Activity of nitrogen-containing and non-nitrogen-containing bisphosphonates on tumor cell lines

We synthesized and tested three series of bisphosphonates for their activity in inhibiting the growth of three human tumor cell lines: MCF-7 (breast), NCI-H460 (lung), and SF-268 (CNS). The first series of compounds consisted of 49 nitrogen-containing bisphosphonates, the most active species being a tetrakispivaloyloxymethyl (POM) ester, having an (average) IC ₅₀ of 6.8 μM. The second series of compounds consisted of nine terphenylbisphosphonates, the most active species also being a POM ester, having an IC₅₀ of 2.2 μM. The third series of compounds consisted of seven halogen or cyanophenylbisphosphonates, the most active species again being a POM ester, having an IC₅₀ of 500 nM. Taken together, these results are of interest because they show that bisphosphonate esters can have potent activity against a variety of tumor cell lines, with the most active terphenyl- and halophenyl-containing species having IC₅₀ values ∼10-40x lower than the most potent commercially available bisphosphonates.