Development of 1-aryl-3-furanyl/thienyl-imidazopyridine templates for inhibitors against hypoxia inducible factor (HIF)-1 transcriptional activity

Article abstract of DOI:10.1016/j.bmcl.2016.11.009

1,3-Disubstituted-imidazopyridines were designed for developing inhibitors against HIF-1 transcriptional activity. Designed compounds were rapidly synthesized from a key aromatic scaffold via microwave-assisted Suzuki-Miyaura coupling/C[sbnd]H direct arylation sequence. Evaluation of ability to inhibit the hypoxia induced transcriptional activity of HIF-1 revealed that the compound 2i and 3a retained the same level of the inhibitory activity comparing with that of known inhibitor, YC-1 (1). Identified, readily accessible 1-aryl-3-furanyl/thienyl-imidazopyridine templates should be useful for future drug development.

Full text of DOI:10.1016/j.bmcl.2016.11.009

Accepted Manuscript
Development of 1-aryl-3-furanyl/thienyl-imidazopyridine templates for inhib-
itors against hypoxia inducible factor (HIF)-1 transcriptional activity
Shinichiro Fuse, Toshiaki Ohuchi, Yasunobu Asawa, Shinichi Sato, Hiroyuki
Nakamura
PII:
S0960-894X(16)31149-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.11.009
BMCL 24404
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 October 2016
2 November 2016
4 November 2016
Please cite this article as: Fuse, S., Ohuchi, T., Asawa, Y., Sato, S., Nakamura, H., Development of 1-aryl-3-furanyl/
thienyl-imidazopyridine templates for inhibitors against hypoxia inducible factor (HIF)-1 transcriptional activity,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.11.009
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Development of 1-aryl-3-furanyl/thienyl-imidazopyridine templates for
inhibitors against hypoxia inducible factor (HIF)-1 transcriptional activity
Shinichiro Fuse, Toshiaki Ohuchi, Yasunobu Asawa, Shinichi Sato, and Hiroyuki Nakamura*
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of
Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan
*Corresponding author.
e-mail address: hiro@res.titech.ac.jp
Abstract: 1,3-Disubstituted-imidazopyridines were designed for developing inhibitors against HIF-1
transcriptional activity. Designed compounds were rapidly synthesized from a key aromatic scaffold
via microwave-assisted Suzuki-Miyaura coupling/C-H direct arylation sequence. Evaluation of ability
to inhibit the hypoxia induced transcriptional activity of HIF-1 revealed that the compound 2i and 3a
retained the same level of the inhibitory activity comparing with that of known inhibitor, YC-1 (1).
Identified, readily accessible 1-aryl-3-furanyl/thienyl-imidazopyridine templates should be useful for
future drug development.
Keyword: hypoxia inducible factor (HIF)-1, imidazopyridine, C-H direct arylation, microwave
Hypoxia-inducible factor (HIF) 1 is member of the basic helix-loop-helix proteins of the
PER-ARNT-single-minded protein family of transcription factors.1 HIF-1 regulates the expression of
genes involved in angiogenesis, cellular energy metabolism, and cell survival during cancer
development. HIF-1 forms a heterodimer with its oxygene-sensitive HIF-1 and a constitutively
expressed HIF-1 subunits.2 Under aerobic conditions (normoxia), proline residues in HIF-1 are
hydroxylated by prolyl hydroxylase (PHD),3-4 then ubiquitinated by von Hippel-Lindau protein,5-13
and degraded by 26S proteasomes. HIF-1 is also regulated by factor inhibiting HIF (FIH), a HIF
asparagine hydroxylase.14-16 Hydroxylation of transactivation domains of HIF-1 by FIH avoids
interaction of HIF-1with p300/CBP coactivator that leads to the repression of HIF-mediated
transcription activity.17-18 Under low oxygen conditions (hypoxia), ability of the PHD is suppressed
and HIF-1 is stabilized. The resultant HIF-1 forms the heterodimer with its  subunit and
translocates into the nucleus. HIF-1 binds to hypoxia response elements (HREs) and activates several
hundred genes involved in angiogenesis (VEGF), glucose transport (GLUT1), glycolytic pathways
(LDH-A), ROS signals (iNOS), erythropoiesis (EPO) and other processes. Therefore, HIF-1 is
regarded as a promising drug target in cancer chemotherapy19-23 and variety of HIF-1 inhibitors have

