ATRA-hydrazonate derivatives and their copper complexes against hormone-dependent (MCF-7), hormone-independent (MDA-MB-231and BT-20) breast cancer and androgen-independent (PC3) prostate cancer cell lines

Article abstract of DOI:10.1016/j.inoche.2012.05.027

Retinoids, the derivatives of vitamin A, are known to exhibit anticancer properties through binding to nuclear retinoic acid receptors (RARs). However, several factors such as high lipophilicity, short half life, associated toxicity and appearance of resistant cells during differentiation therapy has limited their therapeutic potential. Here we report synthesis of aryl/heterocyclic analogs of retinoid trans-2-octenal with and without copper complexation. The biological activity of these novel synthetic compounds was tested against multiple human cancer cell lines: breast cancer cell lines MCF-7, BT-20, MDA-MB-231 and prostate cancer cell line PC-3, all of which differ in their expression of RAR subunits. The retinoid-derivatives were found to be effective in inhibiting the growth of all the cell lines, particularly those that express RAR α. Synthesis of hydrazonate analogs of retinoic acid and their copper conjugation is therefore an effective strategy to design novel anticancer compounds.

Full text of DOI:10.1016/j.inoche.2012.05.027

Inorganic Chemistry Communications 23 (2012) 17–20
Contents lists available at SciVerse ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
ATRA-hydrazonate derivatives and their copper complexes against
hormone-dependent (MCF-7), hormone-independent (MDA-MB-231and BT-20)
breast cancer and androgen-independent (PC3) prostate cancer cell lines
Alok Vyas a, Sommai Patitungkho b, Abeda Jamadar b, Shreelekha Adsule c, Subhash Padhye a,c,
,
⁎
c
c,⁎⁎
Aamir Ahmad
, Fazlul H. Sarkar
a
ISTRA, Department of Chemistry, Abeda Inamdar College, Azam Campus, Pune 411001, India
Department of Chemistry, University of Pune, Pune-411 007, India
b
c
Karmanos Cancer Institute, Wayne State Medical School, Detroit, MI-48201, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Retinoids, the derivatives of vitamin A, are known to exhibit anticancer properties through binding to nuclear
retinoic acid receptors (RARs). However, several factors such as high lipophilicity, short half life, associated
toxicity and appearance of resistant cells during differentiation therapy has limited their therapeutic potential.
Here we report synthesis of aryl/heterocyclic analogs of retinoid trans-2-octenal with and without copper com-
plexation. The biological activity of these novel synthetic compounds was tested against multiple human cancer
cell lines: breast cancer cell lines MCF-7, BT-20, MDA-MB-231 and prostate cancer cell line PC-3, all of which dif-
fer in their expression of RAR subunits. The retinoid-derivatives were found to be effective in inhibiting the
growth of all the cell lines, particularly those that express RAR α. Synthesis of hydrazonate analogs of retinoic
acid and their copper conjugation is therefore an effective strategy to design novel anticancer compounds.
© 2012 Elsevier B.V. All rights reserved.
Received 25 January 2012
Accepted 15 May 2012
Available online 5 June 2012
Keywords:
All-trans retinoic acid (ATRA)
Copper complex
Breast cancer
Prostate cancer
Retinoids are natural or synthetic derivatives of vitamin A, which are
small lipophilic molecules capable of modulating cell differentiation,
proliferation and exerting antitumoral activities through interaction
with specific nuclear receptors and activating or down regulating
certain gene expressions [1,2]. Retinoids have been known to possess
additional therapeutic benefits such as inhibition of inflammation, kera-
tinization, and cell growth [3]. They bind to nuclear retinoic acid recep-
tors, (RARs) and retinoid X receptors (RXRs), which endows them, with
the observed biological activities [4,5]. The changes in the expression of
these receptors have been shown to be the possible cause of malignant
transformation in human cells [6,7]. Simeone and co-workers have
reviewed the ability of the retinoids, viz; all-trans retinoic acid (ATRA),
9-cis- retinoic acid and N- (4-hydroxyphenyl) retinamide (fenretinide),
in inhibiting cell proliferation and promoting apoptosis in breast cancer
cells [8]. The compounds have also been found to inhibit growth of pros-
tate and ovarian cancers in animal models [9,10].
cytotoxic agents [11–13]. For example, Uslu and co-workers demon-
strated that the combination of ATRA and zoledronic acid, is a strong
inducer of apoptotic related cell death in ovarian cancer cells. The com-
bination therapy significantly induced pro-apoptotic genes such as
tumor necrosis factor receptor super family (TNFRSF), and caspase 4.
Several reports have discussed the in vitro and pre-clinical models of
breast cancer employing MCF-7 cell xenografts, in which ATRA alone
or in combination with Tamoxifen induce apoptosis and arrest cancer
growth, through regulation of multiple signal transduction pathways
[14–16] Recently Ratnam and co-workers have evaluated the efficacy
of adjuvant therapy involving estrogen, tamoxifen and ATRA in estro-
gen sensitive MCF-7, T47D and ZR-75-1 breast cancer cells [17]. Almost
every major retinoid is currently in clinical trial by itself or in combina-
tion with interferons and estrogen antagonists to treat or prevent the
progression of breast cancer [18,19].
Marder and co-workers [20] have recently indicated that structural
modifications in the three sub-units of ATRA can lead to subsequent al-
teration in its binding ability to the RAR and RXR, which in turn can
modulate the antiproliferative potential of synthetic retinoids. A recent
report by Bisceglie et al., describes preparation and characterization of
9-cis-Retinal thiosemicarbazone and its transition metal complexes
which were active against Human leukemic monocyte lymphoma
(U937) cells [21]. One of the most biologically active analog of all-
trans-retinoic acid (ATRA) is 4-[(1E)-2-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydro-2-naphthalenyl)-1-propen-1-yl] benzoic acid (TTNPB),
which exerts antiproliferative effects against breast cancer [22–25].
Some encouraging reports from the pre-clinical trials have demon-
strated the efficacy of using the combination of retinoids and known
⁎
Correspondence to: S.B. Padhye, ISTRA, Department of Chemistry, Abeda Inamdar
Senior College, University of Pune, Azam Campus, Pune 411001, India. Tel./fax: +91 20
26446970.
⁎⁎ Correspondence to: A. Ahmad, Karmanos Cancer Institute, Wayne State Medical
School, HWCRC Bldg, Room#707, 4100 John R Street, Detroit, MI 48201, USA. Tel.: +1
313 576 8315; fax: +1 313 576 8389.
E-mail addresses: sbpadhye@hotmail.com (S. Padhye), ahmada@karmanos.org
(A. Ahmad).
1387-7003/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2012.05.027

