title: Hydrophilically enhanced 3-carboranyl thymidine analogues (3CTAs) for boron neutron capture therapy (BNCT) of cancer.
abstract: Five novel 3-carboranyl thymidine analogues (3CTAs) were designed and synthesized for boron neutron capture therapy (BNCT) of cancer. Phosphorylation of all five 3CTAs was catalyzed by recombinant human thymidine kinase (hTK1) using adenosine triphosphate (ATP) as the phosphate donor. The obtained phosphorylation rates ranged from 4% to 64.5% relative to that of thymidine. The compound with the most favorable hTK1 binding properties had a k(cat)/K(M) value of 57.4% relative to that of thymidine and an IC(50) of inhibition of thymidine phosphorylation by hTK1 of 92 microM. Among the five synthesized 3CTAs, this agent had also the overall most favorable physicochemical properties. Therefore, it may have the potential to replace N5-2OH, the current lead 3CTA, in preclinical studies. An in silico model for the binding of this compound to hTK1 was developed.
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sureshbabu
authors.initials: S
authors.lastname: Narayanasamy
authors.forename: B T S
authors.initials: BT
authors.lastname: Thirumamagal
authors.forename: Jayaseharan
authors.initials: J
authors.lastname: Johnsamuel
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Al-Madhoun
authors.forename: Elena
authors.initials: E
authors.lastname: Usova
authors.forename: Guirec Y
authors.initials: GY
authors.lastname: Cosquer
authors.forename: Junhua
authors.initials: J
authors.lastname: Yan
authors.forename: Achintya K
authors.initials: AK
authors.lastname: Bandyopadhyaya
authors.forename: Rohit
authors.initials: R
authors.lastname: Tiwari
authors.forename: Staffan
authors.initials: S
authors.lastname: Eriksson
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D001665:Binding Sites; D016754:Boron Neutron Capture Therapy; D002384:Catalysis; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000532:radiotherapy; D010766:Phosphorylation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D011994:Recombinant Proteins; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine