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Synthesis, characterization, and antiinflammatory activity of Naproxen complexes with rare earth (III)
Synthesis, Characterization, and Antiinflammatory Activity of Naproxen Complexes With Rare Earth (IIII Zhong Ning Chen, Ru Wen Deng, and Ji Gui Wu Department of Chemistry, Lanzhou University, Lanzhou, People’s Republic of China
ABSTRACT RE(III)complexes of Naproxen(HNap) have been synthesized and characterized by elemental analyses, conductance measurements, solubilitiea, thermal analysis, infrared, proton magnetic resonance, and electronic spectral data. The elemental analyses reveal the presence of 1:3 (metakligand) stoichiometty and the IR spectra suggest the carboxylate group of HNap functions, as a bridging ligand to coordinate to RE(III) ions. The electronic spectra recorded in solid exhibit only slight shifts in visible regions, on which /3, 6 and bt of covalent parameters have been calculated. Formalin-induced rat paw edema and croton oil-induced rat ear edema inflammatory models were chosen to examine the antiiiammatory activity of Nd(III) complex, which ascertained enhanced antiinflammatory activity relative to the ligand.
INTRODUCTION is a nonsteroidal antiinflammatory analgesic useful in the treatment of artbritis and chronic and acute pain states [l]. Many studies show that although rare earth elements are not vital for biological systems, they have many pharmaceutical actions, such as antiinflammation, antibiosis, antitumor, anticoagulation, and depressing blood sugar [2-41. In recent years, many investigations for rare earth antiinflammatory drugs have been made, and some of them have been applied clinically [4]. So, it is worthwhile to undertake the synthesis, characterization, and antiinflammatory activity of HNap complexes with rare earth(lH) (Scheme 1): 0 0-M .* Naproxen(HNap)(I)
R-
Ho\
//
l+C\,,H
/
+c<*M
“\ IID-
M
III
Iv
SCHEME 1
Addressreprintrequeststo: Professor R. W. Deng, Department of Chemistry, -0~ Lanxhou 730000, P. R. China. Journal of Inorganic Biochemistry, 41,81-87 0 1992 Elsevier Science Publishing Co., Inc.,
University,
(199(L)
655 Avenue of the Americas, NY, NY 10010
81 0162-0134/92/$5.00
82
2. N. Chen et al.
EXPERIMENTAL. Materials and Measurements RE(III) chlorides were obtained by dissolving 99.95% RE,O, with stoichiometric amounts of 1: 1 chlorhydric acid, the solutions obtained were put on a water bath to evaporate until a crystal film appeared, then cooled, then the crystals separated out. Naproxen was of medicinal purity from the Second Medicinal Factory. of Chongqing (China). The other chemicals used were of analytical reagent or high purity grade. Rare earth contents in all complexes were determined by incandescing the samples for one hour at 8OO”C, then the residues were dissolved with 1:l chlorhydric acid, the solutions obtained were titrated with EDTA and xylenol orange as indicators. Elemental analyses of carbon and hydrogen were measured on a Carlo Erba 1106 elemental analyser. IR spectra were obtained on a Nicolet 170SX infrared spectrometer in KBr discs. ‘H NMR spectra were recorded on a FT-8OA NMR spectrometer in CDCl, using DSS as an internal reference. Electronic spectra were run on a Shimadzu UV-240 spectrophotometer. Thermal analyses were done on a PCT-2 differential thermal analy ser. Preparation of the Sodium of HNap HNap was dissolved with an equimolar amount of NaOH aqueous medium. The reaction mixture was stirred until clear, then the solution was put on a water bath to evaporate until a crystal film appeared, the white product obtained was taken by filtration and dried over a molecular sieve under vacuum. Anal. Calc. for C,,H,,O,Na: C, 66.6; H, 5.15%. Found: C, 66.7; H, 5.18%. Preparation
of the Complexes
