- Email: [email protected]
Structural characterization and SOD activity of copper–oxaprozinate
Inorganic Chemistry Communications 7 (2004) 1071–1074 www.elsevier.com/locate/inoche
Structural characterization and SOD activity of copper–oxaprozinate Sabari Dutta a, Subhash Padhye a
a,*
, Vickie Mckee
b
Department of Chemistry, University of Pune, Ganeshkhind Road, Pune 411 007, India Department of Chemistry, Loughborough University, Leicestershire, LE11 3TU, UK
b
Received 21 April 2004; accepted 19 July 2004 Available online 25 August 2004
Abstract SOD activity of the diaryl substituted heterocyclic COX-2 inhibitor, viz. oxaprozin (2), is synergistically enhanced upon copper conjugation compared to analogous copper compounds of established COX-1 inhibitors like aspirin (1) and ibuprofen (3). A ‘‘paddle-wheel’’ structure is reported for the dimeric copper complex of oxaprozin. Ó 2004 Elsevier B.V. All rights reserved. Keywords: X-ray crystal structure; COX inhibitors; Oxaprozin; Copper conjugation; SOD activity
A wide range of non-steroidal anti-inflammatory compounds (NSAIDs) have been in clinical practice for the treatment of inflammatory disorders including arthritis and cancer as well as for prevention of myocardial infarction and AlzheimerÕs disease [1–5]. NSAIDs have been shown to be potent inhibitors of prostaglandin synthesis through inhibition of one of the obligatory enzyme, in the inflammatory cascade viz. cyclooxygenase, which exists in two isoforms referred as COX-1 and COX-2, respectively [6–8]. Compounds inhibiting COX-1 enzymes have been shown to cause gastrointestinal irritations and kidney damages since the enzyme is involved in the physiological function of protecting gastric mucosa [9–12]. Consequently, research efforts have been directed towards evolving compounds which are specific COX-2 inhibitors [13], nitric oxide (NO) releasing agents [14], leukotriene pathway inhibitors [15] SOD mimetics [16] and metal complexes of NSAIDs [17] which can minimize deleterious effects of NSAIDs.
The beneficial effects of copper in minimizing inflammation were noted in the 1940s with trials of the efficacy of Cu complexes for the treatment of arthritis [18]. Interest in the possible beneficial effects of Cu complexes was renewed with SorensonÕs suggestion in 1976 [19a] that the active form of the antiinflammatory drugs may actually be the Cu(II) complexes of such drugs in vivo. Later work corroborated his findings that copper complexes of the anti-inflammatory drugs were more active than either their parent inorganic Cu(II) salt or the parent NSAID [20]. An excellent account of these findings is available through reviews by Sorenson [19b] and more recently by Lay and co-workers [21]. A careful survey of these reports indicates that copper complexes of COX-2 inhibitors have remained less explored.
HO O
O
*
Corresponding author. Tel.: +91 20 2560 1227; fax: +91 20 2569 1728. E-mail address: [email protected] (S. Padhye). 1387-7003/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.inoche.2004.07.022
N O O
CH2CH
OH Oxaprozin(2)
CH Me
Me
MeO Aspirin(1)
OH
Me
Ibuprofen(3)
O
1072
S. Dutta et al. / Inorganic Chemistry Communications 7 (2004) 1071–1074
Oxaprozin (4,5-diphenyl-2-2 oxazole-propionic acid) (2) is the first representative member of the diaryl substituted heterocyclic COX-2 inhibitor currently in clinical practice [22]. Given in a single or divided daily doses of 600–1800 mg/day, it is found to be comparable to 2600–3900 mg/day of aspirin. It is found to be more effective in controlling inflammation and also inflicts fewer gastrointestinal side effects than aspirin. We were thus motivated to undertake synthesis and characterization of copper conjugates of 2 along with those of 1 and 3 which are non-selective COX inhibitors [23,24] and compare their superoxide radical scavenging activities which are proposed to account for their anti-inflammatory activities as well as gastric damage sparing activities [25]. Copper (II) complexes of 1 and 3 were prepared by methods reported in the literature [23,24] and the same was followed for complex 2. The measurements of SOD activity were carried out using the NBT assay method described by Bhirud and Shrivastav [26] using KO2–DMSO solution as the source of superoxide ions [27]. The blue color developed due to the formation of formazon dye was measured immediately at 560 nm against an appropriate blank. The unit SOD activity was expressed as the concentration of the complex causing 50% inhibition of KO2–DMSO mediated formazon dye formation. The crystallographic data were collected on a Bruker SMART 1000 diffractometer at 150(2) K. The structure was solved by direct methods and refined by full-matrix least-squares on F2 using the SHELXTL suite of programs [28]. All non-hydrogen atoms were refined with anisotropic atomic displacement factors and the hydrogen atoms were inserted at calculated positions using a riding model. Details of the data collection and structure solution are given in Table 1.
