& 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] J¦rúme Marrot,[a]

Mohamed Haouas,[a] Francis Taulelle,[a] R¦mi Dessapt,[c] H¦lÀne Serier-Brault,[c] Eric RiviÀre,[d]

Tadahiko Kubo,[e] Eric Oldfield,*[b] and Anne Dolbecq*[a]

Abstract: Six polyoxometalates containing MnII, MnIII, or FeIII

as the heteroelement were synthesized in water by treating

MoVI precursors with biologically active bisphosphonates

(alendronate (Ale), zoledronate (Zol), an n-alkyl bisphospho-nate (BPC9), an aminoalkyl bisphosphonate (BPC8NH2)) in thepresence of additional metal ions. The Pt complex was syn-thesized from a polyoxomolybdate bisphosphonate precur-

sor with MoVI ions linked by the 2-pyridyl analogue ofalendronate (AlePy). The complexes Mo4Ale2Mn, Mo4Zol2Mn,

Mo4Ale2Fe, Mo4Zol2Fe, Mo4(BPC8NH2)2Fe, and Mo4(BPC9)2Fe

contain two dinuclear MoVI cores bound to a central hetero-metallic ion. The oxidation state of manganese was deter-

mined by magnetic measurements. Complexes Mo12(AlePy)4

and Mo12(AlePy)4Pt4 were studied by solid-state NMR spec-

troscopy and the photochromic properties were investigatedin 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 potentcompound was MnIII-containing Mo4Zol2Mn (IC50�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 theeffects of bisphosphonates on isoprenoid biosynthesis/pro-

tein prenylation. The results indicate an important role for

both the heterometallic element and the bisphosphonateligand in the mechanism of action of the most active

compounds.

Introduction

Polyoxometalates (POMs) constitute a large family of anionicmetal oxide clusters of d-block transition metals in high oxida-tion states (WVI, MoV,VI, VIV,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, [NH3iPr]6[Mo7O24] , also known as PM-8, inhibitsthe growth of human Co-4 (colon cancer), MX-1 (breastcancer), and CAT (lung cancer) cell lines.[5] Its photoreducedform 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 inredox 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 andthe 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 H2O3PC(OH)(R)PO3H2, are

one such class of bioactive molecules that are of interest inthe 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 totreat bone resorption diseases. Furthermore, some BPs also

have activity against parasitic protozoa, as well as tumorcells.[13] BPs have very recently been found to inactivate human

epidermal growth factor receptors to exert antitumor activityin some systems.[14]

[a] Dr. A. Saad, Dr. G. Rousseau, Prof. P. Mialane, Dr. J. Marrot, Dr. M. Haouas,Dr. F. Taulelle, Dr. A. DolbecqInstitut Lavoisier de Versailles, UMR 8180Universit¦ de Versailles St-Quentin en Yvelines45 Avenue des Etats-Unis, 78035 Versailles cedex (France)E-mail : anne.dolbecq@uvsq.fr

[b] Dr. W. Zhu, Prof. Dr. E. OldfieldDepartment of ChemistryUniversity of Illinois at Urbana-Champaign600 South Mathews Avenue, Urbana, Illinois 6180 (USA)E-mail : eo@chad.scs.uiuc.edu

[c] Dr. R. Dessapt, Dr. H. Serier-BraultInstitut des Mat¦riaux Jean Rouxel, Universit¦ de NantesCNRS, 2 Rue de la HoussiniÀre, BP 3222944322 Nantes cedex (France)

[d] Dr. E. RiviÀreInstitut de Chimie Mol¦culaire et des Mat¦riaux d’Orsay, UMR 8182Universit¦ Paris-Sud, 91405 Orsay cedex (France)

[e] Dr. T. KuboDepartment of Orthopaedic SurgeryGraduate School of Biomedical SciencesHiroshima University, 1-2-3 KasumiMiniami-ku, Hiroshima 734-8551 (Japan)

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201406565.

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Full PaperDOI: 10.1002/chem.201406565

Once deprotonated, BPs act as multidentate ligands and canform stable POM complexes.[15] In earlier work, we reported the

antitumor cell growth inhibition activity of a broad range ofPOM/BP hybrids.[16] However, more recently, we found that the

addition of geranylgeraniol (GGOH), which rescues tumor cellsfrom BP cell growth inhibition,[17] had little or no appreciablerescue effect with the most potent vanadium POM/BP com-pounds. This means that, with the earlier compounds, the ac-tivity was essentially metal-based with no significant effects on

protein prenylation; this is an undesirable effect for targetingthe ras-based signaling pathways present in many tumor cell

types. Herein, we elected to explore the effects of the additionof a second heterometallic element (Mn, Fe, or Pt) on thestructures and properties of a series of molybdenum–BP com-plexes. We reasoned that the addition of a second metal might

impart interesting properties, including, perhaps, targeting ofisoprenoid biosynthesis by the BP ligands. We investigatedplatinum heterometal complexes because cis-platin (cis-[PtCl2(NH3)2]) is a potent anticancer drug. Additionally, we in-vestigated complexes with iron and manganese, which might

have interesting redox properties and biological activities. Forexample, MnIII porphyrins modulate redox-based signaling

pathways[18] and MnIII salens have superoxide dismutase and

catalase activities and activity in some tumor cell lines (for ex-ample, MCF-7).[19] We chose to use the clinically used BPs zo-

ledronate (Zometa) and alendronate (Fosamax), as well asmore lipophilic species and those designed to contain metal–

ligand binding sites, in our synthetic work. The structures andligand abbreviations used herein are shown in Scheme 1.

