Biomimetic reduction of nimesulide with NaBH4 catalyzed by metalloporphyrins.

Article abstract of DOI:10.1248/cpb.50.1421

The biomimetic reduction of anti-inflammatory drug, nimesulide (1) with sodium borohydride catalyzed by 5,10,15,20-tetraarylporphyrinatoiron(III) chlorides [TAPFe(III)Cl] has been studied in organic solvents under anaerobic and aerobic conditions.

Full text of DOI:10.1248/cpb.50.1421

October 2002
Communications to the Editor
Chem. Pharm. Bull. 50(10) 1421—1422 (2002)
1421
group to amino group. The presence of two peaks around
3394 and 3339 cmϪ1 in IR spectrum also confirms the forma-
tion of 2. The reduction of nimesulide is directly propor-
tional to the substrate, NaBH4 and iron(III) porphyrin ratio
under N2 atmosphere. As the ratio of iron(III) porphyrin and
NaBH4 is increased to 1 : 1200 mmol the reduction of nime-
sulide has completed within 1 h, whereas the complete reduc-
tion has not taken place even after 24 h with lower ratios of
iron(III) porphyrin and NaBH4. The results are presented in
the Table 1.
Biomimetic Reduction of Nimesulide
with NaBH4 Catalyzed by
Metalloporphyrins
Shive Murat Singh CHAUHAN,*
Srinivas Appan KANDADAI, and Anil KUMAR
Department of Chemistry, University of Delhi; Delhi 110 007,
India. Received April 22, 2002; accepted July 29, 2002
The change of central metal atom of porphyrin from Fe to
Mn, Ni, Co showed lesser catalytic activities than the Fe. The
catalytic ability of metalloporphyrins are found to be in the
following order: TPPFe(III)ClϾTPPMn(III)ClϾTPPNi(II)Ͼ
TPPCo(II). However, the reduction of 1 with NaBH4 cat-
alyzed by robust iron(III)porphyrins like Cl8TPPFe(III)Cl
and Cl8Cl8TPPFe(III)Cl gave 2 in 95% and 96% respectively
as compared to 89% with TPPFe(III)Cl.
The biomimetic reduction of anti-inflammatory drug, nime-
sulide (1) with sodium borohydride catalyzed by 5,10,15,20-
tetraarylporphyrinatoiron(III) chlorides [TAPFe(III)Cl] has
been studied in organic solvents under anaerobic and aerobic
conditions.
Key words biomimetic reduction; nimesulide; metalloporhyrin; sodium
borohydride; 4-aminonimesulide; 4Ј-hydroxynimesulide
Nimesulide (4-nitro-2-phenoxymethanesulfonanilide) (1)
is a potent nonsteroidal anti-inflammatory, analgesic and
anti-pyretic agent. It inhibits cyclooxygenase-2 selectively1,2)
and reduces prostaglandin proinflammatory activity without
interfering with the production of cytoprotective prosta-
glandins of gastric mucous membrane.3) 4-Aminonimesulide
(2) (reductive metabolite) and 4Ј-hydroxynimesulide (3) (ox-
idative metabolite) have been reported as minor and major
metabolites of 1, respectively, in urine and feces4—6) of man
(Chart 1).
Further 1 is a protonophore and mitochondrial NAD(P)H
oxidant agent whereas 2 has been reported as supressor of
the above mitochondrial responses.7) It has also been shown
that the reduced metabolite (2) partly protects against accu-
mulation of reactive oxygen species (ROS) derived from the
organelle under conditions of oxidative stress.7) The combi-
nation of sodium borohydride and metalloporphyrins have
been shown to mimic the various redox transformations
of organic substrates catalyzed by cytochrome P450 and
NAD(P)H, in absence or presence of molecular oxygen.8—14)
Herein, we report the biomimetic reduction of 1 with sodium
borohydride catalyzed by metalloporphyrins in organic sol-
vents under anaerobic and aerobic conditions.
The TLC examination of reduction of 1 after 30 min shows
the presence of two additional products along with 2 and
they disappeared after 1 h. Further, the Rf values of these
products are found to be similar to that of 4-nitrosonime-
sulide16) (4) and 4-hydroxylaminonimesulide17) (5) (Rf val-
ues 1ϭ0.71, 2ϭ0.43, 4ϭ0.63, 5ϭ0.28, silica gel, eluent
100% chloroform). This is further confirmed by HPLC [wa-
ters, C18 m-bondapak, methanol : water (60 : 40 v/v)] analy-
ses (retention times of 1 is 14.12, 2 is 9.04, 4 is 13.02 and 5
is 5.65). The reaction of 4 and 5 with NaBH4 catalyzed by
TPPFe(III)Cl gives 2 in 98% and 99% yield, respectively and
complete conversion was observed within 30 min. Therefore,
the reduction of 1 with NaBH4/5,10,15,20-tetraarylporphyri-
natoiron(III) chlorides (TAPFe(III)Cl) system is believed to
proceed through 4 and 5 intermediates to form 2 either by
Chart 1
In a typical run sodium borohydride (1200 mmol) was
added to a mixture of 1 (100 mmol) and 5,10,15,20-
tetraphenylporphyrinatoiron(III) chloride (TPPFe(III)Cl, 1
mmol) in methanol : dichloromethane (9 : 1, v/v) under nitro-
gen atmosphere. The reaction was stirred for 1 h at room
temperature. The progress of the reaction was monitored by
TLC and HPLC. The solvent was removed under reduced
pressure and the residue was chromatographed on silica gel
to give 2 in 89% yield (Chart 2, Table 1). The formation of 2
was confirmed by comparison of HPLC retention time as
well as other spectroscopic data15) with that of authentic sam-
ple.
The presence of molecular ion peak at 277 in electron im-
pact (EI)-MS shows the complete reduction of 1 to 2. Fur-
ther, the presence of a peak at 199 shows the loss of
–SO2CH3 group from the parent molecule. The appearance
1
of broad singlet at 3.7 ppm in H-NMR shows the presence
of –NH2 group in the compound. The upfield chemical shifts
of aromatic protons show the complete reduction of nitro
Chart 2
© 2002 Pharmaceutical Society of Japan
* To whom correspondence should be addressed. e-mail: smschauhan@chemistry.du.ac.in

