Activity of sulfonium bisphosphonates on tumor cell lines

We investigated three series of sulfonium bisphosphonates for their activity in inhibiting the growth of three human tumor cell lines. The first series consisted of 6 cyclic sulfonium bisphosphonates, the most active species having an (average) IC₅₀ of 89 μM. The second consisted of 10 phenylalkyl and phenylalkoxy bisphosphonates, the most active species having an IC₅₀ of 18 μM. The third series consisted of 17 n-alkyl sulfonium bisphosphonates, the most active species having an IC₅₀ of ∼240 nM. Three QSAR models showed that the experimental cell growth inhibition results could be well predicted. We also determined the structures of one sulfonium bisphosphonate bound to farnesyl diphosphate synthase, finding that it binds exclusively to the dimethylallyl diphosphate binding site. These results are of interest since they show that sulfonium bisphosphonates can have potent activity against a variety of tumor cell lines, the most active species having IC₅₀ values much lower than conventional nitrogen-containing bisphosphonates.