Inorg. Chem. 1988, 27, 3131-3137
3131
Contribution from the Institute of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Synthesis and Characterization of N(8)-Coordinated Metal Complexes of the Anti-Hyperuricemia Drug Allopurinol: Bis (allopurinol)triaqua(sulfato)metal(11) Hydrates (Metal = Co, Ni, Zn, Cd) Gaby Hanggi, Helmut Schmalle, and Erich Dubler* Received January 5, 1988
Four metal complexes of allopurinol have been synthesized in the form of single crystals from aqueous solutions: bis(a1lopurinol)triaqua(sulfato)metal(II) hydrates with the general formula M"(allop~rinol)~S0~~4H~O (M = Co, Ni, Zn, Cd). They crystallize in the triclinic space group PI with 2 = 2 formula units per cell. Cell dimensions are a = 8.527 (1) A,b = 9.927 (3) A, c = 10.550 (1) A, a = 96.00 (2)O, j3 = 92.75 ( 1 ) O , y = 95.95 ( 2 ) O , and V = 881.8 (5) A3 for the cobalt complex, a = 8.479 (2) A, b = 9.849 (3) A, c = 10.558 (3) A,a = 95.74 (2)O, j3 = 92.60 ( 2 ) O , y = 95.06 (2)", and V = 872.6 (8) A3 for the nickel com lex, a = 8.548 (3) A, b = 9.892 (2) A, c = 10.565 (3) A,a = 95.95 (2)O, j3 = 92.83 (3)O, y = 95.34 (2)', and V = 883.2 (8) for the zinc complex, and a = 8.678 (3) A, b = 10.102 (3) A, c = 10.594 (4) A, a = 96.02 (3)O, j3 = 92.62 (3)O, y = 95.43 (3)O, and V = 918.0 (10) A' for the cadmium complex. The structures of the cobalt and cadmium complexes were solved by Patterson syntheses on the basis of 7474 and 9962 observed reflections and refined to R values of 0.033 and 0.029, respectively. On the basis of single-crystaland powder X-ray diffraction data, thermoanalyticalmeasurements, and IR spectra, the nickel and zinc complexes are shown to be isostructural with their cobalt and cadmium analogues. The structure of these complexes may be represented by the formula [M"S04(C~H4N40)2(H20)3]~H20. The metal ions are situated in the center of a slightly distorted octahedron with two N(8)-coordinatingallopurinol ligands in trans positions. N(8) and not N(9) is the preferred coordination site of neutral, unsubstituted allopurinol in the complexes described here. Allopurinol is protonated at N(l) and N(9); the corresponding H atoms as well as the H atoms of the water molecules are involved in an extended hydrogen-bonding system. Stacking of the purine bases with essentially superimposed six-membered rings and mean stacking distances of about 3.24 8, are
1,
observed. Hydrogen-bonding distances resulting from the structure analysis and coordination of the metal to a ring nitrogen atom are consistent with the interpretation of the IR data. The thermal decomposition of the complexes is a two-step reaction, including a dehydration followed by a decomposition to the corresponding metal oxides.
Introduction The interaction of metal ions with nucleic acid bases, nucleosides, or nucleotides has been the subject of numerous chemical and crystallographic One interesting aspect of such investigations is the antitumor activity established for different metal complexes, as e.g. C ~ S - P ~ ( N H ~which ) ~ Cis~ believed ~ , ~ to be based on the interaction of the metal atom with cellular DNA. Whereas the formation of metal complexes of adenine and guanine, the major purine bases occuring in D N A and RNA, has been studied intensively in solution as well as in the solid ~ t a t e ,only ~.~ a small amount of crystallographic data of metal complexes of oxopurines (Figure 1) such as hypoxanthine (I) and its 7-deaza-8-aza isomer allopurinol (IV), xanthine (11), and uric acid (111) have been reported. These complexes have been proven much more difficult to c r y ~ t a l l i z e . ~ Xanthine oxidase is a molybdenum- and iron-containing enzyme, which is capable of catalyzing the oxidation of a wide variety of aromatic heterocycles and aldehydes to their hydroxy derivatives6 A biologically important reaction catalyzed by this enzyme is the oxidation of hypoxanthine, formed by degradation of nucleic acids, via xanthine to uric acid, which subsequently is released from the active site of the enzyme. In the case of metabolic errors, the uric acid level may be increased and sodium hydrogenurate hydrate crystals are deposited in joints. This disease, known as gout, is clinically treated by the drug allopurinol (pyrazolo[3,4d] pyrimidin-6-one), Allopurinol is currently the drug of choice, worldwide, for the treatment of hyperuricemia and gouty arthritis? It is also a substrate for xanthine oxidase. The enzymatic oxidation product of allopurinol is alloxanthine (V; pyrazolo[3,4-d]pyrimidin-2,6-dione), which is believed to bind extremely tightly to the reduced form of the molybdenum center to inhibit the enzyme and thus to inhibit the production of uric acid.6 Patients receiving the drug allopurinol therefore excrete much of their purine as hypoxanthine and xanthine. For the coordination of the molybdenum center by alloxanthine different structural models have been developed. A coordination of the nitrogen atom N(8) to Mo(1V) has been proposed on the basis of EPR experiments by Hawkes et a1.* whereas a Mo(1V) alloxanthine complex coordinating through N(9) and stabilized *To whom correspondence should be addressed.
