The synthesis of 5-functional 3-hydroxypyridin-4-ones and their impact on the chelating properties of the ligands

Article abstract of DOI:10.1246/cl.141133

The presence of the 5-functional group on 3-hydroxypyridin-4-ones (HPOs) can significantly change their chelating properties because the 5-position is adjacent to one of the chelating moieties. A 5-methoxy-substituted HPO has been successfully synthesized using a 5-bromo analogue with NaOMe in the presence of a copper(I) catalyst. The atomic charges and stability constants of the HPOs with either electron-donating or election-withdrawing groups on the 5-position were compared. The result showed that the 5-substituted HPOs possess lower stability constants, compared to those of the 5-unsubstituted analogue (deferiprone).

Full text of DOI:10.1246/cl.141133

Received: December 19, 2014 | Accepted: January 21, 2015 | Web Released: January 31, 2015
CL-141133
The Synthesis of 5-Functional 3-Hydroxypyridin-4-ones and Their Impact
on the Chelating Properties of the Ligands
1
1
1
2
Yu-Lin Chen, Jing Chen, Yongmin Ma,* and Robert C. Hider
College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P. R. China
Department of Pharmacy, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
1
2
(
E-mail: yongmin.ma@zcmu.edu.cn)
The presence of the 5-functional group on 3-hydroxypyr-
idin-4-ones (HPOs) can significantly change their chelating
properties because the 5-position is adjacent to one of the
chelating moieties. A 5-methoxy-substituted HPO has been
successfully synthesized using a 5-bromo analogue with NaOMe
in the presence of a copper(I) catalyst. The atomic charges and
stability constants of the HPOs with either electron-donating or
election-withdrawing groups on the 5-position were compared.
The result showed that the 5-substituted HPOs possess lower
stability constants, compared to those of the 5-unsubstituted
analogue (deferiprone).
Cl
OCH3
OR3
Br
OR3
R2
Br
c
N
N
R2
6
7
d
b
O
O
O
OR3
R2
OR3
R2
OR3
R2
MeO
a
Br
f
N
H
N
H
N
H
5
4
8
2
3
R
R
= Me or Et
= Me or Bn
e
e
O
O
O
Br
OR3
R2
MeO
OR3
R2
MeO
OH
f
g
N
1
N
N
The influence of 3-hydroxypyridin-4-ones (HPOs) has been
1
R
9
R
1
widely investigated on systemic iron overload, neurodegener-
10
11
1
2
,3
4
5
6
R = Me or Et
ative disorders, microbial infections, cancer, and diabetes.
Indeed, 1,2-dimethyl-3-hydroxypyridin-4-one (marketed by
Apotex Inc. as Ferriprox , the first orally active chelating
TM
Scheme 1. Synthesis of 5-methoxy HPOs. a) Br2; b) POCl3;
1
c) NaOMe/60 °C; d) NaOMe/110 °C; e) R I/K2CO3; f) NaOMe/
agent) is one of the three drugs used in clinics for the treatment
1
2
3
CuBr/DMF/110 °C; g) H2/Pd-C (R = R = Me, R = Bn).
7
of iron overload diseases. The optimization of HPO structures
is still required to maximize their activity and to minimize their
toxicity for different applications. Various substitutions on the
convenient use as a good leaving group. Bromine was success-
fully introduced to the C5 position of the pyridinone by adding
molecular bromine dropwise to 3-hydroxy-protected pyridinones
4. The attempted direct methoxylation of the resulting 5-bromo
compounds 5 to the methoxy derivative, by treatment with
sodium methoxide under reflux conditions, failed. This may be
due to the effect of the 4-oxo group on the substitution reaction.
Compound 5 was then treated with POCl3 to form 4-chloro
compound 6. This compound was further reacted with sodium
methoxide at 60 °C to afford 4-methoxy-monosubstituted pyr-
idine derivative 7. At this stage, 4-chloro rather than 3-bromo
was substituted as the halide at the para-position of pyridine is
more easily substituted. When the resulting 5-bromo-4-methoxy
compound 7 was reacted with sodium methoxide in dimethyl-
formamide (DMF) at 110 °C, the desired 4,5-dimethoxy deriv-
ative was not achieved. Instead, compound 5 was the isolated
product (Scheme 1).
