Targeting Cancer Cells with a Bisphosphonate Prodrug.

Abstract

Nitrogen-containing bisphosphonates have antitumor activity in certain breast cancer and myeloma patients. However, these drugs have limited oral absorption, tumor cell entry and activity, and cause bone side effects. The potencies of phosphorylated antiviral drugs have been increased by administering them as prodrugs, in which the negative charges on the phosphate moieties are masked to make them lipophilic. We synthesized heterocyclic bisphosphonate (BP) prodrugs in which the phosphonate moieties are derivatized with pivaloyloxymethyl (pivoxil) groups and that lack the hydroxy "bone hook" on the geminal carbon. When the lipophilic BP prodrugs enter tumor cells, they are converted into their active forms by intracellular esterases. The most active BP prodrug, tetrakispivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (7), was found to potently inhibit the in vitro growth of a variety of tumor cell lines, especially hematopoietic cells, at nanomolar concentrations. Consistent with this fact, compound 7 inhibited the prenylation of the RAP1A small GTPase signaling protein at concentrations as low as 1-10 nm. In preclinical studies, 7 slowed the growth of human bladder cancer cells in an immunodeficient mouse model. Thus, 7 is significantly more active than zoledronic acid, the most active FDA-approved BP, and a potential anticancer therapeutic.

• Authors: Kenji Matsumoto, Kosuke Hayashi, Kaoru Murata-Hirai, Masashi Iwasaki, Haruki Okamura, Nagahiro Minato, Craig T Morita, Yoshimasa Tanaka
• Journal: ChemMedChem (ChemMedChem) Vol. 11 Issue 24 Pg. 2656-2663 (12 16 2016) ISSN: 1860-7187 [Electronic] Germany
• PMID: 27786425 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Diphosphonates
• Prodrugs
• Thiazoles
• tetrakispivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Biological Assay
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Diphosphonates (chemical synthesis, chemistry, pharmacology)
• Disease Models, Animal
• Drug Delivery Systems
• Humans
• Inhibitory Concentration 50
• Mice
• Molecular Structure
• Neoplasms (drug therapy)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Thiazoles (chemical synthesis, chemistry, pharmacology)