1422
Vol. 50, No. 10
Yield (%)a)
Table 1. Reduction of Nimesulide and Related Compounds with NaBH4 Catalyzed by TAPFe(III)Cl under N2 Atmosphere
Run
System
NaBH4 (mmol)
Time (h)
Conversion (%)a)
1
2
3
4
5
6
7
8
9
1
200b)
200
400
24
24
12
2
12
54
76
9
23
47
68
89
95
96
98
99
1/TPPFe(III)Cl
1/TPPFe(III)Cl
1/TPPFe(III)Cl
1/TPPFe(III)Cl
1/Cl8TPPFe(III)Cl
1/Cl8Cl8TPPFe(III)Cl
4/TPPFe(III)Cl
5/TPPFe(III)Cl
800
91
1200
1000
1000
800
1
100
100
100
100
100
0.5
0.5
0.5
0.5
800
a) Based on the substrate, b) NaBH4 alone.
Table 2. The Reduction of Nimesulide with NaBH4 Catalyzed by
TAPFe(III)Cl in Presence of Added Molecular Oxygena)
5) Sarkar P., McIntosh J. M., Leavitt R., Gouthro H., J. Anal. Toxico., 21,
197—202 (1997).
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S. A., Curti C., Br. J. Pharm., 131, 1154—1160 (2000).
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11.
% Yieldb)
S. No.
Metalloporphyrin
2
3
1
2
3
TPPFe(III)Cl
Cl8TPPFe(III)Cl
Cl8Cl8TPPFe(III)Cl
20
11
10
Trace amounts
9) Sakaki S., Koga H., Tao K-I., Yamashita T., Iwashita T., Hamada T., J.
Chem. Soc. Dalton. Trans., 2000, 1015—1017.
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11) Okamoto T., Oka S., J. Org. Chem., 49, 1589—1594 (1984).
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519—522.
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(1985).
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Bull., 41, 292—295 (1993).
4.5
4.8
a) 100 eq of molecular oxygen, Sub : cat : NaBH4ϭ100 : 1 : 400 mmol after 2 h at
25 °C, b) Based on the substrate and HPLC analyses, retention time of 2 is 9.04 and 3
is 11.86.
stepwise 1eϪ or 2eϪ processes.
The reaction of 1 with NaBH4 catalyzed by TAPFe(III)Cl
in presence of molecular oxygen gives 3 along with 2. (Chart
2, Table 2) The structure of 3 was confirmed by the compari-
son of HPLC retention time with that of authentic sample as
well as by other spectroscopic data.18)
15) Data of 4-aminonimesulide (2): mp 169—171 °C; 1H-NMR (300 MHz,
CDCl3, d ppm): 2.90 (s, 3H, CH3SO2), 3.7 (br s, 2H, NH2), 6.16 (s,
1H, NH), 6.35 (s, 1H, Ar-3H), 6.40 (d, 1H, Jϭ8.45 Hz, Ar-5H), 6.99
(d, 2H, Jϭ7.35 Hz, ArЈ-2H, ArЈ-6H), 7.16 (d, 1H, Jϭ8.45 Hz, Ar-6H),
7.35 (m, 3H, ArЈ-3H, ArЈ-4H, ArЈ-5H); IR (KBr, cmϪ1): 3394, 3339,
3062, 2922, 2853, 1615, 1585, 1508, 1463, 1324, 1214, 1152, 969,
863, 797, 725, 688, 489; EI-MS (m/z): 277 (Mϩ), 206, 199, 171, 154,
99, 77, 43.
16) Data of 4-nitrosonimesulide (4): It is synthesized by potassium dichro-
mate oxidation of 5 at 0 °C. mp 111—113 °C; 1H-NMR (300 MHz,
CDCl3, d ppm): 3.21 (s, 3H, CH3SO2), 6.79 (s, 1H, NH), 7.07 (d, 2H,
Jϭ7.2 Hz, ArЈ-2H, ArЈ-6H), 7.46 (m, 3H, ArЈ-3H, ArЈ-4H, ArЈ-5H),
7.66 (s, 1H, Ar-3H), 7.78 (d, 1H, Jϭ9.0 Hz, Ar-6H), 8.01 (d, 1H, Jϭ