Results and Discussion

Synthesis and characterization

We synthesized two classes of compounds and investigatedtheir structures, as well as spectroscopic and magnetic proper-

ties. We also investigated their activity in tumor cell growth in-hibition, including GGOH cell growth–rescue experiments to

determine whether the BP ligands were inhibiting tumor cell

growth (by targeting FPPS/protein prenylation). Full synthesisand characterization details are described in the Experimental

Section. The first class of compounds consisted of POMs withthe general formula Mo4(BP)2M (M = Mn, BP = Ale, Zol; M = Fe,

BP = Ale, Zol, BPC8NH2, BPC9), whereas the second class consist-ed of Mo12(BP)4 derivatives, one of which contained Pt. The

synthetic routes to all compounds are shown in Scheme 2. The

synthesis strategies were different for the two families of heter-

ometallic compounds. The Fe-containing POMs were isolatedby using a one-pot procedure similar to that used for the CrIII-

containing molybdenum–BPs,[20] with a series of BPs (Ale,BPC8NH2, BPC9, and Zol) as precursors. To study the influence

of the nature of the heterometallic element, two Mn deriva-tives were also synthesized; this time with only Ale and Zol,

which are the clinically used BPs. Several factors, such as pH,

the nature of the Mo precursor (sodium versus ammoniumsalt), stoichiometry, and the nature of the counterions, were

varied to isolate crystalline products. Hydrothermal conditionswere used in the case of BPs with low solubility to increase

product yield and crystallinity.With PtII as the heterometallic element, the synthetic strat-

egy involved a two-step procedure (Scheme 2). BP AlePy was

chosen as the ligand because of the ability of the amino andpyridine groups to chelate to PtII.[21] First, complex Mo12(AlePy)4

was isolated at pH 3 by using a procedure similar to that usedfor other Mo12(BP)4 derivatives.[16a, 22] Then, this Mo12(AlePy)4

complex was reacted with an excess of [PtCl2(dmso)2] . The sim-ilarity of the IR spectra of Mo12(AlePy)4 and Mo12(AlePy)4Pt4 (Fig-

ure S1 in the Supporting Information) indicate that the Mo12

core is maintained in the platinum complex. Elemental analysisresults indicated the presence of four PtII per Mo12(AlePy)4 and

two chloride ions per Pt, which supports a structure in whichPtCl2 is bonded to the two aminopyridyl nitrogen atoms (that

is, PtCl2N2, similar to cis-platin; Figure S2 in the Supporting In-formation) in Mo12(AlePy)4Pt4.

The POMs were characterized in the solid state by single-

crystal XRD (except for Mo4Zol2Mn and Mo12(AlePy)4Pt4), ele-mental analysis, and IR spectroscopy. It was not possible to iso-

late single crystals of Mo4Zol2Mn of sufficient quality for crystal-lographic analysis. However, as in the case of Mo12(AlePy)4Pt4,

its proposed structure is supported by elemental analysis re-sults as well as by a comparison of its IR spectrum with that of

Scheme 1. Abbreviations and structures of the BPs used in this study.

Scheme 2. Synthetic pathways to all of the compounds discussed herein.

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Mo4Zol2Fe (Figure S1 in the Supporting Information), the struc-ture of which is known.

Structures and stability

As noted above, the structures of all compounds (except

Mo4Zol2Mn and Mo12(AlePy)4Pt4) were determined by means ofsingle-crystal XRD. Results are shown in Figures 1 and 2. The

structures of the inorganic core in Mo4(BP)2M complexes aresimilar to those of the known {(Mo2O6)2(O3PC(R)(O)PO3)2M} (R =

(CH2)3NH3, M = VIV,[23] CrIII ;[20] R = CH3, M = VIV,[23] CrIII, FeIII, MnII[24])complexes. The structures are centrosymmetric and containtwo {Mo2O6} dimeric units with face-shared MoVI octahedra

(light gray; Figure 1) bound to an octahedrally coordinatedmetallic ion, M, which is located on a (pseudo) inversion center(Figure 1). In each MoVI dimer, molybdenum ions are connected

to a pentadentate BP ligand by P¢O¢Mo and C¢O¢Mo bonds.The BP ligands are also bound to the central 3d metal ion.

Bond valence sum calculations (Figures S3–S8 in the Support-ing Information) support the assignment of MoVI and FeIII oxi-

dation states in Mo4Ale2Fe, Mo4Zol2Fe, Mo4(BPC8NH2)2Fe, andMo4(BPC9)2Fe, as well as the reduction of MnIII of the Mn(OAc)3

precursor into MnII in Mo4Ale2Mn. The nature of the reductantis unknown. In this last compound, the geometry of the MnO6

octahedron (white; Figure 1) is regular with Mn¢O distances in

the 2.094(1)–2.194(1) æ range, as expected for MnII.[25]

The structure of the inorganic POM core is similar in the fiveMo4(BP)2M (M = Mn, Fe) complexes (Figure 1); however, thesupramolecular arrangements of the hybrid POMs vary consid-

erably from one complex to another and are dependent onthe nature of the organic arm of the BP ligand. In Mo4Ale2M

(M = Mn, Fe), the three protons of the NH3+ groups of the

alendronate ligand undergo hydrogen-bonding interactionswith the oxygen atoms of neighboring POMs (Figure 2 a).

These N¢H···O bonds involve bridging and terminal oxygenatoms of the {Mo2O6} dimers, and the terminal oxygen atoms

of the phosphonate groups. Hydrogen bonds are also ob-served between the N¢H group of the imidazole in Mo4Zol2Fe

and the oxygen atom of the phosphonate group, which is

bound to the central FeIII (dark gray; Figure 2 b). The chainlengths of the BPs are identical in BPC8NH2 and BPC9, but the

supramolecular arrangements in Mo4(BPC8NH2)2Fe andMo4(BPC9)2Fe are different, due to the existence of N¢H···O

bonds between the ammonium group and oxygen atoms ofthe phosphonate groups in Mo4(BPC8NH2)2Fe, whereas only hy-

drophobic/van der Waals interactions occur between the alkyl

chains in Mo4(BPC9)2Fe (Figure 2 c–e). The geometries of the hy-drogen-bonding interactions associated with the structures de-

picted in Figure 2 are given in Table S1 in the SupportingInformation.

The structure of the Mo12(AlePy)4 complex (Figure 3) is bestdescribed as the connection of four trimeric {Mo3O8} units

through two oxygen atoms, one from a P¢O bond and one

from a Mo¢O bond (Figure 3 a), as observed previously withother Mo12(BP)4 complexes.[16a, 22, 26] An octahedrally coordinated

sodium ion (white hatched sphere; Figure 3 b) occupies thecenter of the POM and acts as a template ion. Intra- and inter-

molecular N¢H···O hydrogen bonds between the protonatedamino group and the pyridine group of the AlePy ligand, and

between the terminal or bridging atoms of the POM core andwater molecules, stabilize the structure (Figure 3 b andTable S1 in the Supporting Information).

It is, of course, of interest to determine to what extenta complex, the structure of which is known in the solid state,

is stable is solution. NMR spectroscopy is, in principle, onepowerful tool that can be used to help answer this question.