been reported.13, 24-30 We have also reported diphenylureas31 and phenoxyacetanilides32-33 as HIF-1
inhibitors.
YC-134 was originally found out as an activator of soluble guanylate cyclase (sGC).35 Park and
co-workers reported an inhibition of transcriptional activity of HIF-1 by YC-1 as well as its mode of
action.36 YC-1 is an attractive template for drug discovery because it can be divided into three
fragments, namely, benzyl moiety, indazole core, and furanyl moiety, and analogues library can be
rapidly constructed by assembling the modified fragments. Previously, we reported the synthesis of 20
YC-1 analogues with modified benzyl moieties and 3 YC-1 analogues with modified furanyl moieties.
Their evaluation of inhibitory ability against HIF-1 transcriptional activity revealed that YC-1
analogues with fluorine-substituted benzyl moieties exerted higher inhibitory ability than that of YC-1
both in vitro and in vivo whereas, modification of the furanyl moiety resulted in decrease of the
inhibitory ability.37
In this paper, we report design and synthesis of YC-1 analogues containing imidazo[1,5-a]pyridine
core instead of indazole core. Structural modification can be readily achieved by rapid, sequential
Pd-catalyzed cross-coupling approach. Total 13 analogues were synthesized and their inhibitory
ability against HIF-1 transcriptional activity was evaluated. We found novel templates 2 and 3
consisting of three fragments, namely, phenyl moiety, imidazopyridine core, furanyl/thienyl moiety
for potent HIF-1 inhibitors (Figure 1).
Figure 1. Chemical structures of YC-1 (1) and novel templates 2 and 3.
In design of new templates, we selected a imidazo[1,5-a]pyridine ring as a core structure. Because
it has common structural features to those of indazole ring as follows: 1) imidazopyridine consists of
bicyclic 5-6 fused ring system; 2) two nitrogen atoms are in the five membered ring; 3) two
substituents can be introduced at the 1 and 3 positions of the core structure. We anticipated that we
could know the influence of the indazole core moiety for HIF-1 transcriptional activity by replacing to
a similar but different core structure.
We first synthesized YC-1 analogue 2a as shown in Scheme 1. 3-Furanyl-imidazopyridine 7 was
constructed in accordance with the procedure reported by Murai and co-workers.38 In detail, thioamide
6 was prepared by coupling between amine 4 and aldehyde 5 in the existence of sulfur. Iodine induced

imidazopyridine ring formation and the following regioselective iodination by
1,3-diiodo-5,5-dimethylhydantoin (DIH) afforded iodoimidazopyridine 8. The following
Suzuki-Miyaura cross-coupling reaction39-40 of 8 with benzylboronic acid afforded coupling product
9a. In a similar manner, various arylboronic acids were reacted with 8 to afford coupling products
9b-9e. The subsequent Vilsmeier-Haack reaction and the reduction of the resultant aldehydes afforded
the desired YC-1 analogues 2a-2e.
Scheme 1. Reagents and conditions: (a) sulfur, DMF, 60 oC, 3 h, 65%; (b) iodine, pyridine, THF, 0 oC
to rt, 40 min, 64%; (c) DIH, DMF, rt, 1 h, 75%; (d) BnB(OH)2, 70 oC or ArB(OH)2, 80 oC, K2CO3,
DME/H2O, 12 h, 9c: 81%, 9d: 69%; (e) POCl3, DMF, 0 oC to rt, 1 h; 10e: 66%, 2 steps from 8; (f)
NaBH4, MeOH, rt, 5 min, 2a: 25%, 3 steps from 8, 2b: 11%, 3 steps from 8. 2c: 61%, 2 steps from 9c,
2d: 33%, 2 steps from 9d, 2e: 67%. DMF: N,N-dimethylformamide; THF: tetrahydrofuran; Bn:
benzyl; DME: 1,2-dimethoxyethane.
We anticipated that the 1,3-diaryl imidazopyridines can be rapidly prepared through sequential
cross-coupling approach. Thus, we decided to synthesize analogues 2 and 3 via Suzuki-Miyaura
coupling/C-H direct arylation sequence from a key aromatic scaffold41-49 12 that can be prepared from
imidazo[1,5-a]pyridine (11) as shown in Scheme 2.

