& Structure–Activity Relationships Polyoxomolybdate Bisphosphonate Heterometallic Complexes: Synthesis, Structure, and Activity on a Breast Cancer Cell Line Ali Saad, [a] Wei Zhu, [b] Guillaume Rousseau, [a] Pierre Mialane, [a] JØrôme Marrot, [a] Mohamed Haouas, [a] Francis Taulelle, [a] RØmi Dessapt, [c] HØlne Serier-Brault, [c] Eric Rivire, [d] Tadahiko Kubo, [e] Eric Oldfield,* [b] and Anne Dolbecq* [a] Abstract: Six polyoxometalates containing Mn II , Mn III , or Fe III as the heteroelement were synthesized in water by treating Mo VI precursors with biologically active bisphosphonates (alendronate (Ale), zoledronate (Zol), an n-alkyl bisphospho- nate (BPC 9 ), an aminoalkyl bisphosphonate (BPC 8 NH 2 )) in the presence of additional metal ions. The Pt complex was syn- thesized from a polyoxomolybdate bisphosphonate precur- sor with Mo VI ions linked by the 2-pyridyl analogue of alendronate (AlePy). The complexes Mo 4 Ale 2 Mn, Mo 4 Zol 2 Mn, Mo 4 Ale 2 Fe, Mo 4 Zol 2 Fe, Mo 4 (BPC 8 NH 2 ) 2 Fe, and Mo 4 (BPC 9 ) 2 Fe contain two dinuclear Mo VI cores bound to a central hetero- metallic ion. The oxidation state of manganese was deter- mined by magnetic measurements. Complexes Mo 12 (AlePy) 4 and Mo 12 (AlePy) 4 Pt 4 were studied by solid-state NMR spec- troscopy and the photochromic properties were investigated in the solid state; both methods confirmed the complexa- tion of Pt. Activity against the human breast adenocarcino- ma cell line MCF-7 was determined and the most potent compound was Mn III -containing Mo 4 Zol 2 Mn (IC 50  1.3 mm). Unlike results obtained with vanadium-containing polyoxo- metalate bisphosphonates, cell growth inhibition was res- cued by the addition of geranylgeraniol, which reverses the effects of bisphosphonates on isoprenoid biosynthesis/pro- tein prenylation. The results indicate an important role for both the heterometallic element and the bisphosphonate ligand in the mechanism of action of the most active compounds. Introduction Polyoxometalates (POMs) constitute a large family of anionic metal oxide clusters of d-block transition metals in high oxida- tion states (W VI , Mo V,VI ,V IV,V ) and have a wide range of magnet- ic, [1] redox, [2] and catalytic properties. [3] Biological applications, in particular, anticancer properties, have also been reported. [4] For example, [NH 3 iPr] 6 [Mo 7 O 24 ], also known as PM-8, inhibits the growth of human Co-4 (colon cancer), MX-1 (breast cancer), and CAT (lung cancer) cell lines. [5] Its photoreduced form suppresses the growth of several types of tumors in vivo, [6] and Yamase et al. have shown that the antitumor activi- ty of polyoxomolybdates is due primarily to their activity in redox reactions. [5] The anticancer activity of polyoxotungs- tates, [7] including organotin- [8] and organotitanium-substitut- ed [9] heteropolyoxotungstates, as well as polyoxotungstates containing arsenic and copper, [10] have also been reported and the encapsulation of POMs in chitosan has been investigat- ed. [11] However, there have been very few reports of POMs that contain ligands which are themselves drugs. [12] Bisphospho- nates (BPs), with the general formula H 2 O 3 PC(OH)(R)PO 3 H 2 , are one such class of bioactive molecules that are of interest in the development of hybrid species that might have both redox activity and more conventional activity as enzyme inhibi- tors. BPs function by inhibiting the enzyme farnesyl diphos- phate synthase (FPPS), which is involved in protein prenylation and cell signaling, and have been used for almost 40 years to treat bone resorption diseases. Furthermore, some BPs also have activity against parasitic protozoa, as well as tumor cells. [13] BPs have very recently been found to inactivate human epidermal growth factor receptors to exert antitumor activity in some systems. [14] [a] Dr. A. Saad, Dr. G. Rousseau, Prof. P. Mialane, Dr. J. Marrot, Dr. M. Haouas, Dr. F. Taulelle, Dr.A. Dolbecq Institut Lavoisier de Versailles, UMR 8180 UniversitØ de Versailles St-Quentin en Yvelines 45 Avenue des Etats-Unis, 78035 Versailles cedex (France) E-mail : anne.dolbecq@uvsq.fr [b] Dr. W. Zhu, Prof. Dr. E. Oldfield Department of Chemistry University of Illinois at Urbana-Champaign 600 South Mathews Avenue, Urbana, Illinois 6180 (USA) E-mail : eo@chad.scs.uiuc.edu [c] Dr. R. Dessapt, Dr. H. Serier-Brault Institut des MatØriaux Jean Rouxel, UniversitØ de Nantes CNRS, 2 Rue de la Houssinire, BP 32229 44322 Nantes cedex (France) [d] Dr. E. Rivire Institut de Chimie MolØculaire et des MatØriaux d’Orsay, UMR 8182 UniversitØ Paris-Sud, 91405 Orsay cedex (France) [e] Dr. T. Kubo Department of Orthopaedic Surgery Graduate School of Biomedical Sciences Hiroshima University, 1-2-3 Kasumi Miniami-ku, Hiroshima 734-8551 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406565. Chem. Eur. J. 2015, 21, 10537 – 10547 # 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 10537 Full Paper DOI: 10.1002/chem.201406565