HPO ring can significantly change their properties.8
­16
The
synthesis of hundreds of HPO analogues has been reported for
the last thirty years, with substitution mainly located on the 1- or
,10,15
2
-positions of the HPO ring.8
Only a few reports focus on
the synthesis of 5- or 6-substituted HPOs. 5-Substituted HPOs
are of great interest, although the 5-position has much lower
reactivity compared with the 2-position.17 The 5-substituent can
significantly influence the chelating properties of the HPOs
because the position is adjacent to one of the chelating moieties
(4-oxo). In this study, the synthesis of a 5-methoxy-substituted
HPO is described. In combination with our previous reports on
8
18
14
the 5-unsubstituted (1), 5-methyl (2), and 5-fluoro (3) HPO
analogues (Chart 1), their chelating properties and calculated
1
9
CHelpG atomic charges were compared.
The synthetic procedure employed for the desired products
is summarized in Scheme 1. To introduce a methoxy group on
the C5 position, the C5­H requires to be halogenated first.
Bromine was selected as the halogenated reagent because of its
We then attempted to use a catalyst in order to facilitate the
methoxylation reaction. Copper(I) halides have been reported to
be capable of catalyzing the reaction of nonactivated heteroaryl
2
0,21
O
halides with alkoxide.
When the methyloxylation reaction of
R
OH
compound 5 was repeated with sodium methoxide/DMF in the
presence of copper(I) bromide (10%) at 110 °C, the desired 5-
methoxy-substituted derivative 8 was afforded in a good yield
N
(
70%). When compound 8 reacted with alkyl iodide in the
1
2
3
R=H
presence of K2CO3, because of the presence of two tautomeric
forms of compound 8, methanol was selected as the solvent,
which prefers more polar form pyridine-4(1H)-one to pyridine-
4-ol. After this treatment, only the 1-alkyl derivative 10 was
R=Me
R=F
Chart 1.
Chem. Lett. 2015, 44, 515–517 | doi:10.1246/cl.141133
© 2015 The Chemical Society of Japan | 515

(
a)
(b)100
0
0
0
0
0
0
0
.700
2
LH
2
LH
L
.600
.500
.400
.300
.200
.100
11
80
60
40
20
0
.0
0
250
270
290
310
330
2
6
pH
10
Wavelength/nm
(
c)1
(d)100
.00
.80
.60
.40
.20
8
.5
FeL
FeL2
FeL3
Figure 2. CHelpG atomic charge colors and labels of the
deprotonated compound 11. The more intensively red the color,
the more negative charge; the more intensively green the color,
the more positive charge; the calculated CHelpG atomic charge
numbers are presented in Table 1.
0
0
0
0
80
60
40
20
0
Table 1. Calculated CHelpG atomic charge of the deprotonated
compound 11
1
Labela
Atomic charge
Labela
Atomic charge
0
.0
450
550
650
750
850
1
3
5
pH
7
9
Wavelength/nm
1N
¹0.005
¹0.194
0.282
0.337
0.116
¹0.291
¹0.675
¹0.602
¹0.409
0.046
12C
13H
14H
15H
16H
17H
18H
19H
20H
21H
22H
0.306
0.149
0.020
2C
3C
4C
5C
Figure 1. UV­vis spectra and corresponding speciation plots for
compound 11. (a), (b): the UV­vis spectra and corresponding
speciation plots for pure ligand when [L] = 959.4 ¯M over the
pH range 2­11; (c), (d): the UV­vis spectra and corresponding
0.017
¹0.003
¹0.095
¹0.035
¹0.087
¹0.077
¹0.010
¹0.052
3
+
6C
7O
speciation plots for ligand in the presence of Fe when [L] =
07.2 ¯M and [Fe3 ] = 41 ¯M over the pH range 1­8.5.
+
4
8
9
O
O
obtained. Alternatively, compound 10 can also be achieved via
the alkylation of compound 5 to form intermediate compound 9,
followed by substitution with NaOMe/CuBr. Compound 10
10C
11C
0.262
aLabels are indicated in Figure 2.
1
2
3
(
R = R = Me, R = Bn) was then hydrogenated to remove the
protecting benzyl group to afford the desired chelator 11, with
no effect on the methoxy group (Scheme 1) (see Supporting
Information for synthetic details).
The UV­vis spectra and corresponding speciation plots for
compound 11 are presented in Figure 1 (see also Supporting
Information). For pKa titration, an isosbestic point at ­ =
O
O
OH
OH
N
N
3
00 nm occurs when the [LH] of compound 11 deprotonates.
