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Cobalt(II)-promoted hydrolysis of cephalexin: Crystal structure of the cephalosporoate–cobalt(II) complex
Inorganic Chemistry Communications 9 (2006) 322–325 www.elsevier.com/locate/inoche
Cobalt(II)-promoted hydrolysis of cephalexin: Crystal structure of the cephalosporoate–cobalt(II) complex Zhen-Feng Chen a
a,*
, Yun-Zhi Tang a, Hong Liang
*,a,
Xin-Xian Zhong a, Yan Li
b
College of Chemistry and Chemical Engineering, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, PR China b Institute of Chemistry, Chinese Academy of Sciences, Beijing 10080, PR China Received 25 November 2005; accepted 21 December 2005 Available online 2 February 2006
Abstract The cobalt(II) ion-promoted hydrolysis of the widely used cephalosporin antibiotic cephalexin is confirmed by solid crystallographic characterization of the cephalosporoate–cobalt(II) complex [Co(cephalosporoate)2] Æ 6H2O (1), obtained from an aqueous solution containing Co(OAc)2 and cephalexin. The crystal structure analysis results prove that the double bond of dihydrothiazine ring in cephalosporoate undergoes a shift from position 3–4 to 4–5 in aqueous media at low pH, with the consequent uptake of a proton at C(3) by the a face. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Cobalt; Crystal structure; Cephalexin; Hydrolysis
b-Lactam antibiotics, such as penicillins, cephalosporins and cephalexin represent the most important class of drugs against infectious diseases caused by bacteria through interfering with the enzymes responsible for cell wall peptidoglycan biosynthesis [1]. However, antibiotic efficacy is continuously challenged by the emergence of resistant bacterial strains [2–5], whose main mechanism of bacterial resistance is the production of enzymes with a serine residue known as b-lactamases [2–4,6] capable of inactivating b-lactam antibiotic by cleaving their four-membered ring. The mechanisms of action of the class A, C, and D serine-based b-lactamases are reasonably well investigated [7]. But, the class B Zn2+–b-lactamases have recently become both a major research area and clinical problem since these hydrolyze virtually all the b-lactam antibiotics [8], in which their intrinsic metal-binding site is occupied by a divalent zinc ion having a tetrahedral array of three histidines and water [8]. As with many metallo-b-lactamases, the zinc ion can be replaced by different metal ions
*
Corresponding author. E-mail address: [email protected] (Z.-F. Chen).
1387-7003/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.inoche.2005.12.008
such as Co(II) or Cd(II), and still retain some b-lactamase activity [9–11]. In order to investigate the mechanism of metallo-b-lactamases, the studies on the effects of divalent metal ions on the aqueous hydrolysis of benzyl penicillin [12], cephaloridine [12c], the b-lactam and methanolysis of nitrocefin basing on simplified model for class B b-lactamases [13] were undertaken, and the mechanism of metalion catalysis of b-lactam antibiotics also was proposed [13]. Nonetheless, to date, there is no crystallographic evidence of studies regarding the product of metal ion promoted hydrolysis of the b-lactam in solid state has been reported. Cephalexin (Scheme 1), 7-(a-amino-a-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid, is an orally administered cephalosporin widely used in the treatment of mild to moderate respiratory tract, skin and soft-tissue infections [14]. Studies by Page [12] and Navarro [13d] on the metal ion-catalyzed hydrolysis of the former cephalosporin in aqueous media reveal that the predominant degradation reaction formed a 1:1 complex and gave a tetrahedral intermediate in respect to metal ions coordinated by the b-lactam nitrogen and the adjacent carboxylate group.
Z.-F. Chen et al. / Inorganic Chemistry Communications 9 (2006) 322–325 + H NH3
+ H NH3
O
H NH O
O S 1
N5 4
2 3
H
O C
H2O
+ H NH3
-
COO
Cephalexin
N
O Co C O O (I)
Co(OAc)2
CH3
H H S
NH
H
323
O
NH O C
H H S N
O Co C O O (II)
H H H CH3
H H CH3 H
Scheme 1. Co(cephalosporoate)+.