Table 1 Crystal data and refinement parameters for [Cu2(oxa)4]2DMSO Empirical formula Formula weight Crystal system Space group Unit cell dimensions ˚ a = 21.307(3) A ˚ b = 10.1309(15) A ˚ c = 16.128(2) A Volume Z Density (calculated) Absorption coefficient F (0 0 0) Reflections collected Independent reflections Goodness-of-fit on F2 Final R indices [I > 2r(I)] R indices (all data)
C76H68Cu2N4O14S2 1452.54 Monoclinic P2(1)/c a = 90° b = 105.581(2)° c = 90° ˚3 3353.4(9) A 2 1.439 Mg/m3 0.768 mm1 1508 27,590 7889 [R(int) = 0.0220] 1.035 R1 = 0.0310, wR2 = 0.0786 R1 = 0.0417, wR2 = 0.0837
The [Cu2(oxa)4]2DMSO complex is centrosymmetric where one of the phenyl rings on one ligand is slightly disordered, which has been modeled as 50% disorder over two positions. In addition, while the distinction between the N and O one of the heterocyclic rings seems clear, the other is less obvious (C–N, C–O 1.299 and 1.348 for ‘‘B’’ ring; 1.302 and 1.320 for ‘‘A’’ ring). This may indicate N/O disorder but it has not been modeled since it is not reflected by the atomic displacement parameters of the atoms concerned. The interaction of cupric chloride with the selected cyclooxygenase inhibitors in aqueous methanolic solvent leads to formation of dimeric metal complexes having a molecular formula, viz. [Cu2(R–COO)4L2] (R = aryl/phenyl alkonic acid and L = solvent) where each copper metal center is in an octahedral environment typified by molecular structure of copper acetate [29]. The carboxylate groups act as bridging ligands having a center of symmetry midway between the copper atoms while the solvent molecules used in the synthesis bind at the position trans to the Cu–Cu axis. The room temperature magnetic moments of all synthesized compounds are in the range 1.30–1.40 BM similar to that of copper acetate monohydrate [30] indicating antiferromagnetic exchange interactions between the adjacent copper atoms. It has been established that in the solid state, copper complexes of NSAIDs are typically monomeric or dimeric with bonding to the copper ions through the carboxylate groups [31]. The structure of the copper complex of 2 shown in Fig. 1 is in agreement with this observation. Selected bond lengths and bond angles for the copper compound are given in the supplementary material. The ‘‘paddle-wheel’’ dimeric Cu(II) structure has a Cu– ˚ with octahedral stereochemCu distance of 2.6119(5) A istry around each copper atom tetragonally elongated along the Cu–Cu–O ligands axis due to the Jahn–Teller effect [32]. The rigid geometry of the acetate-type Cu(II) dimers is due to the restricted bite of the bidentate carb˚) oxylate bridges which allows little variation (0.3 A in the Cu–Cu distances from that found in the copper ˚ ) [33]. metal (2.56 A The significant peaks in the IR spectra of copper complexes of ligands 1–3 are summarized in a table in the supplementary material. The frequency separation (Dm 175–180 cm1) between the asymmetric and symmetric vibrational carboxylate modes in present copper compounds indicate a bidentate bridging mode for these groups [34]. The electronic spectra for the three copper complexes obtained in DMSO solvent exhibit one very broad absorption near 680 nm characteristic of the dz2 ! dx2 y2 transition [35]. The band in the region 430 nm is ascribed to ligand to metal charge transfer transition (LMCT) while the higher energy bands in the UV region (340–395 nm) are thought to arise from intra-ligand p–p* transitions [36].
