title: 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: Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, Japan.
authors: Kenji
authors: K
authors: Matsumoto
authors: Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, Japan.
authors: Kosuke
authors: K
authors: Hayashi
authors: Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, Japan.
authors: Kaoru
authors: K
authors: Murata-Hirai
authors: Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, Japan.
authors: Masashi
authors: M
authors: Iwasaki
authors: Department of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan.
authors: Haruki
authors: H
authors: Okamura
authors: Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, Japan.
authors: Nagahiro
authors: N
authors: Minato
authors: Department of Internal Medicine and the Interdisciplinary GraduateProgram in Immunology, University of Iowa Carver College of Medicine, Iowa City Veterans Affairs Health Care System, 601 Highway 6 West, Research (151), Iowa City, IA, 52246, USA.
authors: Craig T
authors: CT
authors: Morita
authors: Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, Japan.|Center for Bioinformatics and Molecular Medicine, Graduate School ofBiomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors: Yoshimasa
authors: 0000-0001-7276-4868
authors: Y
authors: Tanaka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001681:Biological Assay; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D011355:Prodrugs; D013844:Thiazoles; C000621092:tetrakispivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate
keywords: anticancer agents; bisphosphonates; farnesyl diphosphate synthase; lipophilicity; prodrugs