The present work was undertaken to investigate cobalt (II)-promoted hydrolysis of cephalexin by isolating and identifying the cephalosporoate–cobalt(II) complex using X-ray crystal structural analysis. Golden-yellow block crystals of [Co(cephalosporoate)2] Æ 6H2O (1) were obtained through the reaction of cephalexin with Co(OAc)2 Æ 2H2O [15]. Comparing the IR spectra of 1 and cephalexin, there are obvious differences. The intense band attributed to C@O stretching vibrations of the b-lactamic ring with respect to the ligand disappeared in the complex, indicating that the b-lactamic ring is cleaved in the complex [16]. The bands at 1574 and 1377 cm1 are ascribed to ms ðCO 2 Þ and mas ðCO2 Þ, respec tively, and the difference between ms ðCO2 Þ and mas ðCO 2Þ (Dm) lies in the range 185–210 cm1, indicating coordination of the carboxylate group towards Co(II) in monodentate mode [17]. The band at 1695 cm1 assigned to the ligand at acid amide stretching vibrations is not shifted and indicates that acid amide has no direct participation in the bonding linkage with the metallic ions [16]. The broad band at 2600 cm1 of cephalexin attributed to NHþ 3 stretching vibration appears in the same range in 1, but such band does not appear in [Ni(CEX)(OH2)4]BPh4 (CEX, cephalexin) [18], which shows that the side-chain amino group is monoprotonated and not participate in coordination in the cephalosporoate–cobalt(II) complex. The UV-spectrum of 1 in mixed solvent of DMSO and methanol exhibits a maximum intense absorption at 213 nm, undergoing a blue-shift by 52 nm in respect to the free cephalexin, attributable to absorption of the O@C–NH chromophore of amide, showing that the b-lactamic ring is cleaved by the cobalt promoted hydrolysis. Besides, a shoulder peak appears at about 337 nm, corresponding to a charge transfer transition [16,18]. On the basis of IR and UV–Vis analyses, two probable half of cephalosporoate–cobalt(II) complexes are proposed (Scheme 1). The single-crystal X-ray diffraction analysis of 1 confirmed the formation of I (Scheme 1) [19] and is well coincident with those NMR results for b-lactamase-catalyzed hydrolysis of cephalexin [14]. As shown in Fig. 1,
Fig. 1. An ORTEP view (30% probability ellipsoids) showing the solidstate structure and atom-numbering scheme of the compound [Co(CEX)2] Æ 6H2O. The hydrogen atoms are omitted for clarity. Selected ˚ ) and angles(°): Co(1)–O(1) 2.073(4), Co(1)–O(3) bond distances (A 2.103(4), Co(1)–N(1) 2.117(4), C(2)–N(1) 1.274(6), N(1)–C(5) 1.471(6), N(2)–C(9) 1.342(7), N(2)–C(6) 1.461(7), N(3)–C(10) 1.478(6), C(1)–C(2) 1.537(7), C(2)–C(3) 1.503(7); O(1A)–Co(1)–O(1) 92.1(2), O(1)–Co(1)– O(3A) 93.12(14), O(1)–Co(1)–O(3) 165.48(14), O(3A)–Co(1)–O(3) 85.1(2), O(1)–Co(1)–N(1) 77.93(15), O(1)–Co(1)–N(1A) 91.70(15), O(3)–Co(1)– N(1) 88.37(15), O(3)–Co(1)–N(1A) 102.64(15). (#1 x + 1, y + 1, z).
