Anticancer Activity of Polyoxometalate-Bisphosphonate Complexes: Synthesis, Characterization, In Vitro and In Vivo Results

Abstract

We synthesized a series of polyoxometalate-bisphosphonate complexes containing MoVIO6 octahedra, zoledronate or an N-alkyl (n-C6 or n-C8) zoledronate analog, 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 EDX analysis and 31P NMR. We found promising activity against human non-small 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 ~6.1x; C6 ~3.4× and C8 ~1.1x. 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 EGFR (epidermal growth factor receptor) driven cancers.

The crystal structure of tris(1-ethylimidazole-κ1 N)-(sulfato-κ2 O,O′)vanadium(IV), C15H24N6O5SV

“…The range of potential applications of vanadium complexes range from catalysis to bioactivity [4][5][6][7][8][9][10]. The design and synthesis of vanadium complexes will be very meaningful.…”

Decavanadate Inhibits Mycobacterial Growth More Potently Than Other Oxovanadates

“…Vanadium derivatives have been considered as therapeutic agents since 1899 (Lyonnet et al, 1899 ; Crans et al, 2018 ). Recent studies demonstrate that vanadium compounds and salts are effective antidiabetic agents (Sakurai, 2002 ; Thompson and Orvig, 2006 ; Kiss et al, 2008 ; Smith et al, 2008 ; Thompson et al, 2009 ; Willsky et al, 2011 , 2013 ; Crans, 2015 ; Trevino et al, 2015 ; Boulmier et al, 2017 ; Levina and Lay, 2017b ) but their therapeutic properties have been expanded for these materials to be anticancer agents (Lu and Zhu, 2011 ; Leon et al, 2017 ; Medina et al, 2017 ; Crans et al, 2018 ), immunotherapy agents (Lu and Zhu, 2011 ; Selman et al, 2018 ) as well as treatment for other diseases (Zwolak, 2014 ; Pessoa et al, 2015 ). Many of the compounds are coordination complexes, which form vanadate during processing after administration (Thompson et al, 2009 ; Willsky et al, 2011 ).…”

Inhibition of Human Immunodeficiency Virus Type 1 Entry by a Keggin Polyoxometalate

“…However, it caused adverse effects on the hepatic and renal functions [ 36 ]. POMs still suffer from the stigma of this failure, although new generations of POMs including Keggin structures, have been synthesized with less toxicity and greater efficacy, most studies have focused on cancer therapy [ 37 , 38 ], and very few studies have been conducted to investigate the anti-HIV potential in the past decade [ 39 ]. The mechanism of action has remained unclear.…”