1:3 Mixture of RE(lII) chloride and sodium of Naproxen(NaNap) in methanol was stirred in a flask, whereupon the complex precipitated immediately. The products were taken by filtration, washed with methanol, and dried in a vacuum desiccator over a molecular sieve. Investigation of the AntWlammatOry Action Inhibition of Formalin-Induced Rat Paw Edema. Fifty male rats weighing 140 + 10 g were chosen and divided stochastically into five groups of 10 as follows: (1) Physiological brine (control group), (2) HNap, (3) NaNap, (4) Mixture of HNap and Nd(Ill) chloride (1:3), and (5) Nd(IIl) complex. In each group rats received physiological brine or drugs dissolved or suspended in a solution containing 0.2% Tween-80 in water, in a volume of 20 ml/kg and a dose of 20 mg/kg. One hour after oral administration the initial volume of rat hind paw was measured and 0.1 ml, 2.5% formalin, was injected into the subplanter area of the right hind paw. 24 hr later the volume of this paw was remeasured. Mean percent edema and percent inhibition were calculated [5, 61. Inhibition of Croton Oil-Induced Rat Ear Edema. Fifty male rats weighing 26-30 g were chosen and divided stochastically into five groups of 10 as above. The rats were anesthetized with ether and received the test materials in a dose of 20 mg/kg. One hour after oral administration, the croton oil mixture consisting of 2% croton oil, 20% absolute ethanol, 5% distilled water, and 73% diethyl ether was smeared onto the right ear of each rat, the inner and outer surfaces of the ear each
NAPROXEN COMPLEXES WITH RARE EARTH@)
87
TABLE 4. Data for Antiinflammatory Action RatEarEdema
Rat Paw Edema Group physiological brine (control group) HNap Na(Nap) Mixture of HNap and NdCl, (1:3) Nd(Bl) complex
Mean Edema (%)
Inhibition (%)
P
Mean Edema (mg)
36.1 f 4.4
Inhibition (96)
P
16.2 f 1.35
16.0 f 3.2 14.9 f 2.4 17.6 f 1.5
56.4 59.4 52.0
< 0.02 < 0.02 < 0.02
6.8 f 0.81 6.5 f 0.33 7.2 f 0.45
58.0 59.9 55.6
< 0.02 < 0.02 < 0.02
9.4 f 0.8
74.4
< 0.M
4.0 f 0.31
75.6
< 0.02
replacement of the RE(III) ions to Ca@) ions of involvement in the reactions which synthesize and liberate inflammatory substances like histamine and 5-hydroxy-
tryptamine.
REFERENCES 1. J. G. Lombardino, I. G. Gttemess, and E. H. Wiseman, Arzneim-Forsch 25, 1629 (1975). 2. W. W. Monafo, Surgery 80, 465 (1976). 3. S. P. Mital, Curr. Sci. 50, 483 (1981). 4. G. Galos, Ther. Hung. 22. 180 (1974). 5. A. P. Roszkowski, W. H. Rooks II, A. J. Tomolonis, and L. M. Miller, J. Pharmacol. Exp. ‘Ther. 179, 114 (1971). 6. A. M. Edoardo, Inflammation and AntiinJ?ammation, Spectrum Pub., New York, 1977, PP. 109-141. 7. X. Y. Zhu, G. F. Xu, and Z. J. Zhang, Acta Pharmaceutics Sinica 14, 685 (1979). 8. C. G. Van Arman, Anti-inflammatory drugs, Clin. Pharmacol. Therap. (Part 2). 16, 900 (1974). 9. W. J. Geary, Coord. Chem. Rev. 7, 81 (1971). 10. K. Nakamoto, Infrared and Roman Spectra of Inorganic and Coordination Compounds, Wiley, New York, 1986, 4th Ed., p. 232. 11. L. P. Battaglia, A. Bonamartini Corradi, G. Marcotrigiano, L. Menabue, and G. C. Pellacani, J. Am. Chem. Sot. 102, 2663 (1980). 12. L. P. Battaglia, A. Bonamartini Corradi, G. Marcotrigiano, L. Menabue, and G. C. Pellacani, Inorg. Chem. 20, 1075 (1981). 13. L. Antolini, L. Menabue, G. C. Pellacani, M. Saladini, L. P. Battaglia, A. Bonamartini Corradi, and G. Marcotrigiano, J. Chem. Sot. Dalton Trans., 2325 (1984). 14. C. K. J#rgensen, Prog. Inorg. Chem. 4, 73 (1%2). 15. S. P. Sinha, Spectrochim. Acta 22, 57 (1966). 16. M. Mohan, J. P. Tandon, and N. S. Gupta, Znorg. Chim. Acta 111, 187 (1986). 17. A. K. Solanki and A. M. Bhandari, J. Inorg. Nuci. Chim. 41, 1311 (1979). 18. Y. Mizushima, Y. Ishii, and S. Masumoto, Biochem. Pharmacof. 24, 1589 (1975). Received December IO, 1990; accepted January IO, 1991
ABSTRACT RE(III)complexes of Naproxen(HNap) have been synthesized and characterized by elemental analyses, conductance measurements, solubilitiea, thermal analysis, infrared, proton magnetic resonance, and electronic spectral data. The elemental analyses reveal the presence of 1:3 (metakligand) stoichiometty and the IR spectra suggest the carboxylate group of HNap functions, as a bridging ligand to coordinate to RE(III) ions. The electronic spectra recorded in solid exhibit only slight shifts in visible regions, on which /3, 6 and bt of covalent parameters have been calculated. Formalin-induced rat paw edema and croton oil-induced rat ear edema inflammatory models were chosen to examine the antiiiammatory activity of Nd(III) complex, which ascertained enhanced antiinflammatory activity relative to the ligand.