18
A. Vyas et al. / Inorganic Chemistry Communications 23 (2012) 17–20
The major limitation in using ATRA compounds for therapeutic pur-
environment in these compounds [30,31]. The 1H NMR spectra of all
compounds show the proton signal on the azomethine double bond
appearing at around 7.53 ppm while a singlet is observed in range of
9.52–9.75 ppm due the NH proton next to the carboxyl of the hydrazone
ring. Compound L5 shows the hydroxyl peak at 11.84 ppm due to intra-
molecular H-bonding with adjacent hydrazinic carbonyl group.
poses include high lipophilicity, short biological half-life, adverse toxic-
ities and appearance of resistant cells during differentiation therapy.
Some of these can be alleviated by introducing aryl/heterocyclic func-
tionality into the structural motif of trans-2-octenal (1) through
condensation with hydrazides producing highly polar Schiff base li-
gands (Scheme 1). Complexation with redox active transition metal
ions like copper can influence the intracellular redox milieu of the can-
cer cells resulting in selective cytotoxicities towards hormone-
independent cancer cells [26]. In the present communication we have
examined the antiproliferative potential of four ATRA-hydrazonate
derivatives and their copper complexes against hormone-dependent
(MCF-7) as well as hormone-independent (MDA-MB-231and BT-20)
breast cancer cell lines as well as androgen-independent prostate
cancer cell line (PC-3) respectively. Our results indicate that these reti-
noids derivatives are effective in inhibiting the metastasizing cancer cell
lines such as BT-20 and PC-3 and show some specificity towards those
cancer cell lines in which RARα receptor is involved.
The hydrazonate Schiff base ligands employed in the present work
were synthesized in good yields (80–90%) by the condensation reaction
of corresponding retinoidal aldehyde with selected hydrazide in
methanolic solvent using 1:1 stoichiometry. They yield green colored
copper complexes when interacted with CuCl2.2H2O. Their composition-
al analyses indicate a general molecular formula as [M(ligand)(H2O)Cl]
and absence of conductivity in DMSO solvent suggesting a non-
electrolyte nature for them. The parent trans-2-octenal compound (1)
exhibits the carbonyl stretching frequency at 1691 cm−1 which is rep-
laced after the condensation reaction by the imino stretching frequency
at 1637–1657 cm−1 and additional stretches at 945–957 cm−1 due to
hydrazinic N-N and C=O linkages respectively. The appearance of the
ν(N–H) and ν (C=O) stretching vibrations indicate that in the solid
state these ligands essentially exist in the keto form [27]. The broad
band at 1603–1633 cm−1 arises out of the vibrations of the delocalised
(>C=N–N=Cb) linkage [28]. The complexes also display a new band
in the far-infrared region at 355–330 cm−1 which can be assigned to
ν(Cu-Cl) stretching frequencies [29(c)]. Following metal complexation
the imino stretch is shifted to lower wave number whereas the hydra-
zinic N-N band shifts to higher wave numbers indicating participation
of the azomethine group in copper complexation [29]. Free ligands
(L2–L5) exhibit a strong absorption at 284–287 nm attributed to intra-
ligand n-π* transition which undergoes a red shift to 296–302 nm
upon metal complexation due to enolization of the ligand. The additional
broad absorption observed in the visible region 761–935 nm for copper
complexes corresponds to 2B1g→2B2g transition in the square planar
The magnetic susceptibility and EPR data for the complexes C2–C5
are summarized in Table 1. All copper complexes are paramagnetic
having magnetic moments between 1.63 and 1.69 BM indicating
their mononuclear nature. The calculated EPR parameters yielding
the g values g// >g⊥ >ge (2.0023) are consistent with dx2–y2 ground
state in the square-planar geometry for these copper complexes [32].
The Cu+2/Cu+1 reversible redox couple is observed for the present
complexes in the range +0.20 to +0.23 V as shown in Table 1. Addi-
tional peak in the cyclic voltamogram of the parent ligand at – 0.75 V
is due to reduction of the azomethine linkage [33], which is retained
upon metal complexation. The difference potentials (ΔEp=Epc−Epa)
adhere to the Nernstian requirement of 0.059 V while the anodic to
cathodic peak current ratio (ipa/ipc) values are equal to unity for all
copper complexes indicating chemical reversibility of the copper
redox couples. Such reversibility implies stereochemical changes from
square planar copper(II) to tetrahedral copper(I) geometries [34].
These facile interconversions observed for the present complexes
might be of relevance for modulating oxidative stress status of the
cancer cells [35].
When hormone-dependent and independent breast and prostate
cancer cells were treated with DMSO solutions of present retinol an-
alogs and their copper complexes at different concentrations in MTT
assay the heterocyclic hydrazonates were inactive in both cell lines.
In case of aryl hydrazonates the unsubstituted benzoyl derivative L4
and C4 show significant inhibition against hormone-dependent
breast cancer cell line MCF-7 (RARα,β). None of the derivatives
were significantly active against hormone-independent MB-231
(RARγ) as summarized in Fig. 2, while they show promising activity
when screened against metastasizing hormone-independent breast
cancer cells BT-20 (RAR α) and androgen-independent prostate can-
cer PC-3 cell line(RAR α,γ) respectively (Fig. 1). Ligand L4 and its cop-
per conjugate C4 showed significant activity lending support to our
earlier observation that copper is a key metal which helps in enhanc-
ing the biological activity [36,37]. Since the present retinoid deriva-
tives proved to be more efficient in case of metastasizing cancer
cells which contain RARα receptor and the hormone-responsive
MCF-7 breast cancer cells in which RARα,β is involved, it leads us to
believe that they are more specific towards RARα receptors.
Scheme 1. General synthetic scheme for preparation of trans-2-octenal hydrazones (L2–L5) and their copper complexes (C2–C5).