S. Dutta et al. / Inorganic Chemistry Communications 7 (2004) 1071–1074
1073
Fig. 1. Crystal structure for [Cu2(oxa)4]2DMSO.
Oyanagi et al. [37] have reported that NSAIDs exert their anti-inflammatory effects by inhibiting the generation of superoxide radicals, while Ichihara and Wasil [38] have shown that NSAIDs eliminate superoxide anions and HOCl produced by neutrophils. Since these radical scavenging activities of NSAIDs have been shown to enhance upon copper conjugation [39], the superoxide dismutase activity of all synthesized copper complexes and their parent ligands were evaluated using the NBT assay. A comparison of these values for the present compounds (Fig. 2) indicates that their radical scavenging activities are synergistically enhanced upon copper conjugation more so for the COX-2 inhibitor like 2.
80
> 65 60 60
IC50 / micro M
50
56.8
52.5
40
An accidental observation was made in case of aspirin ligand which generated higher concentrations of superoxide anions for the initial 60 s before bringing about its quenching. Grootveld and Halliwell [40] have suggested that this may arise from scavenging of the OH radicals by the salicylate rather than through normal metabolic reactions of enzymic hydroxylating systems indicated by the presence of small amount of 2,3-dihydroxybenzoic acid (2,3-DHB) in the blood plasma and urine of healthy adult volunteers after consuming 1 [41]. This observation suggests the hidden danger of generating oxidative stress in the initial period of administration of aspirin in the clinical practice. On the other hand, once activated the copper–aspirinate complex quenches the superoxide anions present in the solution for the remaining period. It is interesting to note that the Cu2+/1+ redox couples of the present copper conjugates (+0.30 to +0.08 V) are very similar to the redox potentials of the native SOD enzyme [42] which may be of relevance to their anti-inflammatory activities. Present studies thus clearly establish that copper conjugation in case of COX-2 inhibitors like 2 significantly enhances its SOD activity thereby offering the possibility of lowering its therapeutic dose which may be beneficial in its clinical use.
17
20
Supplementary material
10.1 0.72 SOD enzyme
CuCl2
Cu- Oxaprozin
Oxaprozin
Cu-ibuprofenate
Ibuprofen
Cu-aspirinate
Aspirin
0
Fig. 2. The SOD-like activities described by their IC50 values.
Crystallographic data have been deposited with the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336 033; e-mail; [email protected]) and are available on request quoting the deposition numbers CCDC 230424. Analytical data of the compounds and Selected bond lengths and angles for Compound 2 are provided as supplementary material in doi:10.1016/j.inoche. 2004.07.022.
1074
S. Dutta et al. / Inorganic Chemistry Communications 7 (2004) 1071–1074
Acknowledgement S.D. thanks CSIR for SRF Fellowship.