This technique cannot, however, be readily used for the para-magnetic polyoxomolybdates reported herein because theycontain FeIII or MnII,III ions, which induce very large line broad-

ening.[27] Also, because of its very poor solubility, diamagneticMo12(AlePy)4 could not be studied in solution by 31P NMR spec-

troscopy. For the manganese- and iron-containing POMs, thestability in solution was thus assessed from two experiments.

Figure 1. Mixed polyhedral and ball-and-stick representations of theMo4(BP)2M POMs. Light-gray polyhedra MoO6, dark-gray octahedra FeO6,white octahedra MnO6, hatched white spheres P, black spheres C, gray spher-es N, white spheres O, small black spheres H.

Figure 2. Hydrogen-bond interactions (depicted as black dotted lines) in thestructures of a) Mo4Ale2Fe, b) Mo4Zol2Fe, Mo4(BPC8NH2)2Fe (c) top and d) sideviews), and e) Mo4(BPC9)2Fe. Light-gray octahedra MoO6, dark-gray octahedraFeO6, black spheres C, gray spheres N, white hatched spheres P, white spher-es O, small black spheres H.

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The first one was a dissolution–reprecipitation experiment con-

ducted on Mo4Ale2Fe as a representative example. We foundthat the IR spectra of the as-synthesized Mo4Ale2Fe POM andof the powder isolated by precipitation of a solution of

Mo4Ale2Fe with NH4Cl (Figure S1 in the Supporting Informa-tion) were identical, which suggested that the hybrid POM re-mained stable in solution. The second experiment was the re-cording of the UV/Vis spectrum of Mo4Zol2Mn every 2 h over10 h. The spectra immediately after dissolution and 10 h laterwere similar (Figure S9 in the Supporting Information), which

showed the absence of degradation of this compound.

Solid-state NMR spectroscopy

Because we were unable to determine the structure of the

Mo12(AlePy)4Pt4 complex by means of crystallography, we de-termined the solid-state NMR spectra of Mo12(AlePy)4 (which is

essentially insoluble in water) and Mo12(AlePy)4Pt4 by using

one and two-dimensional magic-angle sample spinning tech-niques. The 1D 31P{1H} MAS NMR spectrum of Mo12(AlePy)4 (Fig-

ure 4 a) exhibits four resolved lines at d = 18.1 (23 %), 20.0(23 %), 25.3 (27 %), and 26.4 ppm (27 %), which is in agreement

with the four crystallographic P sites (Figure S10a in the Sup-porting Information). The 2D 31P{1H}–31P{1H} DQ–SQ correlation

experiment shows strong dipolar coupling between the reso-nances at d= 18.1 and 26.4 ppm, as well as those at d= 20.0

and 25.3 ppm, which is consistent with two distinct AlePy envi-ronments, similar to the observation of two pairs of signals in

the range of d= 26–27 and 29–33 ppm observed for alendro-

nate in [(Mo2O2X2(H2O))4(Ale)4]8¢, in which X = O or S.[28] TheMAS NMR spectrum of the platinum complex Mo12(AlePy)4Pt4

(Figure 4 b) shows two signals, centered at d�21 and 25 ppm;these values are about the same as those observed with

Mo12(AlePy)4, but with clear line broadening. Broadening couldbe due to either low crystallinity in Mo12(AlePy)4Pt4 or dynamic

disorder, since we also observed much less efficient cross-

polarization (CP) transfer in CPMAS experiments comparedwith that in Mo12(AlePy)4 (Figure S10b in the Supporting

Information).The 1H MAS spectrum of Mo12(AlePy)4 (Figure 5 a) consists of

a dominant resonance at d= 4.2 ppm due to water molecules,with a very small shoulder at d�2 ppm, and two other signalscentered at d�8 and 18.4 ppm. The resonances d�2 and

Figure 3. Mixed polyhedral and ball-and-stick representations of a) a trime-tallic unit and b) the complete structure of Mo12(AlePy)4 with inter- and intra-molecular hydrogen-bond interactions between pyridine and alkylaminoprotons and the oxygen atoms of the Mo core (more details are given inTable S1 in the Supporting Information). Gray polyhedra MoO6, white hatch-ed spheres P, black spheres C, gray spheres N, white spheres O, small blackspheres H, double hatched sphere Na; the arrows indicate the atoms thatconnect to another trimetallic unit ; for clarity, only a trimetallic unit and oneC atom of the BP chain of the adjacent POM are represented.

Figure 4. 31P{1H} MAS NMR spectra of a) Mo12(AlePy)4 and b) Mo12(AlePy)4Pt4.Inset : 31P{1H}–31P{1H} DQ–SQ MAS NMR spectrum of Mo12(AlePy)4.

Figure 5. 1H MAS NMR spectra of a) Mo12(AlePy)4 and b) Mo12(AlePy)4Pt4.Inset : 31P{1H} CPMAS HETCOR NMR spectrum of Mo12(AlePy)4. Projectionsalong the 31P and 1H dimensions are shown.

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8 ppm are assigned to methylene and aromatic protons of theAlePy ligands. The signal at d�18 ppm arises from acidic pro-

tons, and the results of a 2D 31P{1H} HETCOR experiment (insetin Figure 5) clearly indicates close proximity between this/

these proton/s and the phosphorus responsible for the reso-nance at d = 20 ppm. Close inspection of the structure indi-

cates that of the four phosphonate groups (P1, P2, P3, and P4)only one, P2, is involved in a strong hydrogen-bonding interac-

tion through its terminal P=O group (Figure 3 b). More specifi-

cally, P2 has a 1.7 æ intermolecular N¢H···O=P hydrogen bondbetween the protonated pyridine group (N24¢H24) and the

terminal oxygen (O29) of the phosphonate P2 (Table S1 in theSupporting Information) in the crystal structure. From these

observations, we thus assign the 31P NMR signals (d) as follows:P1/P2 = 25 ppm/20 ppm and P3/P4 = 18 ppm/26 ppm, in

which P1 and P4 correspond to (P¢(OMo)3) and P2 and P3 cor-

respond to (O=P¢(OMo)2). The signal at d = 18.4 ppm in the 1Hspectrum thus corresponds to the pyridinium proton of the

AlePy ligand. The 1H MAS spectrum of the Pt complexMo12(AlePy)4Pt4 (Figure 5 b) is very similar to that of

Mo12(AlePy)4 ; the only difference is the absence of the reso-nance at d = 18.4 ppm, which is clearly a consequence of com-

plexation of pyridine to Pt.

