title: Activity of sulfonium bisphosphonates on tumor cell lines.
abstract: 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 microM. The second consisted of 10 phenylalkyl and phenylalkoxy bisphosphonates, the most active species having an IC50 of 18 microM. The third series consisted of 17 n-alkyl sulfonium bisphosphonates, the most active species having an IC50 of approximately 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.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hudock
authors.forename: Kilannin
authors.initials: K
authors.lastname: Krysiak
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: Kyle
authors.initials: K
authors.lastname: Bergan
authors.forename: Fenglin
authors.initials: F
authors.lastname: Yin
authors.forename: Annette
authors.initials: A
authors.lastname: Leon
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D051228:Geranyltranstransferase / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000201:enzymology
chemical_list: D004164:Diphosphonates; D013450:Sulfones; D051228:Geranyltranstransferase