1 is a 1:2 complex, in which Co atom is coordinated to two cephalosporoate, the local coordination environment around the Co(II) can be best described as distorted octahedral with O(1),O(1A),O(3),O(3A) forming the equatorial plane and N(1) and N(1A) occupying the axial positions, which is different from either the tetrahedral metal site embedded in a His3Cys coordination polyhedron or a pentacoordinated Co(II) site with three His, a Cys and a solvent ligand for Co(II)-substituted bLII [20]. The C–N bond in b-lactamic ring of the cephalexin is hydrolyzed by cobalt(II) ions’ promotion giving rise to the cephalosporoate and generates a new carboxylate group, whilst the side-chain amino group is still in its monoprotonated form. The O atom of the new carboxylate and cleaved N-atom of dihydrothiazine coordinate to Co(II) ion to form a stable six-membered ring. Simulta-
324
Z.-F. Chen et al. / Inorganic Chemistry Communications 9 (2006) 322–325
neously, the O atom of the adjacent carboxylate of the dihydrothiazine ring coordinates to Co(II) ion, and forms another stable five-membered ring. Thus each cephalosporoate acts as a tridentate ligand affording two co-edge chelating rings. Such coordination mode distinguishes greatly from that of the previous proposed by Moratal and others. In the latter cases, the cephalexin anion was regarded as a bidentate ligand, bound to the metal ion through the carbonyl and amino–NH2 groups of the side chain [16,18,21]. Our results imply that cephalexin undergoes hydrolysis in the presence of metal ions under weak acid condition in good agreement with the facts that transition metal ions cause a great increase in the rate of hydrolysis of b-lactam antibiotics [12,22]. The average ˚, Co–O and Co–N bond lengths are 2.088 and 2.117(4) A respectively, comparable to those for Co2EDTA Æ 2H2O [23]. It is noted that the C(2)–N(1) bond distance of ˚ attributable to C@N double bond [24] and 1.274(6) A ˚ attributable to C–C single bond, C(2)–C(3) of 1.503(7) A confirmed the solution NMR results, namely, the cephalosporoate compound in aqueous media at an acidic pH undergoes a shift in the double bond of dihydrothiazine ring from position 3–4 to 4–5, with the consequent uptake of a proton at C(3). In addition, the configuration of 1 proves that the uptake of the proton by the a face (compound I), not by the b face (compound II), indicating that this reaction is controlled by steric constraints, due to the bulky phenyl group on the other side of the ring. The other geometrical data of ligand are in normal range comparable with those of the cephalosporin [25]. The cell packing of 1 shows that the uncoordinated oxygen atoms of carboxylate, amide, side-chain ammonium groups in cephalosporoate and co-crystallized water molecules are involved in the H-bonding system as found in the clathrate-type complexes formed by cephalexin with a vari-
Fig. 2. Packing view of compound 1 showing 3D network formed via hydrogen bonds.