Scheme 2. Sequential Suzuki-Miyaura coupling/C-H direct arylation approach for the synthesis of
YC-1 analogues 2 and 3.
Scheme 3. Reagents and conditions: (a) NIS, THF, 0 oC, 1 h, 12: 75%, 15: 5%, 16; 3.5%; (b) Pd(PPh3)4,
o
K2CO3, 1,4-dioxane, conditions A: reflux, 24 h, 48%, conditions B: 110 C, M.W. 1 h, 49%. NIS:
N-iodosuccinimide; M.W.: microwave.
The key aromatic scaffold 12 was prepared by iodination of imidazopyridine 11 using NIS (Scheme
3). It was important to add NIS solution in THF dropwisely, with maintaining the reaction temperature
at 0 oC for obtaining sufficient selectivity. Lucus and coworkers reported the same iodination reaction
using I2 and NaHCO3 in H2O/EtOH.50 Although we examined the reported conditions, it took longer
reaction time (12 h) and inferior selectivity (12:15:16 = 38:17:10) was observed.
Suzuki-Miyaura coupling of the key aromatic scaffold 12 was examined using boronic acid 17
(Scheme 4). Combinations of Pd sources {Pd(PPh3)4,51 Pd2(dba)352}, ligands {none, [(tBu3P)H]BF4,53
and PCy3∙BF4}, bases (K2CO3, Na2CO3, and K3PO4), and solvents (DME, DMF, 1,4-dioxane, toluene,
and THF) were examined. The use of Pd(PPh3)4 afforded superior results comparing with the use of
Pd2(dba)3. The combination of Pd(PPh3)4 and K2CO3 in 1,4-dioxane at reflux temperature for 24 h

o
afforded the best yield (conditions A: 48%). To our delight, microwave-irradiation (110 C)
accelerated the reaction and aryl iodide 12 was consumed only for 1 h to afford 13a in a comparable
yield (conditions B: 49%).
C-H direct arylation of substituted imidazopyridine 13a with furanyl iodide 18 was examined in
accordance with the previously reported procedure by Gevorgyan (entry 1),54 Murai (entry 2),55 Rossi
57
(entry 3),56 and Doucet (entry 4) as shown in Table 1. Doucet conditions afforded the best result
(30% yield with 24% recovery of 13a). In order to optimize the reaction conditions, combinations of
ligand (PPh3, dppf, PCy3∙BF4, and PivOH), base (TBAOAc, CsOAc, K2CO3, KOAc, and Cs2CO3),
solvent (toluene, DMA, p-xylene, and DMSO) were examined, however, yield was not improved. To
our delight, microwave-irradiation accelerated the reaction (entry 4 vs. entry 5). Lower temperature
and shorter reaction time conditions afforded the desired product 14a in superior yield (entry 5).
Table 1. C-H direct arylation of substituted imidazopyridine 13a with furanyl iodide 18
entry
Pd cat.
ligand additive
base
solvent
temp./time
yield of
14aa
5%
ND*2
ND*2
30%
47%
recovery
of 13ab
46%
ND*2
ND*2
24%
1
2
3
4
5
Pd(OAc)2
[Pd(phen)2](PF6)2
Pd(OAc)2
PPh3
-
TBAOAc toluene
150 oC/12 h
150 oC/12 h
150 oC/12 h
150 oC/12 h
100 oC/1.5 h
(M.W.)
-
-
-
-
-
-
-
DMA
DMA
DMA
DMA
-
Pd(OAc)2
CuI
-
CsOAc
CsOAc
Pd(OAc)2
20%
a Yield was determined by 1H NMR analysis.
b Not detected.
TBA: tetrabutylammonium; phen: phenanthroline; DMA: N,N-dimethylacetamide; M.W.: microwave.
The designed analogues 2 and 3 were rapidly synthesized as shown in Scheme 4.
Microwave-assisted Suzuki-Miyaura coupling of the key aromatic scaffold 12 with six arylboronic
acids were carried out to give desired 3-aryl-imidazopyridines 13a-13f. Microwave-assisted C-H
direct arylation of 13a-13f with 5-iodofuran-2-carbaldehyde or 5-bromothiophene-2-carbaldehyde
and the following NaBH4-mediated reduction afforded the desired 1,3-diaryl-imidazopyridines 2f-2i
and 3a-3c. It should be noted that the developed microwave-assisted sequential coupling approach
allowed us to obtain desired products 2 and 3 at short times (total reaction time: c.a. 2.5 h) from the

