One category of boron neutron capture therapy (BNCT) agents that has received extensive attention during recent years is 3-carboranyl thymidine analogues (3CTAs). These molecules are phosphorylated to the corresponding 5'-monophosphates by human thymidine kinase 1 (TK1), an enzyme that is up-regulated in dividing malignant cells. Thus, these phosphorylated molecules are selectively entrapped in tumor cells due to the acquired negative charge. This review will analyze design strategies applied for the synthesis of boron-containing nucleosides in general and in particular reference to 3CTAs. Results of biological studies with these molecules will be discussed.
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Cellular influx, efflux, and anabolism of 3-carboranyl thymidine analogs: potential boron delivery agents for neutron capture therapy.
J Pharmacol Exp Ther
November 2013
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.).
3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 ((10)B) delivery agent for neutron capture therapy (NCT). N5-2OH is an excellent substrate of thymidine kinase 1 and its favorable biodistribution profile in rodents led to successful preclinical NCT of rats bearing intracerebral RG2 glioma. The present study explored cellular influx and efflux mechanisms of N5-2OH, as well as its intracellular anabolism beyond the monophosphate level.
View Article and Find Full Text PDFN3-substituted thymidine bioconjugates for cancer therapy and imaging.
Future Med Chem
April 2013
Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA.
The compound class of 3-carboranyl thymidine analogues (3CTAs) are boron delivery agents for boron neutron capture therapy (BNCT), a binary treatment modality for cancer. Presumably, these compounds accumulate selectively in tumor cells via intracellular trapping, which is mediated by hTK1. Favorable in vivo biodistribution profiles of 3CTAs led to promising results in preclinical BNCT of rats with intracerebral brain tumors.
View Article and Find Full Text PDFSynthesis of N3-substituted carboranyl thymidine bioconjugates and their evaluation as substrates of recombinant human thymidine kinase 1.
Eur J Med Chem
February 2013
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Four different libraries of overall twenty three N3-substituted thymidine (dThd) analogues, including eleven 3-carboranyl thymidine analogues (3CTAs), were synthesized. The latter are potential agents for Boron Neutron Capture Therapy (BNCT) of cancer. Linker between the dThd scaffold and the m-carborane cluster at the N3-position of the 3CTAs contained amidinyl-(3e and 3f), guanidyl-(7e-7g), tetrazolylmethyl-(9b1/2-9d1/2), or tetrazolyl groups (11b1/2-11d1/2) to improve human thymidine kinase 1 (hTK1) substrate characteristics and water solubilities compared with 1st generation 3CTAs, such as N5 and N5-2OH.
View Article and Find Full Text PDFSynthesis, chemical and enzymatic hydrolysis, and aqueous solubility of amino acid ester prodrugs of 3-carboranyl thymidine analogs for boron neutron capture therapy of brain tumors.
Eur J Med Chem
September 2012
Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt.
Various water-soluble L-valine-, L-glutamate-, and glycine ester prodrugs of two 3-Carboranyl Thymidine Analogs (3-CTAs), designated N5 and N5-2OH, were synthesized for Boron Neutron Capture Therapy (BNCT) of brain tumors since the water solubilities of the parental compounds proved to be insufficient in preclinical studies. The amino acid ester prodrugs were prepared and stored as hydrochloride salts. The water solubilities of these amino acid ester prodrugs, evaluated in phosphate buffered saline (PBS) at pH 5, pH 6 and pH 7.
View Article and Find Full Text PDFThymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors.
Proc Natl Acad Sci U S A
November 2008
Department of Pathology, Division of Biostatistics, Ohio State University, Columbus, OH 43210, USA.
The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl] thymidine, designated N5-2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma model. Target validation was established using the thymidine kinase (TK) 1(+) wild-type, murine L929 cell line and its TK1(-) mutant counterpart, which were implanted s.c.
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