0020-1669/88/ 1327-3131$01.50/0
by a N(8)-H-N(enzyme) hydrogen bond is assumed by Stiefel? According to Stiefel, N(9) coordination to molybdenum by xanthine is also believed to occur in the biological mechanism of oxidation of this molecule (where N(7), but not C(8), would represent an alternative coordination site) to uric acid. Alternative models including Mo(1V) binding of xanthine followed by disulfide attack at C(8), as well as a model where a nucleophile X- attached to molybdenum first attacks C(8), followed by Mo(1V) attachment to N(9), have also been presented.' In addition, allopurinol is used in the treatment of leukemia in conjunction with the antitumor drug 6-mercaptopurine. The inhibition of xanthine oxidase by allopurinol reduces the elimination of 6-mercaptopurine, whose oxidation is also catalyzed by this enzyme.IO Crystallographic investigationsof metal complexes of allopurinol and of 8-azahypoxanthine (VI) elucidate the potential coordinating capacity of the nitrogen atom N(8) and allow a comparison with the metal binding sites N(7) and N(9) of the naturally occurring purines hypoxanthine and xanthine. Coordination sites of unsubstituted oxopurines established by X-ray crystallography so far are as follows: (a) N ( 7 ) of monodentate hypoxanthine in M11(hyxan)S04.5H20with M = Co, Ni,",12 in Ru"'(hyxan)(NH3)5C13-3H20,13 and in Cd*'(8-azahy~an-)~-4H~O~~ (hyxan = (1) Barton, J. K.; Lippard, S. J. In Nucleic Acid Metal Interactions; Spiro, T. G., Ed.; Metal Ions in Biology 1; Wiley: New York, 1980; p 31.
(2) Marzilli, L. G. Prog. Inorg. Chem. 1977,23, 255 and references therein. (3) Rosenberg, B.; Van Camp, L.; Trosko, J. E.; Mansour, V. H. Nature (London) 1969, 222, 385. (4) Hodgson, D. J. Prog. Inorg. Chem. 1977, 23, 211. (5) Sletten, E. G. The Jerusalem Symposia on Quantum Chemistry and Biochemistry; Jerusalem Academy of Sciences and Humanities: Jerusalem, 1977; Vol. 9, p. 53, and references therein. (6) Hille, R.; Massey, V. In Nucleic Acid Metal Interactions; Spiro, T. G., Ed.; Metal Ions in Biology 7; Wiley: New York, 1985; p 443. (7) Robbins, K.; Revankar, G. R.; O'Brien, D. E.; Springer, R. H.; Novinson, T.; Albert, A.; Senga, K.; Miller, J. P.; Streeter, D. G. J . Heterocycl. Chem. 1985, 22, 601 and references therein. (8) Hawkes, T. R.; George, G. N.; Bray, R. C. Biochem. J. 1984,218,961. (9) Stiefel, E. I. Prog. Inorg. Chem. 1977, 22, 1 and references therein. (10) Mutschler, E. Arzneimittelwirkungen, Lehrbuch der Pharmakologie; Wissenschaftliche Verlagsgesellschaft: Stuttgart, FRG, 198 1; p 193. (11) Dubler, E.; Hanggi, G.; Bensch, W. J. Inorg. Biochem. 1987,29, 269. (12) Dubler, E.; Hanggi, G.; Schmalle, H. Acta Crystallogr., Sect. C Cryst. Struct. Comrnum. 1987, C43, 1872.