9.0 Hz, Ar-5H); IR (KBr, cmϪ1): 3369, 3015, 2958, 2862, 1627, 1566,
1518, 1493, 1404, 1289, 1145, 1020, 887, 786, 745, 645, 524; EI-MS
(m/z): 292 (Mϩ), 262, 247, 187, 172, 154, 99, 77, 43.
The low catalytic activity of TPPFe(III)Cl with molecular
oxygen in presence of reductant NaBH4 is due to formation
of m-oxo dimer,19) whereas the high-valent iron-oxo interme-
diates formed from the halogenated and perhalogenated
iron(III)porphyrin with molecular oxygen under reduc-
tive conditions are responsible for aromatic hydroxyla-
tion.11,12,20,21) The presence of molecular oxygen has remark-
ably effected the reduction of 1. As the amount of oxygen
bubbled into the reaction mixture is increased, the yield of 2
is further decreased even with 1200 mmol of NaBH4. The de-
tailed study on the oxidation of 1 with monooxygen donors
catalyzed by metalloporphyrins will be published elsewhere.
In conclusion, the reduction of nimesulide 1 with cy-
tochrome P450-NAD(P)H model system (TAPFe(III)Cl-
NaBH4) under anaerobic conditions gives exclusively reduc-
tive metabolite 2 whereas the oxidative metabolite 3 has also
been formed along with 2 under aerobic conditions.
17) Data of 4-hydroxylamine nimesulide (5): It is synthesized from 1
under mild and neutral conditions using Zn and NH4Cl. mp 163—
167 °C; 1H-NMR (300 MHz, DMSO-d6,
d ppm): 2.86 (s, 3H,
CH3SO2), 4.78 (s, 2H, NHSO2 and OH), 6.14 (d, 1H, Jϭ2.2 Hz, Ar-
3H), 6.34 (dd, 1H, Jϭ8.53 Hz, Jϭ2.2 Hz, Ar-5H), 7.01 (d, 2H, Jϭ
7.83 Hz, ArЈ-2H, ArЈ-6H), 7.05 (d, 1H, Jϭ8.53 Hz, Ar-6H), 7.11 (t,
1H, Jϭ7.83 Hz, AArЈ-4H), 7.35 (t, 2H, Jϭ7.83 Hz, ArЈ-3H, ArЈ-5H),
8.47 (s, 1H, NHOH); IR (KBr, cmϪ1): 3412, 3352, 3028, 2949, 1619,
1578, 1515, 1478, 1401, 1311, 1267, 1150, 1079, 971, 856, 802, 741,
680; EI-MS (m/z): 294 (Mϩ), 262, 247, 183, 168, 91, 77, 57, 41.
18) Data of 4Ј-hydroxynimesulide (3): mp 124—126 °C; 1H-NMR (300
MHz, CDCl3, d ppm): 2.93 (s, 3H, CH3SO2), 6.7 (s, 1H, NH), 7.07 (d,
2H, Jϭ7.47 Hz, ArЈ-3H, ArЈ-5H), 7.23 (d, 2H, Jϭ7.47 Hz, ArЈ-2H,
ArЈ-6H), 7.34 (d, 1H, Jϭ8.5 Hz, Ar-6H), 7.46 (s, 1H, Ar-3H), 7.59 (d,
1H, Jϭ8.5 Hz, Ar-5H); IR (KBr, cmϪ1): 3482, 3286, 2924, 2854,
1591, 1519, 1342, 1215, 1153, 1078, 973, 908, 802, 469; EI-MS (m/z):
324 (Mϩ), 307, 275, 256, 223, 204, 154, 149, 123, 89, 71, 57, 41.
19) Ellis P. E., Jr., Lyons J. E., Coord. Chem. Rev., 105, 181—193 (1990).
20) Grinstaff M. W., Hill M. G., Birnbaum E. R., Schaefer W. P., Labinger
J. A., Gray H. B., Inorg. Chem., 34, 4896—4902 (1995).
Acknowledgements The authors are thankful to Council of Scientific
and Industrial Research (CSIR) and University Grants Commission (UGC),
New Delhi, India, for financial support.
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