INTRODUCTION is a nonsteroidal antiinflammatory analgesic useful in the treatment of artbritis and chronic and acute pain states [l]. Many studies show that although rare earth elements are not vital for biological systems, they have many pharmaceutical actions, such as antiinflammation, antibiosis, antitumor, anticoagulation, and depressing blood sugar [2-41. In recent years, many investigations for rare earth antiinflammatory drugs have been made, and some of them have been applied clinically [4]. So, it is worthwhile to undertake the synthesis, characterization, and antiinflammatory activity of HNap complexes with rare earth(lH) (Scheme 1): 0 0-M .* Naproxen(HNap)(I)
R-
Ho\
//
l+C\,,H
/
+c<*M
“\ IID-
M
III
Iv
SCHEME 1
Addressreprintrequeststo: Professor R. W. Deng, Department of Chemistry, -0~ Lanxhou 730000, P. R. China. Journal of Inorganic Biochemistry, 41,81-87 0 1992 Elsevier Science Publishing Co., Inc.,
University,
(199(L)
655 Avenue of the Americas, NY, NY 10010
81 0162-0134/92/$5.00
82
2. N. Chen et al.
EXPERIMENTAL. Materials and Measurements RE(III) chlorides were obtained by dissolving 99.95% RE,O, with stoichiometric amounts of 1: 1 chlorhydric acid, the solutions obtained were put on a water bath to evaporate until a crystal film appeared, then cooled, then the crystals separated out. Naproxen was of medicinal purity from the Second Medicinal Factory. of Chongqing (China). The other chemicals used were of analytical reagent or high purity grade. Rare earth contents in all complexes were determined by incandescing the samples for one hour at 8OO”C, then the residues were dissolved with 1:l chlorhydric acid, the solutions obtained were titrated with EDTA and xylenol orange as indicators. Elemental analyses of carbon and hydrogen were measured on a Carlo Erba 1106 elemental analyser. IR spectra were obtained on a Nicolet 170SX infrared spectrometer in KBr discs. ‘H NMR spectra were recorded on a FT-8OA NMR spectrometer in CDCl, using DSS as an internal reference. Electronic spectra were run on a Shimadzu UV-240 spectrophotometer. Thermal analyses were done on a PCT-2 differential thermal analy ser. Preparation of the Sodium of HNap HNap was dissolved with an equimolar amount of NaOH aqueous medium. The reaction mixture was stirred until clear, then the solution was put on a water bath to evaporate until a crystal film appeared, the white product obtained was taken by filtration and dried over a molecular sieve under vacuum. Anal. Calc. for C,,H,,O,Na: C, 66.6; H, 5.15%. Found: C, 66.7; H, 5.18%. Preparation
of the Complexes
1:3 Mixture of RE(lII) chloride and sodium of Naproxen(NaNap) in methanol was stirred in a flask, whereupon the complex precipitated immediately. The products were taken by filtration, washed with methanol, and dried in a vacuum desiccator over a molecular sieve. Investigation of the AntWlammatOry Action Inhibition of Formalin-Induced Rat Paw Edema. Fifty male rats weighing 140 + 10 g were chosen and divided stochastically into five groups of 10 as follows: (1) Physiological brine (control group), (2) HNap, (3) NaNap, (4) Mixture of HNap and Nd(Ill) chloride (1:3), and (5) Nd(IIl) complex. In each group