References [1] R. Udassin, I. Ariel, N. Kitrassky, M. Chevion, Free Rad. Biol. Med. 10 (1991) 1. [2] D.J. Schmeling, R.A. Drongowski, A.G. Koran, Prog. Clin. Biol. Res. 53 (1989) 299. [3] J. Schreiber, G.L. Foureman, M.F. Hughes, R.P. Mason, T.E. Eling, J. Biol. Chem. 264 (1989) 7936. [4] J.R.J. Sorenson, Prog. Med. Chem. 26 (1989) 437. [5] D.L. Dewitt, J. Biol. Chem. 265 (1990) 5192. [6] H.P. Rang, M.M. Dale, Pharmacology, Churchill Livingstone, New York, 1987. [7] (a) J.R. Vane, Nature 231 (1971) 232; (b) J.R. Vane, R.J. Flower, R.M. Botting, Stroke 21 (1990) 12; (c) J.R. Vane, Angew. Chem., Int. Ed. Engl. 22 (1983) 741; (d) J.R. Vane, Proc. Natl. Acad. Sci. USA 91 (1994) 2046; (e) J.R. Vane, Y.S. Bakhle, R.M. Bottling, Ann. Rev. Pharmacol. Toxicol. 38 (1988) 97; (f) J.R. Vane, Inflamm. Res. 47 (Suppl. 2) (1998) S78. [8] P. Prasit, D. Riendeau, Ann. Rep. Med. Chem. 32 (1997) 211. [9] J.F. Fries, J. Rheumatol. 18 (1991) 6. [10] T. Shea-Donshue, L. Steel, E. Montcalm-Mazzilli, A. Dubois, Gastroenterology 284 (1990) 292. [11] H.R. Herschman, Biochim. Biophys. Acta 125 (1996) 1299. [12] Martin Beuk, Angew. Chem., Int. Ed. Engl. 38 (5) (1999) 631. [13] N.M. Davies, J.Y. Saleh, N.M. Skjodt, J. Pharm. Pharmacol. Sci. 3 (2000) 137. [14] S. Fiorucci, L. Santucci, B. Federici, E. Antonelli, E. Distrutti, O. Morelli, G. Di Renzo, G. Coata, G. Cirino, P. Del Soldato, A. Morelli, Aliment. Pharmacol. Ther. 13 (1999) 421. [15] C.J. Malemud, V.M. Goldberg, Front. Biosci. 4 (1999) 762. [16] (a) D.P. Riley, Chem. Rev. 99 (1999) 169; (b) S.L. Henke, Expert Opin. Ther. Pat. 9 (1999) 169. [17] Q. Zhou, T.W. Hambley, B.J. Kennedy, P.A. Lay, P. Turner, B. Warwick, J.R. Biffin, H.L. Regtop, Inorg. Chem. 39 (2000) 3742. [18] (a) L. Franco, D. Doria, Pharmacol. Res. 36 (1997) 395; (b) E. Fenz, Munch. Med. Wochenschschr. 88 (1941) 1101. [19] (a) J.R.J. Sorenson, J. Med. Chem. 19 (1976) 135; (b) J.R.J. Sorenson, Prog. Med. Chem. 26 (1989) 437; (c) J.R.J. Sorenson, US Patent #5,082,834, 1992. [20] M.A. Mendez-Rojas, F. Cordova-Lozanao, G. Gojon-Zorilla, M.A. Quiroz, Polyhedron 18 (1999) 2651.
[21] J.E. Weder, C.T. Dillon, T.W. Hambley, B.J. Kennedy, P.A. Lay, J.R. Biffin, H.L. Regtop, N.M. Daview, Coord. Chem. Rev. 232 (2002) 95. [22] J.J. Talley, D.L. Brown, J.S. Carter, M.J. Graneto, C.M. Koboldt, J.L. Masferrer, W.E. Perkins, Y.Y. Zhang, K. Seibert, J. Med. Chem. 43 (2000) 775. [23] (a) V. Brumas, B. Brumas, G. Berthon, J. Inorg. Biochem. 57 (1995) 191; (b) D.R. Faiser, S.K. Lynch, G.O. Garlisle, J. Inorg. Nucl. Chem. 43 (1981) 2747. [24] A.L. Abuhijleh, T. Pollitte, C. Woods, Inorg. Chim. Acta 215 (1994) 131. [25] (a) J.R.J. Sorenson, V. Kishore, A. Pezeshk, L.W. Oberley, S.W.C. Leuthauser, Inorg. Chim. Acta 91 (1984) 285; (b) U. Weser, K.H. Sillinger, E. Lengfelder, W. Werner, J. Strahle, Biochim. Biophys. Acta 631 (1980) 232; (c) S.T. Shuff, P. Chowdhary, M.F. Khan, J.R.J. Sorenson, Biochem. Pharmacol. 43 (1992) 1601. [26] R.G. Bhirud, T.S. Shrivastava, Inorg. Chim. Acta 173 (1990) 121. [27] R.L. Arudi, A.O. Allen, B.H.J. Bielski, FEBS Lett. 135 (1981) 265. [28] G.M. Sheldrick, SHELXTL Version 6.12, Bruker AXS, Madison, WI. [29] M. Costillo, J.J. Criado, B. Macia, M.V. Vaquero, Inorg. Chim. Acta 124 (1986) 127. [30] R.L. Dutta, A. Syamal, Elements of Magnetochemistry, second ed., Affiliated East west Press Pvt. Ltd., 1993. [31] J.N. van Nickerk, F.R.L. Schoeing, Acta Crystallogr. 6 (1983) 227. [32] P. de Meester, S.R. Fletcher, A.C. Skapski, J. Chem. Soc., Dalton Trans. 23 (1973) 2575. [33] D.R. Fraiser, S.K. Lynch, G.O. Garlisle, J. Inorg. Nucl. Chem. 43 (1981) 2747. [34] K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordination Compounds, fourth ed., Wiley, New York, 1986. [35] L. Mishra, K.K. Upadhyay, Ind. J. Chem. 33A (1994) 683. [36] R.M. Silverstein, G.C. Bassler, T.C. Morill, Spectrometric Identification of Organic Compounds, fifth ed., Wiley, USA. [37] Y. Oyanagi, Biochem. Pharmacol. 