ety of naphthalene derivatives [25,26], giving a threedimensional network (Fig. 2). Acknowledgements The authors thank the National Natural Science Foundation of China (No. 20361002, 30460153), Chinese Ministry of Education (TRAPOYT, NCET-04-0836) for financial support. The authors thank Dr. Xuhui Zhu at the Institute of polymer optoelectronic materials and devices, South China University of Technology for helpful discussions. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.inoche. 2005.12.008. References [1] A. Gringauz, Introduction to Medicinal Chemistry, Wiley-VCH Inc., New York, 1997, 216. [2] A. Philippon, J. Dusart, B. Joris, J.-M. Fre`re, Cell Mol. Life Sci. 54 (1998) 341. [3] J.-M. Fre`re, Mol. Microbiol. 16 (1995) 385. [4] K. Bush, G.A. Jacoby, A.A. Medeiros, Antimicrob. Ag. Chemother. 39 (1995) 1211. [5] R. Hakenbeck, J. Coyette, Cell Mol. Life Sci 54 (1998) 332. [6] R.P. Ambler, Philos. Trans. Roy. Soc. London – Ser. B. 289 (1980) 321. [7] D.J. Payne, J. Med. Microbiol. 39 (1993) 93. [8] J.F. Fisher, S.O. Meroueh, S. Mobashery, Chem. Rev. 105 (2005) 395, and reference therein. [9] R.B. Davies, E.P. Abraham, Biochem. J. 143 (1974) 129. [10] S.M. Fabiane, M.K. Sohi, T. Wan, D.J. Payne, J.H. Bateson, T. Mitchell, B.J. Sutton, Biochemistry 37 (1998) 12404. [11] J.A. Cricco, E.G. Orellano, R.M. Rasia, E.A. Ceccarelli, A.J. Vila, Coordin. Chem. Rev. 190-192 (1999) 519, and reference therein. [12] (a) W.A. Cressman, E.T. Sugita, J.T. Doluiso, P.J. Niebergall, J. Pharm. Sci. 58 (1969) 1471; (b) N.P. Gensmantel, E.W. Gowling, M.I. Page, J. Chem. Soc., Perkin Trans. 2 (1978) 335; (c) N.P. Gensmantel, P. Proctor, M.I. Page, J. Chem. Soc., Perkin Trans. 2 (1980) 1725. [13] (a) P.J. Montoya-Pelaez, G.T.T. Gibson, A.A. Neverov, R.S. Browm, Inorg. Chem. 42 (2003) 8624; (b) P.J. Montoya-Pelaez, R.S. Browm, Inorg. Chem. 41 (2002) 309; (c) M.I. Page, A.P. Laws, Chem. Commun. (1998) 1609; (d) J.H. Martı´nez, P.G. Navarro, A.A.M. Garcia, P.J.M. de las Parras, Int. J. Biol. Macromol. 25 (1999) 337. [14] B. Vilanova, J. Frau, J. Donoso, F. Mun˜oz, F.G. Blanco, J. Chem. Soc., Perkin Trans. 2 (1997) 2439. [15] The reaction of Co(OAc)2 Æ 2H2O (1 mmol, 0.213 g), cephalexin (2 mmol, 0.695 g), (CH3OH 5 mL), (H2O 15 mL) for six days at 37 °C yield a yellow polyhedral crystalline product. The yield of 1 is 55% based on cephalexin. Anal. Calc.: C, 43.17; H, 5.02; N, 9.47. Found: C, 43.10%; H, 4.97%; N, 9.42%. IR (KBr, cm1): 3485(m), 3065(m), 2600(m), 1695(s), 1608(m), 1574(s), 1460(m), 1377(s), 1330(m), 1264(m), 1195(w), 1140(w), 1080(m), 1648(w), 1029(w), 929(w), 902(m), 853(w), 789(m), 679(w), 550(w), 508(w). [16] M.J. Lozano, J. Borra´s, J. Inorg. Biochem. 31 (1987) 187. [17] A.H. Osman, N.A. El-Maali, A.A.M. Aly, G.A.A. Al-Hazmi, Syn. React. Inorg. Met.– Org. Chem. 32 (2002) 763. [18] J.M. Moratal, J. Borras, A. Donaire, M.J. Martinez, Inorg. Chim. Acta 162 (1989) 113.
Z.-F. Chen et al. / Inorganic Chemistry Communications 9 (2006) 322–325 [19] Crystal data for 1: C32H45N6O16S2, Mr = 892.78, orthorhombic, space ˚ , b = 19.8449(9) A ˚ , c = 9.1068(3) group P2(1)2(1)2, a = 10.8790(3) A ˚ , V = 1966.09(12) A ˚ 3, Z = 2, Dc = 1.506 Mg/m3, l = 0.621 mm1, A R1 = 0.0391, wR2 = 0.0873 (4386 reflections), T = 293 K, Flack parameter, v = 0.00(3). Crystallographic data for the crystal structure reported in this paper have been deposited with the Cambridge Crystallographic Data Center (CCDC No. 283024). This material can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: C44 1223 336033; e-mail: [email protected]. uk). [20] (a) G.S. Baldwin, A. Galdes, H.A.O. Hill, S.G. Waley, E.P. Abraham, J. Inorg. Biochem. 13 (1980) 189; (b) R. Bicknell, A. Schaeffer, S.G. Waley, D.S. Auld, Biochemistry 25 (1986) 7208; (c) R. Bicknell, S.G. Waley, Biochemistry 24 (1985) 6878.
