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Organic & Biomolecular Chemistry
Page 2 of 6
DOI: 10.1039/C7OB02529G
COMMUNICATION
Journal Name
From a mechanistic point of view, IDO1 inhibitors can kill
cancer cells by restoring immune recognition and enhancing T
cell immune responses.21 As a single agent, IDO1 inhibitors
generally exhibited modest antitumor activities in preclinical
studies.4,
22
Therefore, the combination of IDO1 inhibitor-
based immunomodulation with chemotherapy, radiotherapy
and/or immunotherapy, may be a promising strategy against
an array of human cancers.23,
24
Numerous studies have
suggested that the efficacy of traditional cancer
chemotherapies were improved by concomitant
administration of an IDO1 inhibitor.22,
In mouse tumor
25
Fig. 2 Design of dual IDO1- and DNA- targeting agents.
models, 1-MT displayed remarkable synergism with various
chemotherapeutic (e.g. platinum compounds, taxane
derivatives and cyclophosphamide) without increased
toxicity.22, 26
The synthetic route of hybrid compounds 17 and 18 is
outlined in Scheme 1. Starting from commercially available 1-
and 2-nitro-1H-indole 6a and 6b, they were transformed to 5-
and 6-nitrogramine 7a and 7b by the Mannich reaction, which
reacted with diethyl acetamidomalonate in the presence of
NaOH and toluene to give 8a and 8b. Intermediates 10a and
The
alkylating
antitumor
agents,
including
cyclophosphamide, chlorambucil and melphalan, are widely
used as first line treatment for various cancers in clinic.27-29 On
the basis of the synergistic antitumor effects between IDO1
inhibitors and nitrogen mustards, we envisioned that dual
IDO1 and DNA targeting agents might take advantages of
immune checkpoint therapy and chemotherapy, which could
enhance the anticancer efficacy and reduce systemic toxicity.
10b were obtained by monomethylation of 8a and 8b
,
affording 9a and 9b, which were subsequently saponifed and
decarboxylated under the alkaline condition. Then, after
hydrolysis under the acid condition, 5- and 6-nitro-1-methyl-
tryptophan 11a and 11b were obtained. Followed by
esterification, Boc protection and catalytic reduction,
intermediates 14a and 14b were afforded, which were reacted
with excessive ethylene oxide, and subsequently treated with
POCl3 in the presence of CHCl3 to give nitrogen mustards 16a
and 16b. Finally, deprotection and hydrolysis of 16a and 16b
with 2M HCl under the reflux condition gave the target
The anticancer ability and systemic toxicity of melphalan (5)
is ascribed to the extent of its interstrand cross-linking with
DNA. In consideration of low toxicity of aromatic nitrogen
mustard, we introduced the alkylating pharmacophore N,N-
bis(2-chloroethyl)-amine to the C1- or C2- position of 1-MT (4)
using the pharmacophore fusion strategy (Fig. 2). As a result,
two novel hybrids of 1-MT-bearing nitrogen mustards were
designed and synthesized, which showed potent in vivo
antitumor activity.
compounds 17 and 18
.
Scheme 1. Synthesis of compounds 17 and 18a
O
OH
COOC2H5
NHCOCH3
COOC2H5
COOC2H5
NHCOCH3
COOC2H5
R1
R1
R2
R1
R1
R2
C
R1
R2
N
C
O
d
a
b
c
HN
R2
R2
N
N
N
H
N
N
H
H
7a: R1 = NO2, R2 = H
10a: R1 = NO2, R2 = H
6a: R1 = NO2, R2 = H
8a: R1 = NO2, R2 = H
9a: R1 = NO2, R2 = H
7b
10b
: R1 = H, R2 = NO2
6b
: R1 = H, R2 = NO2
: R1 = H, R2 = NO2
8b
9b
: R1 = H, R2 = NO2
: R1 = H, R2 = NO2
O
O
i
O
O
O
O
R1
OH
f
R1
R2
O
R1
R1
h
g
e
HN
Boc
HN Boc
NH2
NH2
R2
R2
R2
N
N
N
N
13a: R1 = NO2, R2 = H
14a: R1 = NH2, R2 = H
14b
11a: R1 = NO2, R2 = H
12a: R1 = NO2, R2 = H
12b
: R1 = H, R2 = NO2
13b
: R1 = H, R2 = NO2
: R1 = H, R2 = NH2
11b
: R1 = H, R2 = NO2
O
O
O
O
OH
O
R1
R1
R1
j
k
NH2
HN Boc
HN Boc
R2
R2
R2
N
N
N
15a: R1 = N(CH2CH2OH)2, R2 = H
15b
16a: R1 = N(CH2CH2Cl)2, R2 = H
16b
17: R1 = N(CH2CH2Cl)2, R2 = H
18
: R1 = H, R2 = N(CH2CH2Cl)2
: R1 = H, R2 = N(CH2CH2OH)2
: R1 = H, R2 = N(CH2CH2Cl)2
aReagents and Conditions: (a) Dimethylamine, formaldehyde, AcOH, 30 min, 0 oC; 3 d, rt; 15% aq. NaOH solution, 0 oC, yield 73%;
(b) Diethyl acetamidomalonate, NaOH, PhMe, 110 C, 10 h, yield 64%; (c) MeI, NaH, DMF, rt, overnight, yield 77%; (d) 4% aq.
o
o
NaOH solution, EtOH, N2, 76 C, 6 h; (e) 6M aq. HCl solution, reflux, 10 h, two steps yield 76%; (f) SOCl2, EtOH, reflux, 6 h, yield
93%; (g) (Boc)2O, Et3N, DCM, rt, overnight, yield 95%; (h) Pd/C, H2, Ethyl acetate, rt, overnight; (i) Ethylene oxide, MeOH, rt,
overnight, two steps yield 95%; (j) POCl3, CHCl3, 60 oC, 3 h; (k) 2M aq. HCl solution, reflux, 2.5 h, two steps yield 73-80%.
2 | J. Name., 2012, 00, 1-3
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