Journal article
Targeting Cancer Cells with a Bisphosphonate Prodrug
ChemMedChem, Vol.11(24), pp.2656-2663
12/16/2016
DOI: 10.1002/cmdc.201600465
PMCID: PMC5605902
PMID: 27786425
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.
Details
- Title: Subtitle
- Targeting Cancer Cells with a Bisphosphonate Prodrug
- Creators
- Craig T Morita - 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 , Iowa City, IA, 52246, USAKenji Matsumoto - Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, JapanKosuke Hayashi - Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, JapanKaoru Murata-Hirai - Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, JapanMasashi Iwasaki - Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, JapanHaruki Okamura - Department of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, JapanNagahiro Minato - Center for Innovation in Immunoregulative Technology and Therapeutics, Department of Immunology and Cell Biology, Graduate School ofMedicine, Kyoto University, Kyoto, 606-8501, JapanYoshimasa Tanaka - Center for Bioinformatics and Molecular Medicine, Graduate School ofBiomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
- Resource Type
- Journal article
- Publication Details
- ChemMedChem, Vol.11(24), pp.2656-2663
- DOI
- 10.1002/cmdc.201600465
- PMID
- 27786425
- PMCID
- PMC5605902
- ISSN
- 1860-7179
- eISSN
- 1860-7187
- Grant note
- I01 BX000972 / BLRD VA P30 CA086862 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
- Language
- English
- Date published
- 12/16/2016
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984094321002771
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