metal-organic compounds m494 # 2002 International Union of Crystallography DOI: 10.1107/S010827010201497X Acta Cryst. (2002). C58, m494±m497 The calcium-binding properties of pamidronate, a bone-resorption inhibitor Daniel Ferna Ândez, a * Daniel Vega b and Andre Âs Goeta c a Escuela de Ciencia y Tecnologõ Âa, Universidad Nacional de General San Martõ Ân, Calle 91 3391, 1653 Villa Ballester, Buenos Aires, Argentina, b Unidad de Actividad Fõ Âsica, Comisio Ân Nacional de Energõ Âa Ato  mica, Av. Gral. Paz 1499, 1650 San Martõ Ân, Buenos Aires, Argentina, and c Department of Chemistry, University of Durham, Durham DH1 3LE, England Correspondence e-mail: fernande@tandar.cnea.gov.ar Received 23 July 2002 Accepted 19 August 2002 Online 21 September 2002 The title compound, calcium bis(3-ammonio-1-hydroxy- propylidene-1,1-bisphosphonate) dihydrate, Ca 2+ 2C 3 H 10 N- O 7 P 2  2H 2 O, consists of calcium octahedra arranged in columns along the c axis and coordinated by hydrogen- bonded molecular anions. The Ca 2+ cation lies on a twofold axis. Pamidronate adopts a twisted conformation of the hydroxyalkylamine backbone that enables the formation of an intramolecular NÐHO hydrogen bond. The molecular anion is chelating monodentate as well as bidentate, with an OO bite distance of 3.0647 (15) A Ê . Comment gem-Bisphosphonates are commonly used in clinical practice as safe and ef®cacious therapeutic agents for the treatment of a number of bone disorders, such as osteoporosis, Paget's disease and hypercalcaemia associated with malignancy (Compston, 1994; Russell & Rogers, 1999; Rodan & Martin, 2000). These compounds have the PO 3 groups bridged by the geminal C atom, an atomic connectivity which, though chemically and enzymatically non-hydrolizable, resembles that of inorganic pyrophosphate. As has been recognized previously, these compounds are able to affect the growth of calcium hydroxyapatite crystals. In connection with this, the calcium salts of the bisphosphonates etidronate [calcium di- hydrogen 1-hydroxyethane-1,1-diphosphonate dihydrate, CaH 2 EHDP2H 2 O; Cambridge Structural Database (CSD; Allen et al., 1983) refcode CAEHDP (Uchtman, 1972)] and clodronate [calcium dichloromethylene-1,1-diphosphonate pentahydrate, CaH 2 Cl 2 MDP5H 2 O; CSD refcode CAVKUF (Nardelli et al., 1983)] have been studied crystallographically and their chelating capabilities unveiled. Subsequently, biological activity has been associated with the mechanism of action of the bisphosphonates (Felix & Fleisch, 1981). At present, it is known that the surface of bone is resorbed by specialized cells, so the bisphosphonates are incorporated, but not metabolized, by the osteoclasts, thus leading selectively to their loss of activity and death (Fisher et al., 1999; Rogers et al. , 2000; Coxon et al., 2001; van Beek et al., 2002). In a similar manner, bisphosphonates have been found to be inhibitors of diverse enzymes (Bau et al., 1988; Smirnova et al., 1988; Reiersen et al., 1994; Atack & Fletcher, 1994; Gordon- Weeks et al. , 1999) and, as such, they are currently being investigated as herbicides (Chuiko et al. , 1999; Cromartie et al. , 1999) and antiparasitics (Docampo, 2001). In this latter context, molecular modelling work has been carried out to develop a new therapeutic agent for the treatment of Amer- ican trypanosomiasis (Ferna Ândez, 2002). The basis of the design is one of the clinically used bisphosphonates, so to obtain experimental data on the conformation of the ligand in a complex with a divalent metal cation, possibly the true substrate for the enzyme, we undertook the single-crystal X-ray analysis of the title compound, (I), and the results are presented here. In the molecular anion of (I) (Fig. 1), which can also be denoted CaH 2 PAM, the geminal C1 atom is substituted with a pair of negatively charged PO 3 H  groups, an OH group and an alkylamine lateral chain containing a tetrahedral N atom. As with the previously studied free acid, H 3 PAM (Shkol'ni- kova et al., 1990), and the pentahydrated disodium salt, Na 2 HPAM (Vega et al., 2002), (I) has a zwitterionic character, with atom N1 bearing the positive charge, but here the overall charge is 1, so the zwitterion forms a 2:1 complex with Ca 2+ . From Table 1, it is evident that the geometry around the P atoms is tetrahedral. The OÐPÐC bond angles are somewhat less than the ideal tetrahedral value [105.64 (7)±109.90 (7)  ], while the OÐPÐO angles involving the two deprotonated O atoms are the largest in both groups; the PÐO(deprotonated) distances indicate a double delocalized bond and the PÐ O(protonated) bonds are single. These are very similar to the geometric parameters found in the single PO 3 H  group in H 3 PAM, but they differ slightly from those in Na 2 HPAM, where this group has an unequal distribution of the negative charge among the deprotonated O atoms (Vega et al., 2002). The PÐC bond lengths are comparable in the three struc- tures, with values of 1.848 (2) and 1.854 (2) A Ê in H 3 PAM, 1.845 (4) and 1.869 (3) A Ê in Na 2 HPAM, and 1.846 (2) and 1.851 (2) A Ê in (I). However, the PÐCÐP angle in (I) is 2  wider than in the other two compounds. The mutual orientation of the PO 3 groups enables the formation of a planar `W' arrangement of the OÐPÐCÐPÐ O chain, where one protonated and one deprotonated O atom lies in the plane [O2ÐP1ÐC1ÐP2 164.6 (1)  and O6ÐP2Ð Acta Crystallographica Section C Crystal Structure Communications ISSN 0108-2701