rats received physiological brine or drugs dissolved or suspended in a solution containing 0.2% Tween-80 in water, in a volume of 20 ml/kg and a dose of 20 mg/kg. One hour after oral administration the initial volume of rat hind paw was measured and 0.1 ml, 2.5% formalin, was injected into the subplanter area of the right hind paw. 24 hr later the volume of this paw was remeasured. Mean percent edema and percent inhibition were calculated [5, 61. Inhibition of Croton Oil-Induced Rat Ear Edema. Fifty male rats weighing 26-30 g were chosen and divided stochastically into five groups of 10 as above. The rats were anesthetized with ether and received the test materials in a dose of 20 mg/kg. One hour after oral administration, the croton oil mixture consisting of 2% croton oil, 20% absolute ethanol, 5% distilled water, and 73% diethyl ether was smeared onto the right ear of each rat, the inner and outer surfaces of the ear each
NAPROXEN COMPLEXES WITH RARE EARTH@)
87
TABLE 4. Data for Antiinflammatory Action RatEarEdema
Rat Paw Edema Group physiological brine (control group) HNap Na(Nap) Mixture of HNap and NdCl, (1:3) Nd(Bl) complex
Mean Edema (%)
Inhibition (%)
P
Mean Edema (mg)
36.1 f 4.4
Inhibition (96)
P
16.2 f 1.35
16.0 f 3.2 14.9 f 2.4 17.6 f 1.5
56.4 59.4 52.0
< 0.02 < 0.02 < 0.02
6.8 f 0.81 6.5 f 0.33 7.2 f 0.45
58.0 59.9 55.6
< 0.02 < 0.02 < 0.02
9.4 f 0.8
74.4
< 0.M
4.0 f 0.31
75.6
< 0.02
replacement of the RE(III) ions to Ca@) ions of involvement in the reactions which synthesize and liberate inflammatory substances like histamine and 5-hydroxy-
tryptamine.
REFERENCES 1. J. G. Lombardino, I. G. Gttemess, and E. H. Wiseman, Arzneim-Forsch 25, 1629 (1975). 2. W. W. Monafo, Surgery 80, 465 (1976). 3. S. P. Mital, Curr. Sci. 50, 483 (1981). 4. G. Galos, Ther. Hung. 22. 180 (1974). 5. A. P. Roszkowski, W. H. Rooks II, A. J. Tomolonis, and L. M. Miller, J. Pharmacol. Exp. ‘Ther. 179, 114 (1971). 6. A. M. Edoardo, Inflammation and AntiinJ?ammation, Spectrum Pub., New York, 1977, PP. 109-141. 7. X. Y. Zhu, G. F. Xu, and Z. J. Zhang, Acta Pharmaceutics Sinica 14, 685 (1979). 8. C. G. Van Arman, Anti-inflammatory drugs, Clin. Pharmacol. Therap. (Part 2). 16, 900 (1974). 9. W. J. Geary, Coord. Chem. Rev. 7, 81 (1971). 10. K. Nakamoto, Infrared and Roman Spectra of Inorganic and Coordination Compounds, Wiley, New York, 1986, 4th Ed., p. 232. 11. L. P. Battaglia, A. Bonamartini Corradi, G. Marcotrigiano, L. Menabue, and G. C. Pellacani, J. Am. Chem. Sot. 102, 2663 (1980). 12. L. P. Battaglia, A. Bonamartini Corradi, G. Marcotrigiano, L. Menabue, and G. C. Pellacani, Inorg. Chem. 20, 1075 (1981). 13. L. Antolini, L. Menabue, G. C. Pellacani, M. Saladini, L. P. Battaglia, A. Bonamartini Corradi, and G. Marcotrigiano, J. Chem. Sot. Dalton Trans., 2325 (1984). 14. C. K. J#rgensen, Prog. Inorg. Chem. 4, 73 (1%2). 15. S. P. Sinha, Spectrochim. Acta 22, 57 (1966). 16. M. Mohan, J. P. Tandon, and N. S. Gupta, Znorg. Chim. Acta 111, 187 (1986). 17. A. K. Solanki and A. M. Bhandari, J. Inorg. Nuci. Chim. 41, 1311 (1979). 18. Y. Mizushima, Y. Ishii, and S. Masumoto, Biochem. Pharmacof. 24, 1589 (1975). Received December IO, 1990; accepted January IO, 1991