Solid-state photochromic properties

To further confirm the formation of the Pt complex, we com-

pared color changes of Mo12(AlePy)4 and Mo12(AlePy)4Pt4 in the

solid state under UV irradiation by using diffuse reflectancespectroscopy. Molybdenum–BPs exhibit photochromism[29] and

it is thought that UV excitation induces electron transfer froman oxygen atom to an adjacent MoVI, followed by movement

of a hydrogen from the ammonium group of the BP ligandonto the POM (Figure S11 in the Supporting Information). This

results in the formation of a hydroxyl group, which traps the

excited electron on the molybdenum center. Coloration is dueto d–d transitions and/or MoVI/MoV intervalence transfers, and

is correlated with the stabilization of the photoreduced MoV

state through N¢H···O(Mo) bonds. The observation of photo-

chromism in such systems is thus an indication of the exis-tence of hydrogen bonds in the structure.

With 6 W UV excitation at l= 365 nm (3.4 eV), the color ofinitially white Mo12(AlePy)4 shifted from white to orange then

reddish brown (Figure 6 a) and the effect saturated after30 min of irradiation. As shown in Figure 6 b, this color changearises from the growth of a broad absorption band in the visi-ble region (at lmax = 464 nm; 2.67 eV), which mainly dictatesthe photogenerated hue, and a second, less intense absorption

at l�750 nm (1.65 eV). These bands are very similar to thosefound with the other photochromic Mo12(BP)4 compounds

(Mo12(Ale)4, Mo12(Ale-1 C)4, and Mo12(Ale-2 C)4)[22] and, as noted

above, are indicative of a photoreduced Mo12 core. Details ofthe photochromism kinetics are given in Figures S12 and S13

in the Supporting Information, and it is of interest to note thatMo12(AlePy)4 is the fastest photochromic member of the

Mo12(BP)4 series,[22] with a reactivity that is comparable to thefastest organoammonium/POM systems.[30] The color-change

effect is reversible and the bleaching process occurs after

switching off of the UV irradiation and maintainingMo12(AlePy)4 in air, as discussed in the Supporting Information.

The existence of several N¢H···O(Mo) bonds (Figure 3) betweenthe protonated amino and pyridine groups and the oxygen

atoms of the POM may explain this activity. In sharp contrast,complex Mo12(AlePy)4Pt4 does not exhibit any color change

under UV irradiation, which indicates that the photoreduced

state is not stabilized in the Pt complex. Based on the brief dis-cussion outlined above, this lack of photochromism implies

that the alkylamino and pyridine groups are not involved inhydrogen-bond interactions, which is consistent with our pro-

posal that they are bound to PtII (Figure S2 in the SupportingInformation).

Magnetic studies

We next carried out magnetic susceptibility measurements to

deduce the Mn oxidation state in the Mo4Ale2Mn and

Mo4Zol2Mn complexes; the last of which is of particular interestbecause, as discussed below, it had the most potent activity in

tumor cell growth inhibition. The cMT = f(T) curve forMo4Ale2Mn is shown in Figure 7 a (&). The cMT product is con-

stant in the 250–30 K temperature range, with a cMT value of4.235 cm3 mol¢1 K at 250 K; the theoretical cMT value is

4.375 cm3 mol¢1 K for a mononuclear high-spin MnII complex

(S = 5/2), assuming g = 2.0. Beyond 30 K, due to single ion ani-sotropy, the cMT curve continuously decreases, reaching

3.875 cm3 mol¢1 K at 2 K. The magnetization was thus measuredat 3, 4, 6, and 8 K as a function of the magnetic field. As

shown in Figure 7 b, the data can be well fit by using D = +

0.97 cm¢1 and g = 1.97 in the spin Hamiltonian [Eq. (1)]:

H ¼ gbHS¢D½S2z¢

13

SðSþ 1Þ¤ ð1Þ

Figure 6. a) Black and white photographs (see Figure S12 in the SupportingInformation for color photographs) of the powder of Mo12(AlePy)4 at differ-ent UV irradiation times (in min). b) Evolution of the photogenerated ab-sorption in Mo12(AlePy)4 after 0, 1, 3, 5, 7, 10, 15, 20, 25, 30, 40, 50, 90, and120 min of UV irradiation (l= 365 nm).

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in which b is the Bohr magneton, H is the magnetic field, g is

the spectroscopic splitting factor, and D is the axial zero-field

splitting parameter (R = 1.4 Õ 10¢4).[31] The jD j value is higherthan those usually determined with six-coordinated MnII com-

plexes.[32] However, it is known that POM ligands can inducestrong magnetic anisotropy, as exemplified by the D value of

+ 1.46 cm¢1 found in the MnII complex [(As2W20O68)-{Mn(H2O)}]8¢.[33] The cMT = f(T) curve for Mo4Zol2Mn (Figure 7 a(*)) again shows that the cMT product is constant in the

250–30 K temperature range, but with a cMT value of3.05 cm3 mol¢1 K. This value is in good agreement with the the-

oretical cMT value of 3.00 cm3 mol¢1 K, which is calculated byassuming g = 2.0 for a mononuclear S = 2 MnIII complex. Fits of

the M = f(H) curves (Figure 7 c) at T = 3, 4, 6, and 8 K lead tovalues of D = + 3.20 cm¢1 and g = 2.02 (R = 4.6 Õ 10¢4).[34] Both

D and g values fall within the range of those determined formononuclear MnIII complexes.[35] Also, the cMT = f(T) curves ofthe Mo4Ale2Mn and Mo4Zol2Mn complexes can be fitted (Fig-

ure 7 a) by using the parameters deduced from magnetizationdata (R = 3.2 Õ 10¢5 and 1.21 Õ 10¢4,[34] respectively). These re-

sults are thus in agreement with the bond valence sum calcu-lations noted above, which confirms that Mo4Ale2Mn contains

a MnII center, whereas Mo4Zol2Mn contains MnIII.

