Synthesis and SOD activity of manganese complexes of substituted pyridino pentaaza macrocycles that contain axial auxiliary

Article abstract of DOI:10.1016/j.bmcl.2010.03.037

New manganese(II) complexes of substituted pyridino pentaaza macrocyclic ligands were prepared. The amino-, carboxy-, or other functional groups were placed in the vicinity of the axial position of the metal complex. Their SOD-like activity was determined

Full text of DOI:10.1016/j.bmcl.2010.03.037

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2421–2424
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SOD activity of manganese complexes of substituted pyridino
pentaaza macrocycles that contain axial auxiliary
*
Hakyoung Lee, Wonchoul Park, Dongyeol Lim
Department of Chemistry, Sejong University, Seoul 143-747, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
New manganese(II) complexes of substituted pyridino pentaaza macrocyclic ligands were prepared. The
amino-, carboxy-, or other functional groups were placed in the vicinity of the axial position of the metal
complex. Their SOD-like activity was determined by cytochrome c assay and compared with one another.
The activities of pyridine analogs (12a–b and 13) and m-substituted analogs (12c and 12j) were similar
and significantly better than that of the standard compound M-40403. The most potent compound was
an o-aminobenzoyl derivative 12i, while the o-carboxybenzoyl analog 12d was the lowest active
compound.
Received 1 October 2009
Revised 19 February 2010
Accepted 6 March 2010
Available online 11 March 2010
Keywords:
Manganese
SOD mimic
Pentaaza
Ó 2010 Elsevier Ltd. All rights reserved.
Macrocycle
Reactive oxygen species (ROS), such as the superoxide radical
anion (O2ꢀꢁ) and hydrogen peroxide (H2O2), can be generated from
cellular metabolism in aerobic organisms. The imbalance between
ROS production and elimination is implicated in many diseases and
aging, while the overproduced ROS have been shown to oxidize
various biomolecules, including DNA, proteins, and lipids, which
can cause various forms of damage to cells and tissues. Therefore,
antioxidant materials have been considered as therapeutic agents
for a variety of disorders, including ischemia-reperfusion injuries,1
arthritis,2 stroke,3 Parkinson’s disease,4 ALS (Lou Gehrig’s disease),5
and cancer,6 in which ROS play a significant role. So far, many
mimetics of antioxidant enzymes such as superoxide dismutases
(SODs) or catalases have been developed7 and tested in vivo.8 Such
catalytic mimetics of antioxidant enzymes include manganese(III)
and iron(III) porphyrin complexes,9 manganese(II) complexes of
penta-azamacrocycles,10 manganese(II) complexes that centered
on tripodal ligands,11 manganese(III) salen complexes,12,8c and
the tetra-aza[14]annulene-Fe(III) complex.13
phan drug designation for the prevention of radiation or chemo-
therapyÙinduced oral mucositis in cancer patients.
In this Letter, an efficient synthesis and manganese complexes
of new pyridino pentaaza macrocycles that have aminophenyl sub-
stitutent on the pyridine ring (Fig. 1) are described. Their SOD-like
activity was determined via cytochrome c assay and compared
with that of the standard compound, M-40403.
From the conformational analysis of the new ligand, it was ex-
pected that the functional group on the ortho position of the phe-
nyl auxiliary could be positioned over the plane of the Mn complex
via the rotation of biaryl linkage. It was also expected that the cat-
alytic cycle of the superoxide dismutation would be influenced by
the functional group, that is, attached to the R.
The synthesis of the macrocyclic ligands started with the
di(p-methoxybenzyl (PMB)) protected trans-cyclohexyldiamine
1.17 Two N-tosylaziridines were added to the diamine 1 via a ring-
opening reaction in order to produce the bistosyl derivative 2 in
For the Mn(II) complexes of pentaaza macrocycles, Riley et al.
prepared a series of C-substituted 1,4,7,10,13-pentaazacyclopenta-
decane ([15]aneN5) and their corresponding Mn(II) complexes as
their dichlorocomplexes, [Mn([15]aneN5)Cl2].14 Methyl and fuged
cycloalkyl substituents on carbon or pyridino derivatives of the
core structure, [15]aneN5, possess high SOD catalytic activity. In
particular, one of the optimized complexes, M-40403 as shown
in Figure 1, showed in vivo antitumor,15 antiarthritis,10a and
pain-relieving16 activities. Recently, M-40403 has been granted or-
* Corresponding author. Tel.: +82 2 3408 3218; fax: +82 2 462 9954.
E-mail address: dylim@sejong.ac.kr (D. Lim).
Figure 1. Structures of M-40403 and new manganese complexes of pentaaza
macrocyclic derivatives.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.037