+
[LH2] dominates in solution from pH 1 to 3. [LH] dominates in
70%
30%
¹
solution from pH 5 to 8. [L] dominates in solution from pH 11
to 12. The two pKa values (9.90 and 3.36) were determined from
curve fitting analysis of the spectra. For Fe affinity titration,
with a 10:1 molar ratio of L:Fe3+, two isosbestic points occur
in the spectral series: one at ­ = 625 nm, corresponding to the
formation of [Fe L2] and the other at ­ = 525 nm, corre-
sponding to the formation of [Fe L3]. [Fe L ] , [Fe L ] ,
and [Fe L3] dominate in solution from pH 1.2 to 2, pH 3 to 4,
and pH 5 to 8, respectively. The log K1, log ¢2, and log ¢3 values
Figure 3. HPO resonance structures. The percentages of the
resonance structures are from the ref 23.
3+
delocalization. The charge of all the carbon atoms adjacent to
oxygen atoms is positive, the charge of the two carbon atoms
adjacent to the nitrogen atom on the HPO ring is negative, and
the charge of the nitrogen atom is close to neutral.
The physicochemical properties of four different 5-substi-
tuted HPO analogues, compounds 1­3 and 11, are summarized
in Table 2. The stability constants of compounds 1, 2, and 11
were experimentally determined in this study, while those of
compound 3 were taken from ref 14. In a concise fashion, only
the CHelpG atomic charges of the 6 atoms on the HPO ring
are shown for comparison. Compared to compound 1, there are
3
+
+
3+
3+
2+
3+
+
1
2
3
+
(
14.80, 26.81, and 36.08, respectively) were determined from
3+
curve fitting analysis of the spectra. pFe
(19.13) was
determined through export of the stability constants reported
2
2
above into HySS.
The atomic charges using the CHelpG scheme of compound
1
1 are presented in Figure 2 and Table 1 (see also Supporting
Information). The electron delocalization of HPOs is not simple,
which possess two resonance structures23 (Figure 3). The atomic
charges were calculated to reveal the intramolecular electron
3+
decreases in the 4-pKa, pFe , and C2/C4/C6 atomic charges
while there is a significant increase in the C5 atomic charge for
compounds 2, 3, and 11.
516 | Chem. Lett. 2015, 44, 515–517 | doi:10.1246/cl.141133
© 2015 The Chemical Society of Japan

a
Table 2. Experimental stability constants and CHelpG atomic charges on HPO ring atoms of compounds 1­3 and 11
O
R5
OH
N
R5
4-pKad 3-pKae Sum-pKa log K1 log ¢2 log ¢3 pFe3+ g
f
N1
C2
C3
C4
C5
C6
b
b
c
Compound 1
Compound 2
Compound 3
­H
­CH3
­F
3.61
3.37
2.24
3.36
¹0.24
9.83
10.32
9.08
9.90
0.49
13.44
13.69
11.32
13.26
0.25
15.01 27.39 37.35
15.51 28.12 37.93
13.60 24.60 33.00
14.80 26.81 36.08
20.59
19.71
0.028 ¹0.167
0.035 ¹0.184
0.249
0.268
0.242
0.282
0.560 ¹0.394 ¹0.170
0.425 ¹0.114 ¹0.334
18.50 ¹0.011 ¹0.182
19.13 ¹0.005 ¹0.194
0.408
0.337
0.098 ¹0.314
0.116 ¹0.291
0.280 ¹0.164
0.492 ¹0.144
0.510 ¹0.121
b
Compound 11
­OCH3
2
3
minus 1
minus 1
0.50
0.73
0.58 ¹0.88
0.007 ¹0.017
0.019 ¹0.135
¹1.37 ¹0.75
¹0.25 0.07
¹2.12
¹0.18
¹1.41 ¹2.79 ¹4.35 ¹2.09 ¹0.039 ¹0.015 ¹0.007 ¹0.152
¹0.21 ¹0.58 ¹1.27 ¹1.46 ¹0.033 ¹0.027
11 minus 1
0.033 ¹0.223
a
b
c
The labels are the same as those in Figure 2. The experimental stability constants are determined in this study. The experimental stability constants are
d
e
f
from ref 14. 4-pKa is the pKa value of the 4-oxygen of HPO. 3-pKa is the pKa value of the 3-oxygen of HPO. Sum-pKa is the sum of 4-pKa and 3-pKa
values. ¹log[free Fe ] when [ligand]total = 10 M and [Fe ]total = 10 M at pH 7.4.
g
3+
¹5
3+
¹6
The (Fe3 ) log K or ¢ values are directly correlated with the
+
M. A. Santos, Front. Biosci. 2008, 13, 6763.
sum-pKa values (4-pKa plus 3-pKa) and the N1 atomic charges
3
M. Pandolfo, L. Hausmann, J. Neurochem. 2013, 126
(Suppl s1), 142.
