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S. Wang et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 117–121
Fig. 1. Structures of iron chelators for clinical anticancer treatment.
the antiproliferative activity was probably produced by the chelat-
ing effect on the extracellular pool of iron.10 More recently, a
promising iron depletion agent, triapine (Fig. 1) has shown remark-
able antitumor activity on several types of cancers in clinical tri-
als.14 And combined with a range of chemotherapeutics, triapine
has also demonstrated promising results in several phase II clinical
trials.15
During the past few years, 1,4,7-triazacyclononane (TACN)
derivatives have attracted our attention, such as NETA, and its
bifunctional version C-NETA (Fig. 2).16 The origin of interest in
the macrocycle TACN was from the property that TACN can coordi-
nate facially to Fe3+ with the metal lying out of the plane defined
by three nitrogen atoms to form exclusively five-membered che-
late rings. Therefore, TACN appears to be an excellent basic plat-
form to start with for the development of novel iron chelators as
antitumor agents. In this study, a class of TACN-based chelators,
HE-NO2A, HP-NO2A and NE2P2A, as well as the bifunctional ver-
sions of C-NETA, p-NO2-PhPr-NE3TA and p-NH2-PhPr-NE3TA
(Fig. 2) were synthesized. Antiproliferative activity of the above
chelators together with reported chelators C-NETA was evaluated
against HepG2 cancer cells in vitro.
The structures of TACN-based chelators HE-NO2A, HP-NO2A,
NE2P2A, C-NETA, p-NO2-PhPr-NE3TA and p-NH2-PhPr-NE3TA are
shown in Fig. 2. Previously, we reported the synthesis of HE-
NO2A and its analogue HP-NO2A, both of which featured a TACN
platform combining with one hydroxypyridinonate and two car-
boxylic acid pendant arms.17 Recently, a new bifunctional version
of C-NETA, denoted as p-NO2-PhPr-NE3TA, was designed and syn-
thesized in our laboratory.18 Both C-NETA and p-NO2-PhPr-NE3TA
possess a nitro group which can be further converted to an amino
(NH2) or isothiocyanate (NCS) group for conjugation with a recep-
tor-targeting molecule. In particular, p-NO2-PhPr-NE3TA contains a
p-nitro-phenylpropyl group on nitrogen in the pendant arm, and
the long propyl chain in the structure was designed to reduce
potential steric hindrance during the formation of iron complex.
And p-NO2-PhPr-NE3TA possesses seven coordinating groups,
which may be more effective in binding to the hexacoordinate iron
than eight coordination groups in C-NETA. In current study, ligand
Fig. 2. Structures of TACN-based iron-depleting antitumor agents.
amount of 2-aminoethanol in the presence of triethylamine (TEA)
in MeCN gave N-p-nitro-phenylpropyl ethanol amine 2. Subse-
quently, compound 2 was alkylated by tert-butyl bromoacetate
to provide 3, which was further reacted with N-bromosuccinimide
(NBS) and triphenylphosphine (PPh3) to yield corresponding bro-
mide 4. The crucial intermediate 6 was obtained in the coupling
reaction of 4 and 5, which was isolated by column chromatography
in good yield (63.2%). The tert-butyl groups in precursor 6 were
then successfully removed by treatment with trifluoroacetic acid
(TFA) in methylene dichloride (DCM) to afford desired chelator p-
NO2-PhPr-NE3TA (7) in an excellent yield (99.0%). Reaction of
intermediate 6 in 10% Pd/C in methanol under H2 gas at room tem-
perature provided the aniline 8, which was then subjected to
deprotection of tert-butyl groups, thereby affording the desired
chelator p-NH2-PhPr-NE3TA (9) in 93.5% yield.
Chelators synthesized above are based on the TACN derivatives
with acetate pendant arms. However, little has been explored for
other suitable pendent donor groups which is one of the decisive
factors determining the effectiveness of iron chelator.19 Recently,
many reports indicate that replacing carboxylate pendant arms
in chelators with phosphonate pendant arms can accelerate the
metal-binding kinetics.20 In this context, the di-methylphospho-
nate pendant armed TACN derivative NE2P2A was designed and
synthesized. Particularly, NE2P2A contains an additional carboxy-
late pendant arm in combination with TACN platform which is
similar with the coordination groups in DTPA, thus promoting to
form stable complexes with iron in fast thermodynamic kinetics.
An efficient and convenient synthetic route of NE2P2A was devel-
oped as illustrated in Scheme 2. The key step is the coupling reac-
tion of the fragment 11 with 12 in the presence of anhydrous
K2CO3 in MeCN to yield crucial intermediate 13.21 Fragment 11
was synthesized according to a known procedure as reported pre-
viously.22 Briefly, reaction of 2-aminoethanol with excess amount
of benzyl bromoacetate in the presence of anhydrous KHCO3 in
dimethyl formamide (DMF) gave the dialkylated product 10, which
was subsequently converted to bromide 11. A coupling reaction of
11 with 12 gave intermediate 13 in 39.1% yield. The ethyl and ben-
p-NO2-PhPr-NE3TA was synthesized according to
a reported
method with slight modification.18 In the meantime, the reduction
version of p-NO2-PhPr-NE3TA, denoted as p-NH2-PhPr-NE3TA, was
also prepared.
As shown in Scheme 1, the key step for the preparation of the
target ligands p-NO2-PhPr-NE3TA and p-NH2-PhPr-NE3TA is the
coupling reaction of fragment 4 with 5 in the presence of anhy-
drous K2CO3 in acetonitrile (MeCN).17 Specifically, fragment 4
was prepared starting from commercially available material 1-(3-
bromopropyl)-4-nitrobenzene (1). Reaction of
1 with excess