325
[21] K.J. Tack, C.H. Keyserling, J. Mccarty, J. Hedrick, Antimicrob. Ag. Chemother. 41 (1997) 739. [22] M.I. Page, Account. Chem. Res. 17 (1984) 144. [23] P. Gomez-Romero, G.B. Jameson, N. Casan-Pastor, E. Coronado, D. Beltran, Inorg. Chem. 25 (1986) 3171. [24] S. Deguchi, M. Fujioka, Y. Okamoto, T. Yasuda, N. Nakamura, K. Yamaguchi, S. Suzuki, J. Chem. Soc., Dalton Trans. (1996) 1967. [25] G.J. Kemperman, R. de Gelder, F.J. Dommerholt, P.C. RaemakersFranken, A.J.H. Klunder, B. Zwanenburg, Chem. Eur. J. 5 (1999) 2163. [26] G.J. Kemperman, R. de Gelder, F.J. Dommerholt, P.C. RaemakersFranken, A.J.H. Klunder, B. Zwanenburg, Eur. J. Org. Chem. (2001) 3641.
Cobalt(II)-promoted hydrolysis of cephalexin: Crystal structure of the cephalosporoate–cobalt(II) complex Zhen-Feng Chen a
a,*
, Yun-Zhi Tang a, Hong Liang
*,a,
Xin-Xian Zhong a, Yan Li
b
College of Chemistry and Chemical Engineering, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, PR China b Institute of Chemistry, Chinese Academy of Sciences, Beijing 10080, PR China Received 25 November 2005; accepted 21 December 2005 Available online 2 February 2006
Abstract The cobalt(II) ion-promoted hydrolysis of the widely used cephalosporin antibiotic cephalexin is confirmed by solid crystallographic characterization of the cephalosporoate–cobalt(II) complex [Co(cephalosporoate)2] Æ 6H2O (1), obtained from an aqueous solution containing Co(OAc)2 and cephalexin. The crystal structure analysis results prove that the double bond of dihydrothiazine ring in cephalosporoate undergoes a shift from position 3–4 to 4–5 in aqueous media at low pH, with the consequent uptake of a proton at C(3) by the a face. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Cobalt; Crystal structure; Cephalexin; Hydrolysis
b-Lactam antibiotics, such as penicillins, cephalosporins and cephalexin represent the most important class of drugs against infectious diseases caused by bacteria through interfering with the enzymes responsible for cell wall peptidoglycan biosynthesis [1]. However, antibiotic efficacy is continuously challenged by the emergence of resistant bacterial strains [2–5], whose main mechanism of bacterial resistance is the production of enzymes with a serine residue known as b-lactamases [2–4,6] capable of inactivating b-lactam antibiotic by cleaving their four-membered ring. The mechanisms of action of the class A, C, and D serine-based b-lactamases are reasonably well investigated [7]. But, the class B Zn2+–b-lactamases have recently become both a major research area and clinical problem since these hydrolyze virtually all the b-lactam antibiotics [8], in which their intrinsic metal-binding site is occupied by a divalent zinc ion having a tetrahedral array of three histidines and water [8]. As with many metallo-b-lactamases, the zinc ion can be replaced by different metal ions
*
Corresponding author. E-mail address: [email protected] (Z.-F. Chen).
1387-7003/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.inoche.2005.12.008
such as Co(II) or Cd(II), and still retain some b-lactamase activity [9–11]. In order to investigate the mechanism of metallo-b-lactamases, the studies on the effects of divalent metal ions on the aqueous hydrolysis of benzyl penicillin [12], cephaloridine [12c], the b-lactam and methanolysis of nitrocefin basing on simplified model for class B b-lactamases [13] were undertaken, and the mechanism of metalion catalysis of b-lactam antibiotics also was proposed [13]. Nonetheless, to date, there is no crystallographic evidence of studies regarding the product of metal ion promoted hydrolysis of the b-lactam in solid state has been reported. Cephalexin (Scheme 1), 7-(a-amino-a-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid, is an orally administered cephalosporin widely used in the treatment of mild to moderate respiratory tract, skin and soft-tissue infections [14]. Studies by Page [12] and Navarro [13d] on the metal ion-catalyzed hydrolysis of the former cephalosporin in aqueous media reveal that the predominant degradation reaction formed a 1:1 complex and gave a tetrahedral intermediate in respect to metal ions coordinated by the b-lactam nitrogen and the adjacent carboxylate group.
