H. Choe et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4324–4327
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The preparation of the target compounds is described in
Scheme 1. To facilitate the exploration of an assortment of C2 phe-
nyl group, the direct arylation of chromone was conducted prior to
performing amide coupling. The synthesis commenced with treat-
ment of the commercially available 5,7-dihydroxy-4H-chromen-4-
one (3) with methyl 2-bromoacetate in DMF under basic condi-
tions (Route A). We recently reported a straightforward and prac-
tical method for the oxidative cross-coupling of chromones and
unactivated arenes via palladium-catalyzed twofold C–H function-
alization.8a This general synthetic method offers the direct route
for the C2-selective arylation of chromones. Utilizing the method-
ology, a variety of substituted phenyl groups could be installed to
the C2-position to afford flavone derivatives 5. To build amide
group at C7 acetamide appendage, the resulting ester was con-
verted into the desired products 8 using EDCI/DMAP conditions.
Alternatively, commercially available chrysin (6) was treated with
methyl 2-bromoacetate, followed by hydrolysis with lithium
hydroxide to afford the corresponding carboxylic acid 7 (Route
A). The various (hetero)anilines were then coupled with the car-
boxylic acid to furnish the target compounds 8. The resulting com-
pounds were tested over ABL and ABLT315I to determine the
inhibitory effects, and Table 1 lists the chemical structures and
IC50 values of the representative inhibitors.9 Among the flavone
analogs prepared, six compounds were found to have a good po-
tency against both the wild type and T315I mutant of ABL at the
submicromolar level (Table 1).
H
N
O
O
OH
O
N
O
N
H
NH
O
O
2
1
Figure 1. Chemical structures of inhibitor scaffolds under investigation.
Figure 2. The simplified binding mode of flavones-based inhibitors with the ATP
binding site of ABL and design strategy .
We first studied the effect of the substitution in the C2 phenyl
group on the inhibitory activity. The substituent of the benzene
ring was varied to include methyl, dimethyl, nitro or chloro groups.
Unlike our expectation, the substitution on the C2 aryl ring were
deleterious, exhibiting about 10-fold reduction in potency (IC50
relationship (SAR). For these reasons, compound 1 was selected for
further optimization through in-depth structural modification.
To develop more potent ABL inhibitors, we investigated the
binding forces that are responsible for stabilization of compound
1 in the ATP-binding site of ABL kinase. In effort to enhance binding
affinity, we planned to explore the space nearby the C2 and C7
positions of chromone moiety based on the calculated binding free
energies of the derivatives with respect to the wild-type and T315I
mutant ABL kinase. To identify the most suitable gate keeper re-
gion binder, our initial round of analogs was focused on the incor-
poration of substitution on the C2 phenyl group of chromone core
while fixing the C7 acetamide moiety. The chromone scaffold can
be easily installed with various aryl groups at the C2 position by di-
rect arylation.8 We next focused our design attempts on derivatiz-
ing the C7 acetamide appendage, to assess a glycine rich loop by
installing variously substituted (hetero)arenes. Therefore, our de-
sign strategy prioritized the incorporation of suitable pharmaco-
phores into chromone core at the C2 and C7 positions to
generate new molecules with the expectation of combining high
affinity for ABL kinase (Fig. 2).
>20
group in the phenyl group is tolerated (9, ABL IC50 = 4.31
LT315I IC50 = 1.77
M), which indicated that unsubstituted benzene
lM) when compared with hit compound 1. Only fluoride
l
M; AB-
l
at the C2 position could form favorable van der Waals interactions
with the gatekeeping region without causing steric clash. Interest-
ingly, removal of the 5-hydroxyl group resulted in a loss of activity
(ABL IC50 = 15.2 lM), thus revealing the indispensible nature of the
5-hydroxyl group in maintaining activity in this series.
On the basis of these findings, C2-benzene moiety and C5-hy-
droxyl group were fixed to embark upon in-depth structural mod-
ification in order to optimize activity. We planned to exploit the
extended interactions with P-loop residues by preparing related
series of derivatives. Based on the docking study, it appeared that
the substitution pattern around the pyridyl ring of the C7-acetam-
ide appendage was important to its function. Removal of methyl
group in the pyridyl ring decreased the inhibitory activity, imply-
ing the importance of the methyl group at this region for ABL inhi-
Route A:
O
O
OH
O
O
OH
O
O
R
OH
R1
CO2Me
a
CO2Me
b
O
R1
O
OH
5
4
3
c, d
R2
X
1 = H
O
Route B:
O
OH
OH
O
O
OH
a,c
d
CO2H
NH
O
O
R1
O
OH
O
X = CH or N
R1
R1
O
8
6
7
Scheme 1. Reagents and conditions: (a) methyl 2-bromoacetate, K2CO3, DMF, rt, 3 h, 92–95%; (b) Pd(TFA)2, AgOAc, CsOPiv, PivOH, 100 °C, 30–60%; (c) LiOHÁH2O, THF/H2O
(1:1), rt, 2 h, 95–99%; (d) amine, EDCI, DMAP, CH2Cl2, rt, overnight, 55–70%. See Supplementary data for detail.
Choe, Hyeonjeong