A. Vyas et al. / Inorganic Chemistry Communications 23 (2012) 17–20
19
Table 1
X-band ESRa and electrochemicalb data for copper complexes (C2–C5).
Compound
X-band ESR parameters
Electrochemical data
Epc(V)
g//
g
A// (G)
mT
f (cm)
Epa(V)
E1/2
ΔEp
ipa/ipc
x 10−4 cm−1
C2
C3
C4
C5
2.29
2.28
2.27
2.24
2.05
2.09
2.06
2.05
15.9
17.0
13.6
13.3
169
180
144
139
134
126
157
161
+0.15, −0.69
+0.18, −0.75
+0.25, −0.91
+0.17, −0.93
+0.25
+0.25
+0.38
+0.23
+0.20
+0.22
+0.32
+0.20
0.10
0.07
0.13
0.06
0.93
1.00
1.00
0.96
a
At 77 K.
At 298 K in DMSO.
b
The present work has shown that copper conjugation of trans-2-
octenal hydrazones is a promising strategy for evolving effective antican-
cer agents against hormone -dependent as well as hormone-independent
breast and prostate cancers. Although no clear cut trends in the prefer-
ences of sub-set receptor selectivity can be seen with present compounds,
compound C4 seems to be RARα, β subtype-selective agent and thus
shows high sensitivity to both human hormone-dependent and
hormone-independent breast cancer cell lines as well as androgen-
independent human prostate cancer cell line.
Conflict of interest
The authors declare no conflict of interest.
Appendix A. Supplementary material
Fig. 1. Cell growth inhibition by trans-2-octenal benzoyl hydrazonate L4, trans-2-octenal
salicylic hydrazone L5 and their copper conjugates (C4–C5) against human prostate
cancer (PC-3) cell line.
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.inoche.2012.05.027.
Fig. 2. Antiproliferative effects of trans-2-octenal hydrazones (L4–L5) and their copper conjugates (C4–C5) against BT-20 (RARα), MCF-7 (RARα,β), MDA-MB-231 (RARγ) cancer
and MCF10A (RARα,β,γ) normal breast cells lines and their specificities of inhibition against retinoid receptor subtypes.

20
A. Vyas et al. / Inorganic Chemistry Communications 23 (2012) 17–20
synthesis, characterization and DNA interaction studies, Eur. J. Med. Chem. 42
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