Z.-F. Chen et al. / Inorganic Chemistry Communications 9 (2006) 322–325 + H NH3
+ H NH3
O
H NH O
O S 1
N5 4
2 3
H
O C
H2O
+ H NH3
-
COO
Cephalexin
N
O Co C O O (I)
Co(OAc)2
CH3
H H S
NH
H
323
O
NH O C
H H S N
O Co C O O (II)
H H H CH3
H H CH3 H
Scheme 1. Co(cephalosporoate)+.
The present work was undertaken to investigate cobalt (II)-promoted hydrolysis of cephalexin by isolating and identifying the cephalosporoate–cobalt(II) complex using X-ray crystal structural analysis. Golden-yellow block crystals of [Co(cephalosporoate)2] Æ 6H2O (1) were obtained through the reaction of cephalexin with Co(OAc)2 Æ 2H2O [15]. Comparing the IR spectra of 1 and cephalexin, there are obvious differences. The intense band attributed to C@O stretching vibrations of the b-lactamic ring with respect to the ligand disappeared in the complex, indicating that the b-lactamic ring is cleaved in the complex [16]. The bands at 1574 and 1377 cm1 are ascribed to ms ðCO 2 Þ and mas ðCO2 Þ, respec tively, and the difference between ms ðCO2 Þ and mas ðCO 2Þ (Dm) lies in the range 185–210 cm1, indicating coordination of the carboxylate group towards Co(II) in monodentate mode [17]. The band at 1695 cm1 assigned to the ligand at acid amide stretching vibrations is not shifted and indicates that acid amide has no direct participation in the bonding linkage with the metallic ions [16]. The broad band at 2600 cm1 of cephalexin attributed to NHþ 3 stretching vibration appears in the same range in 1, but such band does not appear in [Ni(CEX)(OH2)4]BPh4 (CEX, cephalexin) [18], which shows that the side-chain amino group is monoprotonated and not participate in coordination in the cephalosporoate–cobalt(II) complex. The UV-spectrum of 1 in mixed solvent of DMSO and methanol exhibits a maximum intense absorption at 213 nm, undergoing a blue-shift by 52 nm in respect to the free cephalexin, attributable to absorption of the O@C–NH chromophore of amide, showing that the b-lactamic ring is cleaved by the cobalt promoted hydrolysis. Besides, a shoulder peak appears at about 337 nm, corresponding to a charge transfer transition [16,18]. On the basis of IR and UV–Vis analyses, two probable half of cephalosporoate–cobalt(II) complexes are proposed (Scheme 1). The single-crystal X-ray diffraction analysis of 1 confirmed the formation of I (Scheme 1) [19] and is well coincident with those NMR results for b-lactamase-catalyzed hydrolysis of cephalexin [14]. As shown in Fig. 1,
Fig. 1. An ORTEP view (30% probability ellipsoids) showing the solidstate structure and atom-numbering scheme of the compound [Co(CEX)2] Æ 6H2O. The hydrogen atoms are omitted for clarity. Selected ˚ ) and angles(°): Co(1)–O(1) 2.073(4), Co(1)–O(3) bond distances (A 2.103(4), Co(1)–N(1) 2.117(4), C(2)–N(1) 1.274(6), N(1)–C(5) 1.471(6), N(2)–C(9) 1.342(7), N(2)–C(6) 1.461(7), N(3)–C(10) 1.478(6), C(1)–C(2) 1.537(7), C(2)–C(3) 1.503(7); O(1A)–Co(1)–O(1) 92.1(2), O(1)–Co(1)– O(3A) 93.12(14), O(1)–Co(1)–O(3) 165.48(14), O(3A)–Co(1)–O(3) 85.1(2), O(1)–Co(1)–N(1) 77.93(15), O(1)–Co(1)–N(1A) 91.70(15), O(3)–Co(1)– N(1) 88.37(15), O(3)–Co(1)–N(1A) 102.64(15). (#1 x + 1, y + 1, z).