0 1988 American Chemical Society
3132 Inorganic Chemistry, Vol. 27, No. 18, 1988 O
0
0
H
I
H
IV
H
H
V
VI
Figure 1. Formula and numbering scheme of oxypurines: (I) hypoxanthine; (11) xanthine; (111) uric acid; (IV) allopurinol (pyrazolo[3,4dlpyrimidin-6-one); (V) alloxanthine (pyrazolo[3,4-d]pyrimidin-2,6dione); (VI) 8-azahypoxanthine.
hypoxanthine; 8-azahyxan = 8-azahypoxanthine); (b) N ( 9 ) of monodentate purines in C ~ " ( x a n ) ~ C 1 ~ . 2 Hand ~ OCu11(Hur-)2. 6H20,I5 in C ~ ~ ~ ( a l l o + )inC lthe ~ , ~isostructural ~ complexes Zn11(8-azahyxan-)2.4H2017 and Hg11(8-azahyxan-)2-4H20,18 and in C0~~~(xan-)(drng-)~(Bu~P).H~O~CH~0H~~ (xan = xanthine; Hur = hydrogenurate; all0 = allopurinol; dmg = dimethylglyoxime); (c) N(3) and N ( 9 ) of bridging hypoxanthine in the dimeric complexes C ~ " ( h y x a n ) ~ C 1 ~ . 3 Hand ~ OM"(hyxan)S04.2H20, ~~ M = Cu, Zn, Cd;21 (d) N ( 3 ) and N(7) of hypoxanthine in C ~ ~ ~ ( h y x a n ) S O ~ . Hforming ~ 0 ' * infinite copper-hypoxanthine chains; (e) N ( I ) and N ( 9 ) in (CH3Hg),(8-azahyxan2-)17 and (CH3Hg)2(allo2-).2H20;22(f) N ( 9 ) ,N( 7 ) / O ( 6 ) ,and N( I )/O( 2) chelating xanthine in a trinuclear 3: 1 titanocene-xanthine complex of composition [($-C5H5)2Ti]3Cl(xan2-).23 Whereas all (with one exception) hypoxanthine-metal complexes structurally characterized by X-ray crystallography involve the neutral ligand, the two structures of unsubstituted allopurinol-metal complexes published up to now deal with either deprotonated or protonated ionic ligands. In this paper, the synthesis and X-ray crystallographic, thermogravimetric, and infrared spectroscopic characterization of the first metal complexes of neutral, unsubstituted allopurinol are presented.
Experimental Section Synthesis. Allopurinol was purchased from Sigma Chemical Co., Bble, Switzerland, and the metal sulfates were obtained from Fluka, Buchs, Switzerland. All chemicals were used without further purification. C O ~ ~ ( ~ U O ) , S O ~ . ~To H ,aOsolution . of 100 mg (0.73 mmol) of allopurinol in 10 mL of H 2 0 was added 3.0 g (10.7 mmol) of CoS04.7HzO dissolved in 10 mL of H20. The resulting mixture was heated to boiling and then kept for crystallization at 75 'C. After 2 weeks rose-colored crystals were formed. Ni11(allo)zS04.4H20.This compound was prepared by heating a solution of 100 mg (0.73 mmol) of allopurinol and 5.0 g (19.0 mmol) of NiS04-6Hz0in 20 mL of HzO to boiling and keeping it for crystallization at 75 'C. One week later green crystals could be isolated from the solution.
Kastner, M. E.; Coffey, K. F. K.; Clarke, M. J. K.; Edmonds, S. E.; Eriks, K. J . Am. Chem. SOC.1981, 103, 5747. Purnell, L. F.; Estes, E. D.; Hodgson, D. J. J . Am. Chem. Soc. 1976, 98, 740. Dubler, E.; Hanggi, G. Abstracts of Papers, 24th International Conference on Coordination Chemistry, Athens, Greece; Pergamon: Oxford, England, 1986; p 730. Sheldrick, W. S.; Bell, P. Z . Naturforsch., B Chem. Sei. 1987, 4 2 4 195. Sheldrick, W. S.; Bell, P. 2.Naturforsch., B: Anorg. Chem., Org. Chem. 1986, 41B, 1 1 17. Graves, B. J.; Hodgson, D. J. Inorg. Chem. 1981, 20, 2223. Marzilli, L. G; Epps, L. A,; Sorrell, T.; Kistenmacher, T. J. J . Am.