Tumor cell growth inhibition

We next sought to determine which, if any, of the compounds

synthesized herein had activity against the MCF-7 tumor cellline (a human breast adenocarcinoma cell line). The results on

a molar basis (IC50 values, in mm) and on a per BP basis, whichis more logical when comparisons are to be made with the

pure BPs, are shown in Table 1. We only use the latter values inthe following discussion. As can be seen from the results in

Table 1, the most potent BP is zoledronate, which has an IC50

of 15 mm, whereas alendronate has much less activity with an

IC50 of 210 mm (Table 1). The other BPs, BPC8NH2, BPC9, andAlePy all also have weak activity, in the 120–640 mm range

(Table 1). Complexes Mo4(BPC8NH2)2Fe, Mo4(BPC9)2Fe,

Mo12(AlePy)4, and Mo12(AlePy)4Pt4 are all inactive; this mostlikely to be due to the weak activity of the parent BPs. The

most interesting results are obtained with Mo4Ale2Mn andMo4Zol2Mn. With Mo4Ale2Mn and alendronate, we see that the

IC50 per alendronate decreases from 210 to 11 mm, which isabout four times more active than the best Mo POM/BP thatlacks a heteroatom.[16] This could mean that both the heteroa-

tom and the BP have an effect on cell growth inhibition, al-though the addition of MnIICl2 alone has essentially no effect

(IC50�740 mm) on cell growth (Table 1). We also see that theaddition of GGOH increases the IC50 from 11 to 23 mm(Figure 8); an effect that indicates a direct role for the BPmoiety in cell growth inhibition. This is exactly the effect seen

with pure BPs, such as zoledronate, as shown in Figure 8 a andb. The results in Figure 8 a are all raw IC50 values for the inhibi-tors (in the absence or presence of 20 mm GGOH), those in Fig-

ure 8 b are inhibition results that are all normalized to one forthe activity of a given compound in the absence of GGOH.

That is, an increase in the IC50 from, for example, 10 to 30 mmin the presence of GGOH is a threefold increase, with larger

numbers indicating the importance of inhibiting protein gera-

nylgeranylation. The Mo4Zol2Fe complex has almost the sameIC50 value (13 mm) as that of Mo4Ale2Mn (11 mm), but its inhibi-

tion is rescued even more significantly by the addition ofGGOH (Figure 8). This is consistent with a larger contribution

to cell growth inhibition by the BP zoledronate, which is farmore active alone than alendronate.

Figure 7. a) cMT = f(T) curves related to the complexes Mo4Ale2Mn (&) andMo4Zol2Mn (*). b), c) The M = f(H) curves related to the complexesMo4Ale2Mn (b) and Mo4Zol2Mn (c) recorded at 3, 4, 6, and 8 K. The blacklines were generated from the best-fit parameters given in the text.

Table 1. Human tumor cell (MCF-7) growth inhibition data.

Formula IC50 [mm] IC50 [mm] per BP[a]

Mo4Ale2Fe 55�4.4 110�8.8Mo4(BPC8NH2)2Fe 200�6.1 400�12Mo4(BPC9)2Fe 87�5.5 170�11Mo4Zol2Fe 6.6�0.07 13�0.14Mo4Ale2Mn 5.7�1.4 11�2.8Mo12(AlePy)4 54�0.80 220�3.2Mo12(AlePy)4Pt4 100�6.7 400�27Mo4Zol2Mn 1.3�0.24 2.6�0.48Ale 210�6.0 210�6.0BPC8NH2 640�3.5 640�3.5BPC9 120�15 120�15Zol 15�2.6 15�2.6AlePy 620�6.2 620�6.2[PtCl2(dmso)2] 500�65 n/aMnCl2 740�140 n/a

[a] n/a = not applicable.

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By far the most active compound in this assay is Mo4Zol2Mn,

which, based on magnetic susceptibility measurements, con-tains MnIII. Here, we see that the IC50 for MCF-7 cell growth in-

hibition has decreased to 2.5 mm, which is about a factor of 6increase in activity over that observed with the Mo4Ale2Mn and

Mo4Zol2Fe complexes. There is a major rescue with GGOH, sim-ilar to that found with zoledronate alone.[13d, 36] These results in-dicate that there may be a significant contribution to cell

growth inhibition from the presence of MnIII because the mostactive compound contains MnIII (prior to addition to cells) and

the second most active compound also contains Mn (and maybecome oxidized in cells). More importantly perhaps, these re-

sults are in sharp contrast to those found with two vanadiumBP complexes: (NH4)2Rb2[(V5O9(OH)2(H2O)(O3PC(C3H6NH3)OPO3)2]

·8 H2O (V5(Ale)2) and Na3[V3O3(H2O)(O3PC(C4H6N2)(OH)PO3)3]·12 H2O (V3(Zol)3).[16b] Both of these compounds are slightlymore active than the most active compounds investigated

herein (ca. 0.9 mm, 10 Õ more active than zoledronate for thevanadium compounds reported earlier, versus 2.6 mm, 6 Õ more

active than zoledronate in the current assays). However, asseen in Figure 8 b, there is essentially no GGOH rescue with

V5(Ale)2 or V3(Zol)3 (or with a sodium decavanadate control),

whereas with Mo4Zol2Mn there is about a 600 % increase in theIC50. This means that protein prenylation is being inhibited

with Mo4Zol2Mn, even at this low dosing, which is a desirablefeature for targeting ras-bearing tumors,[36] whereas with vana-

dium-containing species, there is no evidence for significanttargeting of protein prenylation pathways.

Conclusion

We designed and synthesized a series of novel molybdenum–BP complexes containing Mo4 or Mo12 clusters, heterometallic

ions (Mn, Fe, or Pt), and biologically active BP ligands. Com-pounds were characterized by using a variety of techniques, in-

cluding X-ray crystallography, IR spectroscopy, UV/photo-chromism, magnetic susceptibility, and 1D and 2D solid-stateNMR spectroscopy. All compounds were tested for cell growth

inhibition by using the MCF-7 cell line. The most active com-pound, Mo4Zol2Mn, had an IC50 value of 1.3 mm. Unlike the

potent vanadium POM/BP hybrids reported earlier, the BPmoiety here played a role in cell growth inhibition; a desirable

feature that might enable targeting of ras signaling pathways.Magnetic studies showed that Mo4Ale2Mn contained MnII,

whereas Mo4Zol2Mn contained MnIII, which may also contribute

to activity in cells. Future work will be directed toward studiesof the in vivo properties of the most active compounds, as

well as the synthesis of other polyoxomolybdates containingboth Mn and zoledronate analogues[36] to discover better in-

hibitors. With the very recent discovery that zoledronate canalso have potent activity against the tyrosine kinase domain of

human epidermal growth factor receptor, which can contribute

to direct activity against lung, breast, and pancreatic cancer,[14]

it would be of interest to see if better leads based on Mo–BP–

metal hybrids can be developed.