1 is a 1:2 complex, in which Co atom is coordinated to two cephalosporoate, the local coordination environment around the Co(II) can be best described as distorted octahedral with O(1),O(1A),O(3),O(3A) forming the equatorial plane and N(1) and N(1A) occupying the axial positions, which is different from either the tetrahedral metal site embedded in a His3Cys coordination polyhedron or a pentacoordinated Co(II) site with three His, a Cys and a solvent ligand for Co(II)-substituted bLII [20]. The C–N bond in b-lactamic ring of the cephalexin is hydrolyzed by cobalt(II) ions’ promotion giving rise to the cephalosporoate and generates a new carboxylate group, whilst the side-chain amino group is still in its monoprotonated form. The O atom of the new carboxylate and cleaved N-atom of dihydrothiazine coordinate to Co(II) ion to form a stable six-membered ring. Simulta-
324
Z.-F. Chen et al. / Inorganic Chemistry Communications 9 (2006) 322–325
neously, the O atom of the adjacent carboxylate of the dihydrothiazine ring coordinates to Co(II) ion, and forms another stable five-membered ring. Thus each cephalosporoate acts as a tridentate ligand affording two co-edge chelating rings. Such coordination mode distinguishes greatly from that of the previous proposed by Moratal and others. In the latter cases, the cephalexin anion was regarded as a bidentate ligand, bound to the metal ion through the carbonyl and amino–NH2 groups of the side chain [16,18,21]. Our results imply that cephalexin undergoes hydrolysis in the presence of metal ions under weak acid condition in good agreement with the facts that transition metal ions cause a great increase in the rate of hydrolysis of b-lactam antibiotics [12,22]. The average ˚, Co–O and Co–N bond lengths are 2.088 and 2.117(4) A respectively, comparable to those for Co2EDTA Æ 2H2O [23]. It is noted that the C(2)–N(1) bond distance of ˚ attributable to C@N double bond [24] and 1.274(6) A ˚ attributable to C–C single bond, C(2)–C(3) of 1.503(7) A confirmed the solution NMR results, namely, the cephalosporoate compound in aqueous media at an acidic pH undergoes a shift in the double bond of dihydrothiazine ring from position 3–4 to 4–5, with the consequent uptake of a proton at C(3). In addition, the configuration of 1 proves that the uptake of the proton by the a face (compound I), not by the b face (compound II), indicating that this reaction is controlled by steric constraints, due to the bulky phenyl group on the other side of the ring. The other geometrical data of ligand are in normal range comparable with those of the cephalosporin [25]. The cell packing of 1 shows that the uncoordinated oxygen atoms of carboxylate, amide, side-chain ammonium groups in cephalosporoate and co-crystallized water molecules are involved in the H-bonding system as found in the clathrate-type complexes formed by cephalexin with a vari-
Fig. 2. Packing view of compound 1 showing 3D network formed via hydrogen bonds.