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H. Lee et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2421–2424
Scheme 1. Synthesis of protected pentaaza macrocyclic derivative 9.
Scheme 2. Synthesis of tritosylated pyridine derivative.
excellent yield. The cyclization of the bistosyl amide 2 with the tri-
tosylated pyridine derivative 3 was carried out under cesium car-
bonate in dimethylformamide with an 81% yield. This type of
successful macrocyclization that can provide pentaaza macrocyclic
ligands was previously reported.18
The tritosylated pyridine derivative 3 was prepared, as shown in
Scheme2. Thediester of the commerciallyavailable chelidamic acid19
wasfirsttosylatedwitha 98%yield, andthen theproductwasreduced
with sodium borohydride and ditosylated without purification in or-
der to produce the tritosylated pyridine derivative 3.
Following the macrocyclization of 2 as shown in Scheme 1, both
the PMB and tosyl protecting groups of the macrocycle 3 were re-
moved under sulfuric acid to provide the desired macrocycle (85%).
Four Boc groups were introduced on the aliphatic nitrogen atoms
via whole protection of the four secondary amines and a pyridinol
followed by selective removal of the Boc group on the pyridinolic
oxygen, providing the macrocycle 6 with a 92% yield. Replacing
the PMB and tosyl protecting groups with the Boc is necessary
for mild and convenient procedure at the later deprotection step.
The pyridinol derivative 6 was triflated with trifluoromethanesul-
fonic anhydride and the triflate 7 was cross coupled to 2-nitro-
phenylboronic acid via Suzuki reaction20 to provide the biaryl
analog 8. The nitro group in 8 was then converted to amino group
under the Pd/C hydrogenation condition. The direct transformation
of the triflate 7 to the amine 9 by a Suzuki reaction, which was cou-
pled with a 2-aminophenylboronic acid pinacol ester, was prob-
lematic in the purification step.
Derivatization of the amine 9 was performed to incorporate var-
ious pyridine, carboxylic acid, and amine moieties in the pentaaza-
macrocyclic ligand (Scheme 3 and Table 1). For the preparation of
the m,m0-dicarboxybenzanilide 10e, a low yield (36%) was obtained
due to the sluggish hydrolysis of the diacid chloride, which is an
intermediate from the reaction with a benzene triacid chloride.
The nitrobenzanilide derivatives 10f–g were further reduced to
the corresponding aminobenzoyl derivatives 10h–i by using a mix-
ture of Raney Ni and Pd/C as a catalyst. Other conditions, like Raney

H. Lee et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2421–2424
2423
Scheme 3. Derivatization of the protected pentaaza macrocyclic ligand 9.
Table 1
Isolated yields for the derivatization of 9
Product
10a
10b
10ca
10db
10ec
10f
10g
10h
10i
NO2
NH2
NH2
O
O
OH
O
NO2
N
OH
N
OH
R
O
36
OH
Yield (%)
77
96
72
77
95
87
94
88
a
b
c
Isophthaloyl dichloride was used in the reaction and the remaining acid chloride was treated with 0.5 N NaOH solution.
Instead of acid chloride, phthalic anhydride was used in the coupling reaction.
Benzene 1,3,5-triacid chloride was used and the remaining diacid chloride was hydrolyzed with 0.5 N NaOH solution.
R
R
R
Boc
H
O
O
O
N
N
NH
NH
N
Boc
Boc
NH
NH
NH
H
H
Cl
c- HCl/Acetone
1/1
N
N
HN
HN
N
N
MnCl2, MeOH
24~97%
Mn
N
N
N
31~99%
Cl
N
Boc
H
12a~12e
12h~12i
11a~11e
11h~11i
10a~10e
10h~10i
Scheme 4. Boc deprotection and metal complexation of the ligands.
I-
N+
N
H
O
H
O
N
NH
H
H
N
Cl
CH3I, acetone
95%
NH
H
H
Cl
N
N
N
N
Mn
N
Mn
N
Cl
Cl
N
H
N
H
10b
13
Boc
H
N
Boc
Boc
NH2
N
NH2
H
H
i) c-HCl/Acetone
1/1, 86%
Cl
N
N
N
N
N
N Mn
ii) MnCl2, MeOH
88%
N
Cl
N
Boc
H
14
9
Scheme 5. Syntheses of the aminophenyl and N-methyl pyridinium complexes.
Ni, Pd/C or Raney Ni–NaBH4,21 were not efficient for these sub-
strates because they provided a mixture of both the desired prod-
uct and partially reduced hydroxyamino intermediate.
The four Boc protecting groups of the pentaaza macrocycles
10a–e and 10h–i were removed under the HCl/acetone condition
to give new ligands, 11a–e and 11h–i, with 31–99% yields (Scheme
4). The products were then complexed with MnCl2 in MeOH, which
afford new SOD enzyme mimetics, 12a–e and 12h–i, that con-
tained various auxiliary positioned over the plane of the Mn
complex.

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H. Lee et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2421–2424
Table 2
Acknowledgments
SOD-like activities of new compounds
Compound
SOD activitya IC50
,
lM
This work was supported by a grant from Marine Biotechnology
Program funded by Ministry of Land, Transport and Maritime Af-
fairs, Republic of Korea. HRMS (FAB) data were obtained from the
facilities of the Korea Basic Science Institute.
M-40403
12a
12b
12c
12d
12e
12h
12i
2.7 (0.6)
0.58 (0.14)
0.63 (0.09)
0.58 (0.02)
4.7 (1.3)
0.94 (0.26)
0.38 (0.01)
0.59 (0.07)
0.63 (0.07)
2.2 (0.5)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.03.037.
13
14
a
Values are averages of duplicate determinations with pH 7.8, standard devia-
tion is given in parentheses.
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In summary, new manganese complexes of pentaaza macrocyclic
ligands were prepared that bore several functional groups in the
vicinity of the metal site. Their activities were compared with one an-
other. The SOD-like activities of pyridine analogs, 12a–b and 13, and
m-substituted analogs, 12c and 12i, were similar and better than that
of the standard compound M-40403. The most potent compound was
an o-aminobenzoyl derivative 12h, while the o-carboxybenzoyl ana-
log12d wasthecompoundthathadthelowestactivity. Furtherinves-
tigation is needed to understand the effects of the aminobenzoyl
group on the catalytic cycle of superoxide dismutation.
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