Hanggi et al. Table I. Analytical Data (%) of Metal-Allopurinol Complexes of the Type M(all0)~S0~-4H~O' compd Cb H N S HzO M = CO, C O C ~ O H I ~ N ~ O24.06 ~ ~ S , 3.23 22.44 6.42 14.4 M , = 499.28 24.05 3.10 22.48 6.47 14.5 3.23 22.45 6.42 14.4 M = Ni, N i C l o H 1 6 N 8 0 1 ~ 24.07 , M , = 499.04 23.95 3.24 22.70 6.51 14.8 M = Zn, ZnCloH16N80$, 23.75 3.19 22.16 6.34 14.2 M , = 505.72 23.68 3.14 22.44 6.19 14.2 M = Cd, C ~ C I O H ~ ~ N ~ 21.73 O ~ O S2.92 , 20.27 5.80 13.0 M, = 552.75 21.69 2.94 20.40 5.82 12.8
The water content was derived from thermogravimetric analysis. bThe first value given is the calculated value, and the second value, the observed value. Table 11. Structure Determination Parameters of M(allo)zS04~4H20
calcd density, pcm-' obsd density, cryst size, mm abs coeff, p, cm-I max transmission coeff min transmission coeff data collecn range 28, deg range of h,k,l measd no. of rflcns measd (including stds) no. of unique rflcns no. of rflcns with I L 3d1) no. of variables R Rw
M = Co 1.88 1.88 0.40 X 0.38 X 0.13 10.9 0.890 0.730 2-80 -15,15/-17,17/0,19 1 1 569
M = Cd 2.00 2.01 0.31 X 0.44 X 0.57 13.3 0.686 0.606 2-80 -1 5,15/-18,18/0,19 12017
10887 7474
1 1 328 9962
335 0.033 0.037
335 0.029 0.035
Zn11(allo)2S04.4Hz0.This complex was synthesized by adding 3.0 g (10.4 mmol) of ZnS04.7Hz0 in 2.5 mL of HzO to a solution of 50 mg (0.37 mmol) of allopurinol in 2.5 mL of H20. The resulting solution was kept for crystallization at 75 'C. After 5 days colorless crystals were formed. Cd11(aUo)zS04.4H20. To 100 mg (0.73 mmol) of allopurinol dissolved in 5 mL of H 2 0 was added a solution of 5.2 g (20.3 mmol) of CdS04.8/3Hz0in 5 mL of HzO.The reaction mixture was heated and then filtered and kept at 75 OC. After 8 days colorless crystals could be isolated from the solution. The pH values of the reaction solutions described above, measured with a glass pH electrode (Metrohm), were 4.7 (Co), 3.6 (Ni), 4.2 (Zn), and 3.3 (Cd). Depending on the duration of the crystallization process, all syntheses could be performed with high yields of 40-80%. Analytical data of the compounds are summarized in Table I. Crystallographic Studies. Cell parameters of all complexes were derived from precession and Weissenberg photographs and refined by the least-squares method with 25 reflections (1 1 ' < 8 < 20') carefully centered on the diffractometer. Intensity data of the cobalt and cadmium complexes were collected at room temperature on an Enraf-Nonius CAD-4 diffractometer with graphite-monochromatized Mo Ka radiation (A = 0.71073 A). The w-28 scan technique with variable scan speeds of 2.86-10' m i d (Co) and 2.86-20° m i d (Cd) was used. Six standard reflections were checked a t , a n interval of every 3 h. For the cobalt complex 5% loss of intensities during data collection was observed and corrected for in data reduction, whereas for the cadmium complex no significant decrease was noted. Five (Co) or four (Cd) reflections were collected every 300 reflections to control orientation. The data were corrected for Lorentz and polarization effects. A numerical absorption correction based on 14 (Co) or 16 (Cd) carefully indexed crystal faces was applied. Both structures could be solved by Patterson syntheses with s ~ ~ ~ xand s were . 6 ~ refined ~ with SHELX76.2S Least-squares refinements were carried out by minimizing Cw(lFoI - lF,1)2, with w = l/a2(Fo) and anisotropic thermal parameters for all non-hydrogen atoms. Additional structure determination parameters are given in Table 11. In both metal complexes all hydrogen atoms could be localized in difference Fourier maps and were refined with variable positional and
Chem. SOC.1975, 97, 3351.
Sletten, E.Acta Crystallogr., Sect. B Struct. Crystallogr. Ctyst. Chem. 1970, B26, 1609. Dubler, E.; Hanggi, G.; Schmalle, H., to be submitted for publication. Sheldrick, W. S.; Bell, P. Inorg. Chim. Acta 1987, 237, 181. Beauchamp, A. L.; Btlanger-Garitpy, F.; Mardhy, A,; Cozak, D. Inorg. Chim. Acta 1986, 124, L23.
(24) Sheldrick, G. M. In Crystallographic Computing Sheldrick, G. M., Kriiger, C., Goddard, R., Eds.; Oxford University Press: Oxford, England, 1985; p 175. (25) Sheldrick, G. M. SHELX76, Program for Crystal Structure Determination; University of Cambridge: Cambridge, England, 1976.