Experimental Section

General

H2O3PC(C3H6NH2)(OH)PO3H2 (H5Ale),[37] H2O3PC(C4H5N2)(OH)PO3H2

(H5Zol),[38] H2O3PC(C7H14NH2)(OH)PO3H2 (H5(BPC8NH2)),[39] Na2[HO3PC-(C8H17)(OH)PO3H] (Na2H3(BPC9)),[40] Na2[HO3PC(C3H6NHCH2C5H4N)-(OH)PO3H]·3 H2O (Na2H3(AlePy)),[19] and (NH4)5.5Na0.5[(Mo2O6)2-(O3PC(C3H6NH3)(O)PO3)2Mn]·8 H2O (Mo4Ale2Mn)[19] were synthesizedaccording to literature procedures. It should be noted that the for-mula of Mo4Ale2Mn was revised from that in our previous reportafter the discovery of the + 2 oxidation state of Mn in this study.

Rb(NH4)4[(Mo2O6)2(O3PC(CH2C3H4N2)(O)PO3)2Mn]·14 H2O(Mo4Zol2Mn)

Mn(OAc)3·2 H2O (0.070 g, 0.26 mmol) and zoledronic acid (0.137 g,0.5 mmol) were added to a solution of Na2MoO4·2 H2O (0.242 g,1 mmol) in 1 m CH3COONH4/CH3COOH buffer (10 mL). The solutionwas stirred for 5 min, then NH3 (33 % in water) was added drop-wise until pH 7.5 was reached. The solution was left to evaporateand was filtered after 24 h to remove a pink precipitate. Energy-dispersive X-ray spectroscopy (EDX) measurements and IR spec-troscopy results indicated that the precipitate was a manganeseBP complex that did not contain molybdenum. Grayish crystals ofMo4Zol2Mn appeared after 3 days (0.058 g, 16 % based on Mo).FTIR: n= 1576 (m), 1544 (w), 1422 (s), 1290 (w), 1138 (s), 1109 (sh),1045 (s), 976 (m), 912 (s), 873 (s), 785 (s), 696 (m), 656 (m), 619 (w),560 (w), 528 cm¢1 (m); elemental analysis calcd (%) forC10H56MnMo4N8.3O40P4Rb0.7 (M.W. = 1555 g mol¢1): C 7.72, H 3.63,N 7.47, Mn 3.53, Mo 24.67, P 7.97, Rb 3.85; found: C 7.71, H 3.58,N 7.25, Mn 3.60, Mo 24.52, P 7.90, Rb 3.42.

Figure 8. a) Effects of inhibitors on MCF-7 cell growth in the absence (whitebars) or presence of 20 mm GGOH (black bars). b) Same as the results shownin (a), but the compound activities in the absence of GGOH (white bars) arenormalized to one.

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(NH4)5[(Mo2O6)2(O3PC(C3H6NH3)(O)PO3)2Fe]·11 H2O (Mo4Ale2Fe)

H5Ale (0.697 g, 2.80 mmol) and FeCl3·6 H2O (0.378 g, 1.4 mmol)were added to a solution of (NH4)6Mo7O24·4 H2O (0.989 g,0.80 mmol) in water (10 mL). The solution was stirred for 5 min,then NH3 (33 % in water) was added dropwise until pH 6.0 wasreached. The solution was then stirred for 40 min at 90 8C until itbecame clear. After cooling to room temperature, a fine powderwas filtered off and the solution was left to evaporate. Yellow crys-tals appeared after 30 min and were collected after 2 days (1.20 g,61 % based on Mo). FTIR: n= 1602 (sh), 1421 (vs), 1130 (s), 1039(sh), 858 (s), 802 (s), 690 (w), 641 (m), 574 (w), 510 (m), 481 cm¢1

(vw); elemental analysis calcd (%) for C8H60FeMo4N7O37P4 (M.W. =1410 g mol¢1): C 6.81, H 4.29, N 6.95, P 8.79, Mo 27.21, Fe 3.96;found: C 6.89, H 4.15, N 6.99, P 8.68, Mo 26.99, Fe 3.94.

(NH4)5[(Mo2O6)2(O3PC(C7H14NH3)(O)PO3)2Fe]·10 H2O(Mo4(BPC8NH2)2Fe)

A mixture of (NH4)6Mo7O24·4 H2O (0.200 g, 0.16 mmol), FeCl3·6 H2O(70 mg, 0.25 mmol), and H5(BPC8NH2) (0.175 g, 0.57 mmol) in water(20 mL) was stirred and the pH was adjusted to 7.5 by the additionof NH3 (33 % solution). The mixture was heated to 90 8C for 1 h andthen cooled to room temperature. The resulting mixture was fil-tered and the filtrate was left to slowly evaporate. After twoweeks, yellow crystals were collected by filtration (0.145 g, 34 %based on Mo). IR (FTR): n= 1615 (sh), 1417 (s), 1117 (s), 1041 (vs),1018 (vs), 940 (w), 905 (s), 860 (s), 789 (s), 702 (s), 653 (s), 573 (s),513(s), 484 cm¢1 (s) ; elemental analysis calcd (%) forC16H74FeMo4N7O36P4 (M.W. = 1504 g mol¢1): C 12.77, H 4.95, N 6.51,Fe 3.71, Mo 25.51, P 8.24; found: C 12.71, H 4.66, N 6.17, Fe 3.70,Mo 25.82, P 8.38.

Na0.5(NH4)6.5[(Mo2O6)2(O3PC(C8H17)(O)PO3)2Fe]·10 H2O(Mo4(BPC9)2Fe)

A mixture of (NH4)6Mo7O24·4 H2O (0.248 g, 0.20 mmol), FeCl3·6 H2O(0.095 g, 0.35 mmol), and Na2H3(BPC9) (0.258 g, 0.74 mmol) in 1 mCH3COONH4/CH3COOH buffer (5 mL) was stirred and the pH wasadjusted to 7.5 by the addition of NH3 (33 % solution). The mixturewas then sealed in a 23 mL Teflon-lined stainless-steel reactor andheated to 130 8C over a period of 4 h, kept at 130 8C for 20 h, thencooled to room temperature over a period of 36 h. The resultingmixture was filtered and the filtrate was left to slowly evaporate.After 5 days, yellow crystals were collected by filtration (0.075 g,53 % based on Mo). FTIR: n= 1635 (w), 1419 (s), 1115 (m), 1036 (s),1009 (s), 913 (s), 892 (s), 860 (m), 794 (s), 694 (s), 667 (w), 650 (s),571 (vs), 509 (s), 483 cm¢1 (s) ; elemental analysis calcd (%) forNa0.5C18H81FeMo4N6.5O36P4 (M.W. = 1540 g mol¢1): C 14.04, H 5.30,N 5.91, Fe 3.63, Mo 24.92, P 8.05, Na 0.75; found: C 13.98, H 5.38,N 6.22, Fe 3.61, Mo 25.08, P 8.01, Na 0.65.