key aromatic scaffold 12.
Scheme 4. Reagents and conditions: (a) 5 mol% Pd(PPh3)4, arylboronic acid, K2CO3,
1,4-dioxane/H2O, 110 oC, microwave, 1 h, 13a: 49%, 13b: 39%, 13c: 42%, 13d: 59%, 13e: 56%, 13f:
24%;
(b)
5
mol%
Pd(OAc)2,
5-iodofuran-2-carbaldehyde
for
14a-14d
or
5-bromothiophene-2-carbaldehyde for 15a-15c, CsOAc, DMA, 100 oC, M.W., 1.5 h; (c) NaBH4,
MeOH, rt, 5 min, 2f: 37%, (2 steps from 13a), 2g: 10%, (2 steps from 13b), 2h: 42%, (2 steps from
13c), 2i: 10%, (2 steps from 13e), 3a: 23%, (2 steps from 13d), 3b: 24%, (2 steps from 13e), 3c: 44%,
(2 steps from 13f).
The synthesized YC-1 analogues 2a-2i and 3a-3c were tested for their ability to inhibit the hypoxia
induced transcriptional activity of HIF-1 in HRE (×5)-Luc transfected HeLa cells. YC-1 was used as
the positive control. Replacement of the indazole ring to imidazopyridine ring resulted in decrease of
the inhibitory activity (entry 1 vs. 13). Thus, the indazole core structure of YC-1 was proved to have
positive effect for the inhibitory activity. Interestingly, replacement of benzyl group at the 1-position
of 2a to phenyl group did not significantly influence to the inhibitory activity (entry 1 vs. 2).

Substituents on the 1-aryl group in the 1-aryl-3-furanyl-imidazopyridines significantly influence to the
inhibitory activity. In detail, 2c-2e (entries 3-5) containing electron donating 4-MeOPh, 2-MeOPh,
and 4-MePh groups at the C-1 position of imidazopyridine exerted the same level of inhibitory activity
comparing with that of 2b (entry 2), whereas 2f-2h (entries 6-8) containing electron withdrawing
4-F3CPh, 3,5-(F3C)2Ph, and 4-NCPh groups at the C-1 position exerted higher inhibitory activity. In
particular, it is interesting that the inhibitory activity increased on the order of 2e (4-MeOPh) < 2f
(4-F3CPh) < 2h (4-NCPh), although the steric bulkiness of substituent on the 1-aryl group is similar.
Among the 1-aryl-3-furanyl-imidazopyridines, 2i (entry 9) containing 2-HOCH2Ph group at the C-1
position showed highest inhibitory activity and it was similar level comparing that of YC-1 (1) (entry 9
vs. entry 13). Replacement of 3-furanyl group in 2b to 3-thienyl group enhanced inhibitory activity
(entry 2 vs. entry 10). All three 1-aryl-3-thienyl-imidazopyridines exerted good inhibitory activity
(entries 10-12). In particular, the most potent inhibitor 3a retained similar level of inhibitory activity
comparing that of YC-1 (1) (entry 10 vs. entry 13).
Table 2. Evaluation of HIF-1 transcriptional activity of 1,3-disubstituted-imidazopyridine analogues 2
and 3.
IC50a (M)
56 ± 24
70 ± 6
entry
1
compound
2a
2b
2c
2
3
61 ± 6
4
75 ± 5
2d
2e
5
39 ± 5
6
17 ± 5
2f
7
25 ± 12
7.4 ± 0.6
6.5 ± 4.4
3.7 ± 2.7
9.4 ± 0.3
9.1 ± 3.0
1.2 ± 0.5
2g
8
2h
2i
9
10
11
12
13
3a
3b
3c
YC-1
a
HeLa cells stably transfected with HRE-Luc were incubated for 12 h with or without drugs under
normoxic or hypoxic conditions. After removal of supernatant, luciferase assay was performed using a
Luciferase Assay System (Promega, Madison, WI, USA) according to the manufacturer’s instructions.
The drug concentration required to inhibit relative light units by 50% (IC50) was determined from the
semi-logarithmic dose–response plots, and the results are means ± SD of triplicate samples.

In summary, we designed 1,3-disubstituted-imidazo[1,5-a]pyridines for developing inhibitors
against HIF-1 transcriptional activity. Designed compounds were rapidly (total 2.5 h) synthesized
from a key aromatic scaffold 12 via microwave-assisted Suzuki-Miyaura coupling/C-H direct
arylation sequence. Evaluation of ability to inhibit the hypoxia induced transcriptional activity of
HIF-1 revealed that the compound 2i and 3a retained the similar level of the inhibitory activity
comparing with that of YC-1 (1). The current results enable us to create
1-aryl-3-furanyl/thienyl-imidazopyridines as readily accessible and useful scaffolds not only for
HIF-1 inhibitors but also for future drug development.
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Ar
N
design
N
N
N
O
X
OH
OH
X = O or S
YC-1
known HIF-1 inhibitor
imidazopyridine
template