Inorganic Chemistry, Vol. 27, No. 18, 1988 3133
Metal Complexes of Allopurinol Table 111. Positional Parameters of C 0 ( a l l o ) ~ S O ~ - 4 H ~ 0 " atom X Y z U,IUh .A2 0.21026 (3) 0.02965 (2) 0.27436 (2) 0.01600 (4) -0.16976 (5) -0.00765 (4) 0.24629 (4) 0.01680 (4) -0.0243 (1) -0.0344 (1) 0.3203 (1) 0.0238 (2) 0.2244 (1) 0.0263 (2) -0.1560 (1) 0.1371 (1) 0.3251 (1) 0.0239 (2) -0.3058 (1) -0.0373 (1) 0.1264 (1) 0.0317 (3) -0.1903 (1) -0.0958 (1) 0.3379 (1) -0.5222 (1) -0.0923 (1) 0.0225 (3) 0.2372 (2) -0.5776 (1) -0.0108 (1) 0.0265 (4) 0.0788 (1) 0.0279 (3) 0.1680 (1) -0.5103 (1) 0.0844 (1) 0.0201 (3) 0.2100 (1) -0.3729 (1) 0.3112 (1) -0.3050 (1) 0.0065 (1) 0.0188 (3) 0.3839 (1) -0.3838 (1) -0.0908 (1) 0.0194 (3) 0.4761 (1) -0.3430 (1) -0.1687 (1) 0.0309 (3) 0.3166 (2) -0.1666 (1) 0.0523 (1) 0.0225 (3) 0.1497 (1) 0.0220 (3) 0.2256 (1) -0.1507 (1) 0.1683 (1) 0.0231 (3) 0.1596 (1) -0.2781 (1) 0.1749 (1) 0.6155 (1) 0.6307 (1) 0.0213 (3) 0.0855 (2) 0.5288 (1) 0.6960 (1) 0.0214 (3) 0.6665 (1) 0.0208 (3) 0.0585 (1) 0.3970 (1) 0.1302 (1) 0.3534 (1) 0.5594 (1) 0.0169 (3) 0.2243 (1) 0.4328 (1) 0.4852 (1) 0.0182 (3) 0.2516 (1) 0.5771 (1) 0.5213 (1) 0.0213 (3) 0.3291 (1) 0.6630 (1) 0.4668 (1) 0.0366 (3) 0.3848 (1) 0.0229 (3) 0.2655 (2) 0.3409 (1) 0.2021 (1) 0.2154 (1) 0.3974 (1) 0.0209 (3) 0.1179 (1) 0.2242 (1) 0.5045 (1) 0.0193 (3) 0.4395 (1) 0.0905 (1) 0.2309 (1) 0.0308 (3) 0.1242 (1) 0.0269 (3) 0.1355 (1) 0.1359 (1) 0.4278 (1) 0.0353 (4) 0.2864 (2) -0.0680 (1) 0.2778 (1) 0.0417 (4) 0.5484 (2) 0.6923 (1)
0.379 (3) 0.219 (2) 0.373 (2) 0.086 (3) 0.514 (3) 0.471 (3) 0.142 (3) 0.027 (4) 0.301 (3) 0.299 (3) 0.583 (3) 0.499 (4) 0.184 (3) 0.036 (2) 0.328 (2) 0.079 (2)
' zix 13
-0.580 (2) -0.675 (2) -0.088 (2) -0.292 (2) 0.056 (2) 0.169 (3) 0.111 (2) 0.141 (3) -0.034 (3) -0.148 (3) 0.772 (3) 0.667 (3) 0.705 (2) 0.566 (2) 0.360 (2) 0.152 (2)
-0.151 -0.023 0.019 0.222 0.266 0.211 0.056 0.130 0.502 0.433 0.293 0.323 0.662 0.766 0.311 0.536
(2) (2) (2) (2) (2) (3) (2) (3) (3) (3) (3) (3) (2) (2) (2) (2)
0.037 0.031 0.032 0.039 0.044 0.074 0.043 0.086 0.054 0.061 0.067 0.073 0.052 0.028 0.029 0.033
(6) (6) (6) (7) (8) (10) (8) (1 1) (8) (9) (10) (11) (8) (6) (6) (6)
*iea* f a f e a J .
isotropic thermal parameters. The final refinement of the cobalt compound, using 7474 reflections with I 2 3 4 I ) and 335 variable parameters, converged to R = 0.033 and R, = 0.037 with a maximum shift to error ratio of 0.02. The maximum and minimum heights of the final difference Fourier map were 0.41 and -0.79 e.A-' (located 0.67 8, from the cobalt atom), respectively. The structure of the cadmium complex was refined in the same way, except that 16 reflections with F,
