title: Radiolabeled cyclosaligenyl monophosphates of 5-iodo-2'-deoxyuridine, 5-iodo-3'-fluoro-2',3'-dideoxyuridine, and 3'-fluorothymidine for molecular radiotherapy of cancer: synthesis and biological evaluation.
abstract: Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC(50) values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.
authors.affiliation: Department of Radiation Oncology, J. Bruce Henrisken Cancer Research Laboratories, University of Nebraska Medical Center, 986850 Nebraska Medical Center, Omaha, Nebraska 68198-6850, USA. zkortylewicz@unmc.edu
authors.forename: Zbigniew P
authors.initials: ZP
authors.lastname: Kortylewicz
authors.forename: Yu
authors.initials: Y
authors.lastname: Kimura
authors.forename: Kotaro
authors.initials: K
authors.lastname: Inoue
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mack
authors.forename: Janina
authors.initials: J
authors.lastname: Baranowska-Kortylewicz
mesh_terms: D002091:Butyrylcholinesterase / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015179:Colorectal Neoplasms; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005909:Glioblastoma; D006801:Humans; D006868:Hydrolysis; D007457:Iodine Radioisotopes; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000201:enzymology / Q000532:radiotherapy*; D010051:Ovarian Neoplasms; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D013938:Thymidine Monophosphate; D014542:Uridine Monophosphate; D002091:Butyrylcholinesterase