(NH4)5[(Mo2O6)2(O3PC(CH2C3H4N2)(O)PO3)2Fe]·5 H2O(Mo4Zol2Fe)

A mixture of (NH4)6Mo7O24·4 H2O (0.248 g, 0.20 mmol), FeCl3·6 H2O(0.095 g, 0.35 mmol), and zoledronic acid (0.201 g, 0.77 mmol) in1 m CH3COONH4/CH3COOH buffer (5 mL) was stirred and the pHwas adjusted to 6 by the addition of NH3 (33 % solution). The mix-ture was sealed in a 23 mL Teflon-lined stainless-steel reactor andheated to 130 8C over a period of 4 h, kept at 130 8C for 20 h, thencooled to room temperature over a period of 36 h. Yellow crystalswere collected by filtration and were washed with water (0.315 g,67 % based on Mo). FTIR: n= 1652 (w), 1575 (m), 1545 (m), 1429

(vs), 1394 (s), 1313 (w), 1284 (m), 1138 (s), 1118 (s), 1042 (vs), 977(s), 948 (m), 914 (m), 869 (s), 783 (s), 708 (s), 676 (s), 621 (s), 576 (s),516 (s), 481 cm¢1 (s) ; elemental analysis calcd (%) forC10H42FeMo4N9O31P4 (M.W. = 1348 g mol¢1): C 8.92, H 3.14, N 9.35,Mo 28.46, Fe 4.14, P 9.19; found: C 8.87, H 3.09, N 9.36, Mo 28.36,Fe 4.21, P 9.20.

Na3{Na(Mo3O8)4[O3PCC3H6NH2CH2(C5H5N)(O)PO3]4}·25 H2O(Mo12(AlePy)4)

Na2H3(AlePy) (0.308 g, 0.70 mmol) was added to a solution ofNa2MoO4·2 H2O (0.582 g, 2.4 mmol) in water (40 mL) and the pHwas adjusted to 3 by using a 2 m solution of HCl. The solution wasstirred for 1 h at 90 8C, cooled to room temperature, and slowlyevaporated. White crystals (0.240 g, yield 34 % based on Mo) werefiltered off after 3 days. FTIR: n= 1623 (m), 1529 (w), 1451 (m), 1145(sh), 1126 (s), 1056 (sh), 1026 (s), 965 (w), 917 (m), 874 (s), 794 (m),760 (m), 682 (sh), 647 (m), 541 (m), 520 (m), 489 (m), 401 cm¢1 (m);elemental analysis calcd (%) for C40H110Mo12N8Na4O85P8

(3554 g mol¢1): C 13.52, H 3.12, Mo 32.39, N 3.15, Na 2.59, P 6.88;found: C 13.11, H 3.02, Mo 32.41, N 3.01, Na 2.88, P 7.04.

Na8{Pt4Cl8(Mo3O8)4[O3PCC3H6NH2CH2(C5H4N)(O)PO3]4}·30 H2O(Mo12(AlePy)4Pt4)

A solution of [PtCl2(dmso)2] (0.078 g, 0.185 mmol) in water (2 mL)was added to a suspension of Mo12(AlePy)4 (0.12 g, 0.033 mmol) inwater (3 mL), heated to 60 8C, and the pH was adjusted to 3 byusing 2 m HCl. The solution was stirred for 1 h at 90 8C, cooled toroom temperature, and NaCl (0.500 g, 8.55 mmol) added. The solu-tion was stirred for 1 h. A beige precipitate was collected by filtra-tion (0.055 g, yield 35 % based on Mo). FTIR: n= 1612 (m), 1489(w), 1425 (m), 1121 (s), 1024 (s), 922 (sh), 883 (s), 789 (m), 767 (m),676 (sh), 652 (m), 545 cm¢1 (m); elemental analysis calcd (%) forC40H116Cl8Mo12N8Na8O90P8Pt4 (4796 g mol¢1): C 10.02, H 2.44, Cl 5.91,Mo 24.00, N 2.33, Na 3.83, P 5.17, Pt 16.27; found: C 11.02, H 2.45,Cl 3.55, Mo 23.42, N 2.33, Na 4.04, P 5.26, Pt 16.00.

IR spectroscopy

IR spectra were recorded on a Nicolet 6700 FTIR spectrophotome-ter.

X-ray crystallography

Data collection was carried out by using a Siemens SMART three-circle diffractometer for Mo4Ale2Fe and Mo4(BPC9)2Fe and by usinga Bruker Nonius X8 APEX 2 diffractometer for Mo2Ale2Mn,Mo4(BPC8NH2)2Fe, and Mo12(AlePy)4. Both diffractometers wereequipped with a charge-coupled device (CCD) bidimensional de-tector using the monochromatized wavelength l(MoKa) =0.71073 æ. Absorption correction was based on multiple and sym-metry-equivalent reflections in the data set by using the SADABSprogram[41] based on the method of Blessing.[42] The structureswere solved by direct methods and refined by full-matrix least-squares by using the SHELX-TL package.[43] In all structures, thereare small discrepancies between the structures determined by ele-mental analysis and those deduced from the crystallographic atomlist because of the difficulty in locating all disordered water mole-cules (and sometimes the countercations), a common featurefound in other POM structural investigations.[44] In the structures ofMo4Ale2Fe and Mo4(BPC9)2Fe, NH4

+ and H2O could not be distin-guished based on the observed electron densities; therefore, allpositions were labeled O and assigned the oxygen atomic scatter-

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ing factor. Crystallographic data are given in Table 2. Partial atomiclabeling schemes, selected bond lengths, and bond valence sumcalculations[45] are reported in Figures S3–S8 in the SupportingInformation.

CCDC 1039882 (Mo4Ale2Mn), 1039883 (Mo4Ale2Fe), 1039884(Mo4(BPC8NH2)2Fe), 1039885 (Mo4(BPC9)2Fe), 1039886 (Mo4Zol2Fe),and 1039887 (Mo12(AlePy)4) contain the supplementary crystallo-graphic data for this paper. These data can be obtained free ofcharge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.

