Abstract
We synthesized a series of polyoxometalate-bisphosphonate complexes containing Mo(VI)O(6) octahedra, zoledronate, or an N-alkyl (n-C(6) or n-C(8)) zoledronate analogue, and in two cases, Mn as a heterometal. Mo(6)L(2) (L = Zol, ZolC(6), ZolC(8)) and Mo(4)L(2)Mn (L = Zol, ZolC(8)) were characterized by using single-crystal X-ray crystallography and/or IR spectroscopy, elemental and energy dispersive X-ray analysis and (31)P NMR. We found promising activity against human nonsmall cell lung cancer (NCI-H460) cells with IC(50) values for growth inhibition of ∼5 μM per bisphosphonate ligand. The effects of bisphosphonate complexation on IC(50) decreased with increasing bisphosphonate chain length: C(0) ≈ 6.1×, C(6) ≈ 3.4×, and C(8) ≈ 1.1×. We then determined the activity of one of the most potent compounds in the series, Mo(4)Zol(2)Mn(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.