25 (1976) 1473. [38] (a) S. Ichihara, H. Tomisawa, H. Fukazawa, H. Tateishi, R. Joly, R. Heintz, Biochem. Pharmacol. 35 (1986) 3935; (b) M. Wasil, B. Halliwell, C.P. Moorhouse, S.D. C.Hutchinson, H. Barum, Biochem. Pharmacol. 36 (1987) 3947. [39] G.E. Jackson, L. Mkhonta-Gama, A. Voye, M. Kelly, J. Inorg. Biochem. 79 (2000) 147. [40] M. Grootveld, B. Halliwell, Biochem. Pharmacol. 37 (1988) 271. [41] M. Grootveld, B. Halliwell, Biochem. J. 237 (1986) 499. [42] H.A. Azab, L. Banci, M. Borsari, C. Luchinat, M. Sola, M.S. Viezzoli, Inorg. Chem. 31 (1992) 4649.
Structural characterization and SOD activity of copper–oxaprozinate Sabari Dutta a, Subhash Padhye a
a,*
, Vickie Mckee
b
Department of Chemistry, University of Pune, Ganeshkhind Road, Pune 411 007, India Department of Chemistry, Loughborough University, Leicestershire, LE11 3TU, UK
b
Received 21 April 2004; accepted 19 July 2004 Available online 25 August 2004
Abstract SOD activity of the diaryl substituted heterocyclic COX-2 inhibitor, viz. oxaprozin (2), is synergistically enhanced upon copper conjugation compared to analogous copper compounds of established COX-1 inhibitors like aspirin (1) and ibuprofen (3). A ‘‘paddle-wheel’’ structure is reported for the dimeric copper complex of oxaprozin. Ó 2004 Elsevier B.V. All rights reserved. Keywords: X-ray crystal structure; COX inhibitors; Oxaprozin; Copper conjugation; SOD activity
A wide range of non-steroidal anti-inflammatory compounds (NSAIDs) have been in clinical practice for the treatment of inflammatory disorders including arthritis and cancer as well as for prevention of myocardial infarction and AlzheimerÕs disease [1–5]. NSAIDs have been shown to be potent inhibitors of prostaglandin synthesis through inhibition of one of the obligatory enzyme, in the inflammatory cascade viz. cyclooxygenase, which exists in two isoforms referred as COX-1 and COX-2, respectively [6–8]. Compounds inhibiting COX-1 enzymes have been shown to cause gastrointestinal irritations and kidney damages since the enzyme is involved in the physiological function of protecting gastric mucosa [9–12]. Consequently, research efforts have been directed towards evolving compounds which are specific COX-2 inhibitors [13], nitric oxide (NO) releasing agents [14], leukotriene pathway inhibitors [15] SOD mimetics [16] and metal complexes of NSAIDs [17] which can minimize deleterious effects of NSAIDs.
The beneficial effects of copper in minimizing inflammation were noted in the 1940s with trials of the efficacy of Cu complexes for the treatment of arthritis [18]. Interest in the possible beneficial effects of Cu complexes was renewed with SorensonÕs suggestion in 1976 [19a] that the active form of the antiinflammatory drugs may actually be the Cu(II) complexes of such drugs in vivo. Later work corroborated his findings that copper complexes of the anti-inflammatory drugs were more active than either their parent inorganic Cu(II) salt or the parent NSAID [20]. An excellent account of these findings is available through reviews by Sorenson [19b] and more recently by Lay and co-workers [21]. A careful survey of these reports indicates that copper complexes of COX-2 inhibitors have remained less explored.
