Amandine Boulmier1, Xinxin Feng2, Olivier Oms1, Pierre Mialane1, Eric Rivière3, Christopher J Shin2, Jiaqi Yao2, Tadahiko Kubo4, Taisuke Furuta4, Eric Oldfield2,5, Anne Dolbecq1. 1. Institut Lavoisier de Versailles, UMR 8180, Université de Versailles Saint-Quentin en Yvelines, Université Paris-Saclay , 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France. 2. Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 6180, United States. 3. Institut de Chimie Moléculaire et des Matériaux d'Orsay, UMR 8182, Université Paris-Sud, Université Paris-Saclay , 91405 Orsay, France. 4. Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University , Hiroshima, Japan. 5. Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign , 1110 W Green Street, Urbana, Illinois 61801, United States.
Abstract
We synthesized a series of polyoxometalate-bisphosphonate complexes containing MoVIO6 octahedra, zoledronate, or an N-alkyl (n-C6 or n-C8) zoledronate analogue, and in two cases, Mn as a heterometal. Mo6L2 (L = Zol, ZolC6, ZolC8) and Mo4L2Mn (L = Zol, ZolC8) were characterized by using single-crystal X-ray crystallography and/or IR spectroscopy, elemental and energy dispersive X-ray analysis and 31P NMR. We found promising activity against human nonsmall cell lung cancer (NCI-H460) cells with IC50 values for growth inhibition of ∼5 μM per bisphosphonate ligand. The effects of bisphosphonate complexation on IC50 decreased with increasing bisphosphonate chain length: C0 ≈ 6.1×, C6 ≈ 3.4×, and C8 ≈ 1.1×. We then determined the activity of one of the most potent compounds in the series, Mo4Zol2Mn(III), against SK-ES-1 sarcoma cells in a mouse xenograft system finding a ∼5× decrease in tumor volume than found with the parent compound zoledronate at the same compound dosing (5 μg/mouse). Overall, the results are of interest since we show for the first time that heteropolyoxomolybdate-bisphosphonate hybrids kill tumor cells in vitro and significantly decrease tumor growth, in vivo, opening up new possibilities for targeting both Ras as well as epidermal growth factor receptor driven cancers.
We synthesized a series of class="Chemical">polyoxometalate-bisphosphonate complexesclass="Chemical">n class="Chemical">containing MoVIO6 octahedra, zoledronate, or an N-alkyl (n-C6 or n-C8) zoledronate analogue, and in two cases, Mn as a heterometal. Mo6L2 (L = Zol, ZolC6, ZolC8) and Mo4L2Mn (L = Zol, ZolC8) were characterized by using single-crystal X-ray crystallography and/or IR spectroscopy, elemental and energy dispersive X-ray analysis and 31PNMR. We found promising activity against humannonsmall cell lung cancer (NCI-H460) cells with IC50 values for growth inhibition of ∼5 μM per bisphosphonate ligand. The effects of bisphosphonatecomplexation on IC50 decreased with increasing bisphosphonate chain length: C0 ≈ 6.1×, C6 ≈ 3.4×, and C8 ≈ 1.1×. We then determined the activity of one of the most potent compounds in the series, Mo4Zol2Mn(III), against SK-ES-1sarcoma cells in a mouse xenograft system finding a ∼5× decrease in tumor volume than found with the parent compound zoledronate at the same compound dosing (5 μg/mouse). Overall, the results are of interest since we show for the first time that heteropolyoxomolybdate-bisphosphonate hybrids kill tumor cells in vitro and significantly decrease tumor growth, in vivo, opening up new possibilities for targeting both Ras as well as epidermal growth factor receptor driven cancers.
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