ety of naphthalene derivatives [25,26], giving a threedimensional network (Fig. 2). Acknowledgements The authors thank the National Natural Science Foundation of China (No. 20361002, 30460153), Chinese Ministry of Education (TRAPOYT, NCET-04-0836) for financial support. The authors thank Dr. Xuhui Zhu at the Institute of polymer optoelectronic materials and devices, South China University of Technology for helpful discussions. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.inoche. 2005.12.008. References [1] A. Gringauz, Introduction to Medicinal Chemistry, Wiley-VCH Inc., New York, 1997, 216. [2] A. Philippon, J. Dusart, B. Joris, J.-M. Fre`re, Cell Mol. Life Sci. 54 (1998) 341. [3] J.-M. Fre`re, Mol. Microbiol. 16 (1995) 385. [4] K. Bush, G.A. Jacoby, A.A. Medeiros, Antimicrob. Ag. Chemother. 39 (1995) 1211. [5] R. Hakenbeck, J. Coyette, Cell Mol. Life Sci 54 (1998) 332. [6] R.P. Ambler, Philos. Trans. Roy. Soc. London – Ser. B. 289 (1980) 321. [7] D.J. Payne, J. Med. Microbiol. 39 (1993) 93. [8] J.F. Fisher, S.O. Meroueh, S. Mobashery, Chem. Rev. 105 (2005) 395, and reference therein. [9] R.B. Davies, E.P. Abraham, Biochem. J. 143 (1974) 129. [10] S.M. Fabiane, M.K. Sohi, T. Wan, D.J. Payne, J.H. Bateson, T. Mitchell, B.J. Sutton, Biochemistry 37 (1998) 12404. [11] J.A. Cricco, E.G. Orellano, R.M. Rasia, E.A. Ceccarelli, A.J. Vila, Coordin. Chem. Rev. 190-192 (1999) 519, and reference therein. [12] (a) W.A. Cressman, E.T. Sugita, J.T. Doluiso, P.J. Niebergall, J. Pharm. Sci. 58 (1969) 1471; (b) N.P. Gensmantel, E.W. Gowling, M.I. Page, J. Chem. Soc., Perkin Trans. 2 (1978) 335; (c) N.P. Gensmantel, P. Proctor, M.I. Page, J. Chem. Soc., Perkin Trans. 2 (1980) 1725. [13] (a) P.J. Montoya-Pelaez, G.T.T. Gibson, A.A. Neverov, R.S. Browm, Inorg. Chem. 42 (2003) 8624; (b) P.J. Montoya-Pelaez, R.S. Browm, Inorg. Chem. 41 (2002) 309; (c) M.I. Page, A.P. Laws, Chem. Commun. (1998) 1609; (d) J.H. Martı´nez, P.G. Navarro, A.A.M. Garcia, P.J.M. de las Parras, Int. J. Biol. Macromol. 25 (1999) 337. [14] B. Vilanova, J. Frau, J. Donoso, F. Mun˜oz, F.G. Blanco, J. Chem. Soc., Perkin Trans. 2 (1997) 2439. [15] The reaction of Co(OAc)2 Æ 2H2O (1 mmol, 0.213 g), cephalexin (2 mmol, 0.695 g), (CH3OH 5 mL), (H2O 15 mL) for six days at 37 °C yield a yellow polyhedral crystalline product. The yield of 1 is 55% based on cephalexin. Anal. Calc.: C, 43.17; H, 5.02; N, 9.47. Found: C, 43.10%; H, 4.97%; N, 9.42%. IR (KBr, cm1): 3485(m), 3065(m), 2600(m), 1695(s), 1608(m), 1574(s), 1460(m), 1377(s), 1330(m), 1264(m), 1195(w), 1140(w), 1080(m), 1648(w), 1029(w), 929(w), 902(m), 853(w), 789(m), 679(w), 550(w), 508(w). [16] M.J. Lozano, J. Borra´s, J. Inorg. Biochem. 31 (1987) 187. [17] A.H. Osman, N.A. El-Maali, A.A.M. Aly, G.A.A. Al-Hazmi, Syn. React. Inorg. Met.– Org. Chem. 32 (2002) 763. [18] J.M. Moratal, J. Borras, A. Donaire, M.J. Martinez, Inorg. Chim. Acta 162 (1989) 113.
Z.-F. Chen et al. / Inorganic Chemistry Communications 9 (2006) 322–325 [19] Crystal data for 1: C32H45N6O16S2, Mr = 892.78, orthorhombic, space ˚ , b = 19.8449(9) A ˚ , c = 9.1068(3) group P2(1)2(1)2, a = 10.8790(3) A ˚ , V = 1966.09(12) A ˚ 3, Z = 2, Dc = 1.506 Mg/m3, l = 0.621 mm1, A R1 = 0.0391, wR2 = 0.0873 (4386 reflections), T = 293 K, Flack parameter, v = 0.00(3). Crystallographic data for the crystal structure reported in this paper have been deposited with the Cambridge Crystallographic Data Center (CCDC No. 283024). This material can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: C44 1223 336033; e-mail: [email protected]. uk). [20] (a) G.S. Baldwin, A. Galdes, H.A.O. Hill, S.G. Waley, E.P. Abraham, J. Inorg. Biochem. 13 (1980) 189; (b) R. Bicknell, A. Schaeffer, S.G. Waley, D.S. Auld, Biochemistry 25 (1986) 7208; (c) R. Bicknell, S.G. Waley, Biochemistry 24 (1985) 6878.
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