NMR spectroscopy measurements

1H and 31P MAS NMR spectra were recorded on a Bruker AVANCE-500 spectrometer (Larmor frequencies of 500.135, 202.461, and125.768 MHz, respectively) at room temperature (304 K) by usinga 3.2 mm MAS probe. The following conditions were used for re-cording the 1D 1H MAS NMR spectra: 908 1H pulse = 1.8 ms; delaytime between scans = 1 s; 16 scans per spectrum. 31P MAS NMRspectra with high-power proton decoupling were recorded with orwithout CP. The following conditions were used for recording thespectrum with CP in the 2D 31P{1H} CPMAS heteronuclear correla-tion (HETCOR) NMR spectroscopy experiment: the proton radiofre-quency field strength for decoupling was 45 kHz; the contact timewas 2 ms at Hartmann–Hahn match conditions of 53 kHz; thedelay time between scans was 1 s. The direct polarization (DP)31P{1H} MAS NMR spectra were recorded with 908 flip angle pulsesof 2.2 ms duration and 21 s recycle delay, which satisfied the 5 Õ T1

conditions. In these experiments, high-power proton decoupling(75 kHz) was used only during the acquisition time. Sixty-fourscans were collected for each 1D 31P{1H} MAS NMR spectrum. Forthe 2D 31P{1H} CPMAS HETCOR NMR spectroscopy experiment,a total of 64 t1 increments with 256 scans each were collected. The31P{1H}–31P{1H} DQ–SQ MAS spectrum was obtained by using thePOSTC7 sequence with excitation and conversion periods of0.8 ms. The 2D spectra were collected with 128 t1 increments of50 ms and 16 transients each by using the hypercomplex method.Presaturation pulses prior to the first pulse of the 2D sequencewere used to reduce the recycle delay to 10 s without saturation.The spin rate was 20 kHz for 1D 1H MAS, 1D 31P{1H} MAS, and 2D

31P{1H} CPMAS HETCOR, and 10 kHz for 2D 31P{1H}–31P{1H} DQ–SQMAS. 1H chemical shifts were referenced with respect to externaltetramethylsilane (TMS), whereas 31P chemical shifts were refer-enced with respect to 85 % H3PO4, with an accuracy of �0.4 ppm.

Magnetic studies

Magnetic susceptibility measurements were carried out by usinga Quantum Design SQUID Magnetometer with an applied field of1000 Oe for Mo4Ale2Mn and 10 000 Oe for Mo4Zol2Mn as powdersamples pressed into pellets for magnetic ordering of the crystalli-tes. The independence of the susceptibility value with regard tothe applied field was checked at room temperature. The suscepti-bility data were corrected for diamagnetic contributions, as de-duced by using Pascal’s constant tables. All magnetic data were si-mulated by using the FORTRAN program.

Optical measurements

Diffuse reflectance spectra were collected at room temperature ona finely ground sample with a Cary 5G spectrometer (Varian)equipped with a 60 mm diameter integrating sphere and comput-er-controlled by using the “Scan” software. Diffuse reflectance wasmeasured from 250 to 1000 nm with a 2 nm step by using Halonpowder (from Varian) as a reference (100 % reflectance). The reflec-tance data were optimized by using a Kubelka–Munk transforma-tion[46] to better locate the absorption thresholds. The sampleswere irradiated with a Fisher Bioblock UV lamp (lexc = 365 nm,6 W).

Cell-growth inhibition assays

Cell growth inhibition assays were carried out exactly as describedpreviously.[16] Cell growth “rescue” experiments with GGOH werealso carried out as described previously.[13d]

Table 2. Crystallographic data for the complexes reported herein.

Mo4Ale2Mn Mo4Ale2Fe Mo4(BPC8NH2)2Fe Mo4(BPC9)2Fe Mo4Zol2Fe Mo12(AlePy)4

formula C8H56MnMo4N6.50Na0.50O35P4 C8H60FeMo4N7O37P4 C16H82FeMo4N7O36P4 C18H81FeMo4Na0.5N6.5O36P4 C10H42FeMo4N9O31P4 C40H110Mo12N8Na4O85P8

Mr 1377.60 1410.12 1512.35 1539.88 1348.02 3554.32T [K] 200 293 200 293 149 293crystal system monoclinic monoclinic monoclinic monoclinic triclinic orthorhombicspace group P21/n P21/n P21/c P21/n P1 P21212a [æ] 10.860(1) 10.798(4) 12.8986(3) 8.538(9) 10.003(1) 17.472(4)b [æ] 17.096(2) 17.340(6) 23.6753(5) 27.89(13) 12.9246(9) 21.053(4)c [æ] 11.885(1) 11.799(4) 8.4687(2) 23.92(2) 16.529(1) 15.655(4)a [8] 90 90 90 90 78.132(2) 90b [8] 97.055(4) 98.271(7) 107.583(1) 92.35(2) 74.463(2) 90g [8] 90 90 90 90 81.480(2) 90V [æ3] 2189.9(4) 2182.7(14) 2465.3(1) 5707(10) 2005.1(3) 5759(2)Z 2 2 2 4 2 21calcd [g cm¢3] 2.095 2.146 2.026 1.792 2.233 1.863m [mm¢1] 1.653 1.704 1.514 1.314 1.841 1.474data/parame-ters

6397/284 3139/267 7159/305 16250/637 6851/624 16652/635

Rint 0.0231 0.0558 0.0517 0.0897 0.0341 0.0427GOF 1.083 1.052 1.301 1.081 1.039 1.076R1 (>2s(I)) 0.0331 0.0503 0.0602 0.0587 0.0402 0.0452

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Acknowledgements

This work was supported by the CNRS, UVSQ, the French ANR

(grant ANR-11-BS07-011-01-BIOOPOM), the United States PublicHealth Service (National Institutes of Health grant CA158191),

a Harriet A. Harlin Professorship, and the University of Illinois/

Oldfield Research Fund. Gr¦goire Paille and Elodie Rozwadow-ski-Montribot are gratefully acknowledged for their participa-

tion in the synthesis of the compounds.

Keywords: bisphosphonates · cancer · magnetic properties ·NMR spectroscopy · polyoxometalates

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Received: December 19, 2014

Revised: March 12, 2015

Published online on June 11, 2015

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