HO O
O
*
Corresponding author. Tel.: +91 20 2560 1227; fax: +91 20 2569 1728. E-mail address: [email protected] (S. Padhye). 1387-7003/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.inoche.2004.07.022
N O O
CH2CH
OH Oxaprozin(2)
CH Me
Me
MeO Aspirin(1)
OH
Me
Ibuprofen(3)
O
1072
S. Dutta et al. / Inorganic Chemistry Communications 7 (2004) 1071–1074
Oxaprozin (4,5-diphenyl-2-2 oxazole-propionic acid) (2) is the first representative member of the diaryl substituted heterocyclic COX-2 inhibitor currently in clinical practice [22]. Given in a single or divided daily doses of 600–1800 mg/day, it is found to be comparable to 2600–3900 mg/day of aspirin. It is found to be more effective in controlling inflammation and also inflicts fewer gastrointestinal side effects than aspirin. We were thus motivated to undertake synthesis and characterization of copper conjugates of 2 along with those of 1 and 3 which are non-selective COX inhibitors [23,24] and compare their superoxide radical scavenging activities which are proposed to account for their anti-inflammatory activities as well as gastric damage sparing activities [25]. Copper (II) complexes of 1 and 3 were prepared by methods reported in the literature [23,24] and the same was followed for complex 2. The measurements of SOD activity were carried out using the NBT assay method described by Bhirud and Shrivastav [26] using KO2–DMSO solution as the source of superoxide ions [27]. The blue color developed due to the formation of formazon dye was measured immediately at 560 nm against an appropriate blank. The unit SOD activity was expressed as the concentration of the complex causing 50% inhibition of KO2–DMSO mediated formazon dye formation. The crystallographic data were collected on a Bruker SMART 1000 diffractometer at 150(2) K. The structure was solved by direct methods and refined by full-matrix least-squares on F2 using the SHELXTL suite of programs [28]. All non-hydrogen atoms were refined with anisotropic atomic displacement factors and the hydrogen atoms were inserted at calculated positions using a riding model. Details of the data collection and structure solution are given in Table 1.
Table 1 Crystal data and refinement parameters for [Cu2(oxa)4]2DMSO Empirical formula Formula weight Crystal system Space group Unit cell dimensions ˚ a = 21.307(3) A ˚ b = 10.1309(15) A ˚ c = 16.128(2) A Volume Z Density (calculated) Absorption coefficient F (0 0 0) Reflections collected Independent reflections Goodness-of-fit on F2 Final R indices [I > 2r(I)] R indices (all data)
C76H68Cu2N4O14S2 1452.54 Monoclinic P2(1)/c a = 90° b = 105.581(2)° c = 90° ˚3 3353.4(9) A 2 1.439 Mg/m3 0.768 mm1 1508 27,590 7889 [R(int) = 0.0220] 1.035 R1 = 0.0310, wR2 = 0.0786 R1 = 0.0417, wR2 = 0.0837
The [Cu2(oxa)4]2DMSO complex is centrosymmetric where one of the phenyl rings on one ligand is slightly disordered, which has been modeled as 50% disorder over two positions. In addition, while the distinction between the N and O one of the heterocyclic rings seems clear, the other is less obvious (C–N, C–O 1.299 and 1.348 for ‘‘B’’ ring; 1.302 and 1.320 for ‘‘A’’ ring). This may indicate N/O disorder but it has not been modeled since it is not reflected by the atomic displacement parameters of the atoms concerned. The interaction of cupric chloride with the selected cyclooxygenase inhibitors in aqueous methanolic solvent leads to formation of dimeric metal complexes having a molecular formula, viz. [Cu2(R–COO)4L2] (R = aryl/phenyl alkonic acid and L = solvent) where each copper metal center is in an octahedral environment typified by molecular structure of copper acetate [29]. The carboxylate groups act as bridging ligands having a center of symmetry midway between the copper atoms while the solvent molecules used in the synthesis bind at the position trans to the Cu–Cu axis. The room temperature magnetic moments of all synthesized compounds are in the range 1.30–1.40 BM similar to that of copper acetate monohydrate [30] indicating antiferromagnetic exchange interactions between the adjacent copper atoms. It has been established that in the solid state, copper complexes of NSAIDs are typically monomeric or dimeric with bonding to the copper ions through the carboxylate groups [31]. The structure of the copper