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J. B. Porter, G. Xiao, D. van der Helm, J. Med. Chem. 1993, 36,
3+
apparently follow in a similar fashion. In contrast, the pFe
value possesses a more complicated relationship with the pKa
4
5
3
+
and (Fe ) log K or ¢ values. For instance, compound 1
possesses the highest pFe3 value, although compound 2
+
3
+
possesses the highest 3-pK value and (Fe ) log ¢3 values.
a
6
From a sum-pKa perspective, the value is increased by 5-methyl
but is decreased by 5-methoxy and 5-fluorine, compared to 5-
hydrogen. From an individual pK perspective, the 3-pK values
7
8
a
a
were increased by the presence of 5-methyl or 5-methoxy but
decreased in the presence of 5-fluorine. The 4-pKa values were
decreased for all three functional groups. This can be associated
with the fact that all three functional groups significantly raise
the C5 atomic charge, which collaterally reduces the adjacent C4
and C6 atomic charges, compared to 5-hydrogen. Obviously, 5-
fluorine is classified as an electron-withdrawing group, which
reduces all the stability constants reported here, compared to
2
448.
9
1
M. D. Habgood, Z. D. Liu, L. S. Dehkordi, H. H. Khodr, J.
Abbott, R. C. Hider, Biochem. Pharmacol. 1999, 57, 1305.
0 Z. D. Liu, R. Kayyali, R. C. Hider, J. B. Porter, A. E. Theobald,
J. Med. Chem. 2002, 45, 631.
11 Z. D. Liu, H. H. Khodr, D. Y. Liu, S. L. Lu, R. C. Hider, J. Med.
Chem. 1999, 42, 4814.
5-hydrogen. In contrast, 5-methyl is classified as an electron-
1
1
1
1
1
2 Z. D. Liu, S. Piyamongkol, D. Y. Liu, H. H. Khodr, S. L. Lu,
R. C. Hider, Bioorg. Med. Chem. 2001, 9, 563.
3 Y. Ma, W. Luo, P. J. Quinn, Z. Liu, R. C. Hider, J. Med. Chem.
donating group, which increases the most of stability constants
reported here, with the exception of the 4-pKa and pFe3 values,
compared to 5-hydrogen. Although 5-methoxy is classified as
an electron-donating group, it reduces the stability constants
compared to 5-hydrogen. Interestingly, all 5-substituted HPOs
studied here possess lower pFe3 values than deferiprone
+
2
004, 47, 6349.
4 Y. Ma, S. Roy, X. Kong, Y. Chen, D. Liu, R. C. Hider, J. Med.
Chem. 2012, 55, 2185.
5 B. L. Rai, L. S. Dekhordi, H. Khodr, Y. Jin, Z. Liu, R. C. Hider,
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6 B. L. Rai, Z. D. Liu, D. Y. Liu, S. L. Lu, R. C. Hider, Eur. J.
Med. Chem. 1999, 34, 475.
+
(compound 1). This can be associated with the fact that they
possess lower 4-pKa values and significantly higher C5 atomic
charge. This result can be used to manipulate the pFe3 of HPOs
synthesized in the future.
+
1
1
7 Y. M. Ma, R. C. Hider, Tetrahedron Lett. 2010, 51, 1415.
8 Y.-L. Chen, D. J. Barlow, X.-L. Kong, Y.-M. Ma, R. C. Hider,
Dalton Trans. 2012, 41, 6549.
This work was financially supported by the program for the
Zhejiang Leading Team of S&T Innovation (No. 2010R50044-
1
2
2
9 C. M. Breneman, K. B. Wiberg, J. Comput. Chem. 1990, 11,
14).
3
61.
0 M. A. Keegstra, T. H. A. Peters, L. Brandsma, Tetrahedron
1992, 48, 3633.
1 J. Lindley, Tetrahedron 1984, 40, 1433.
Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 515–517 | doi:10.1246/cl.141133
© 2015 The Chemical Society of Japan | 517