title: Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogs for boron neutron capture therapy of cancer.
abstract: A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogs, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2nd generation carboranyl pyrimidine nucleoside analogs (YB18A [3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3-4 times superior as a substrate and inhibitor of hTK1 than N5-2OH (2), a 1st generation carboranyl pyrimidine nucleoside analog. Both 2 and 3 appeared to be 5'-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of 3 with an intratumoral concentration that was approximately 4 times higher than that of 2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogs and will profoundly impact future design strategies for these agents.
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH, USA.
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khalil
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH, USA.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishita
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Nakkula
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH, USA.
authors.forename: Tehane
authors.initials: T
authors.lastname: Ali
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Tiwari
authors.affiliation: College of Pharmacy, Korea University, Sejong, Republic of Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH, USA. Electronic address: tjarks.1@osu.edu.
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000627:therapeutic use*; D016754:Boron Neutron Capture Therapy; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000378:metabolism / Q000532:radiotherapy*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001896:Boron Compounds; D047428:Protein Kinase Inhibitors; D011741:Pyrimidine Nucleosides; D013937:Thymidine Kinase; C092717:thymidine kinase 1
keywords: Boron neutron capture therapy (BNCT); Carborane; Carboranyl pyrimidine nucleoside analog; Thymidine kinase 1 (TK1)