethyl
acetate (3 ꢀ 50 mL) and the combined organic layer was dried over
anhydrous Na2SO4. On evaporation of solvent 6,12-diamino-
chrysene was isolated (158 mg, 76%), mp 282 ꢂC.
4.1.9. N,N-(6,12-Chrysenyl)-bis-(4-(4N-methylpiperazinyl)-
butane)-1,4-diamine (8b)
mp 166e168 ꢂC; IR (film): 3383, 2932, 2849, 2798, 1594, 1524,
1452, 1357, 1277, 1225, 1162, 1113, 1048, 1012; 1H NMR (CDCl3): 1.6
(m, 8H), 2.3 (s, 6H), 2.5(m, 20H), 3.5 (t, 4H), 7.6 (m, 6H), 8.0 (d, 2H,
J ¼ 8 Hz), 8.6 (d, 2H, J ¼ 8 Hz); UV: 370, 286, 234; Mass: 567, 531,
313, 304, 284, 263, 230, 216, 206,154, 130; Anal. Calcd for C36H50N6:
C, 76.3, H, 8.9, N, 14.8. Found: C, 76-61, H, 8.88, N, 14.67.
4.1.5. N,N-(6,12-Chrysenyl)-bis-(4-(1-piperidinyl)-butane)-1,4-
dicarboxiamide (7a)
To acid 6 (520 mg, 2.3 mmol) in dry dichloromethane (50 mL) at
0 ꢂC was added triethylamine (0.34 mL, 1.45 mmol) followed by
isobutyl chloroformate (0.3 mL, 1.4 mmol) and the mixture was
allowed to stir at 0 ꢂC for 10 min. To this mixture was added 2,8-
diaminochrysene (190 mg, 0.7 mmol) and allowed to stir overnight
at room temperature. On completion of the reaction, HCl (10%,
50 mL) was added and the organic layer was washed with saturated
4.1.10. Preparation of the salt of the tetramine 8
The hydrochloride salt of the amine 9 was prepared by mixing it
with excess hydrochloric acid solution in ether for 1 h and filteringof

B.K. Banik, F.F. Becker / European Journal of Medicinal Chemistry 45 (2010) 4687e4691
41 (1998) 3748e3752;
4691
the residue (100% yield). The salt was characterized after regener-
(e) R.B. Perni, M.P. Wentland, J.I. Huang, R.G. Powles, S. Aldous, K.M. Klinbeil,
A.D. Peverley, R.G. Robinson, T.H. Corbett, J.L. Jones, K.C. Mattes, J.B. Rake,
S.A. Coughlin, Synthesis and antitumor activity of 4-aminomethyl-
thioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives,
J. Med. Chem. 41 (1998) 3645e3654;
ating the parent amine by basificationeextraction procedure.
Acknowledgments
(f)P.J.Perry, S.M.Gowan, A.P. Reszka, P. Polucci, T.C. Jenkins, L.R. Kelland, S. Neidle,
1,4 and 2,6-Disubstituted amidoanthracene-9,10-dione derivatives as inhibitors
of human telomerase, J. Med. Chem. 41 (1998) 3253e3260.
We gratefully acknowledge the financial support for this project
from NIH/NCI P20CA138022 (BKB) and Cha Family Fund (FFB). We
are also thankful to the shared resources of the pharmacology core
facility of the University of Texas M.D. Anderson Cancer Center.
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31e48.
[9] T.R. Tritton, Cell surface action of adriamycin, Pharmacol. Ther. 49 (1991)
293e309.
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