complex of 2 shown in Fig. 1 is in agreement with this observation. Selected bond lengths and bond angles for the copper compound are given in the supplementary material. The ‘‘paddle-wheel’’ dimeric Cu(II) structure has a Cu– ˚ with octahedral stereochemCu distance of 2.6119(5) A istry around each copper atom tetragonally elongated along the Cu–Cu–O ligands axis due to the Jahn–Teller effect [32]. The rigid geometry of the acetate-type Cu(II) dimers is due to the restricted bite of the bidentate carb˚) oxylate bridges which allows little variation (0.3 A in the Cu–Cu distances from that found in the copper ˚ ) [33]. metal (2.56 A The significant peaks in the IR spectra of copper complexes of ligands 1–3 are summarized in a table in the supplementary material. The frequency separation (Dm 175–180 cm1) between the asymmetric and symmetric vibrational carboxylate modes in present copper compounds indicate a bidentate bridging mode for these groups [34]. The electronic spectra for the three copper complexes obtained in DMSO solvent exhibit one very broad absorption near 680 nm characteristic of the dz2 ! dx2 y2 transition [35]. The band in the region 430 nm is ascribed to ligand to metal charge transfer transition (LMCT) while the higher energy bands in the UV region (340–395 nm) are thought to arise from intra-ligand p–p* transitions [36].
S. Dutta et al. / Inorganic Chemistry Communications 7 (2004) 1071–1074
1073
Fig. 1. Crystal structure for [Cu2(oxa)4]2DMSO.
Oyanagi et al. [37] have reported that NSAIDs exert their anti-inflammatory effects by inhibiting the generation of superoxide radicals, while Ichihara and Wasil [38] have shown that NSAIDs eliminate superoxide anions and HOCl produced by neutrophils. Since these radical scavenging activities of NSAIDs have been shown to enhance upon copper conjugation [39], the superoxide dismutase activity of all synthesized copper complexes and their parent ligands were evaluated using the NBT assay. A comparison of these values for the present compounds (Fig. 2) indicates that their radical scavenging activities are synergistically enhanced upon copper conjugation more so for the COX-2 inhibitor like 2.
80
> 65 60 60
IC50 / micro M
50
56.8
52.5
40
An accidental observation was made in case of aspirin ligand which generated higher concentrations of superoxide anions for the initial 60 s before bringing about its quenching. Grootveld and Halliwell [40] have suggested that this may arise from scavenging of the OH radicals by the salicylate rather than through normal metabolic reactions of enzymic hydroxylating systems indicated by the presence of small amount of 2,3-dihydroxybenzoic acid (2,3-DHB) in the blood plasma and urine of healthy adult volunteers after consuming 1 [41]. This observation suggests the hidden danger of generating oxidative stress in the initial period of administration of aspirin in the clinical practice. On the other hand, once activated the copper–aspirinate complex quenches the superoxide anions present in the solution for the remaining period. It is interesting to note that the Cu2+/1+ redox couples of the present copper conjugates (+0.30 to +0.08 V) are very similar to the redox potentials of the native SOD enzyme [42] which may be of relevance to their anti-inflammatory activities. Present studies thus clearly establish that copper conjugation in case of COX-2 inhibitors like 2 significantly enhances its SOD activity thereby offering the possibility of lowering its therapeutic dose which may be beneficial in its clinical use.
17
20
Supplementary material
10.1 0.72 SOD enzyme
CuCl2
Cu- Oxaprozin
Oxaprozin
Cu-ibuprofenate
Ibuprofen
Cu-aspirinate
Aspirin
0
Fig. 2. The SOD-like activities described by their IC50 values.
Crystallographic data have been deposited with the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336 033; e-mail; [email protected]) and are available on request quoting the deposition numbers CCDC 230424. Analytical data of the compounds and Selected bond lengths and angles for Compound 2 are provided as supplementary material in doi:10.1016/j.inoche. 2004.07.022.
1074
S. Dutta et al. / Inorganic Chemistry Communications 7 (2004) 1071–1074
Acknowledgement S.D. thanks CSIR for SRF Fellowship.
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