Hydrophilically enhanced 3-carboranyl thymidine analogues (3CTAs) for boron neutron capture therapy (BNCT) of cancer

• Published in: Bioorganic & medicinal chemistry 2006-10, Vol.14 (20), p.6886-6899
• Main Authors: Narayanasamy, Sureshbabu, Thirumamagal, B.T.S., Johnsamuel, Jayaseharan, Byun, Youngjoo, Al-Madhoun, Ashraf S., Usova, Elena, Cosquer, Guirec Y., Yan, Junhua, Bandyopadhyaya, Achintya K., Tiwari, Rohit, Eriksson, Staffan, Tjarks, Werner
• Format: Article
• Language: English
• Subjects: 3-Carboranyl thymidine analogues (3CTAs); Binding Sites; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Boron Neutron Capture Therapy; Boron neutron capture therapy (BNCT); Catalysis; Drug Design; Fundamental and applied biological sciences. Psychology; Humans; Hydrophobic and Hydrophilic Interactions; Medical sciences; Methods. Procedures. Technologies; Models, Molecular; Molecular Conformation; Neoplasms - radiotherapy; Phosphorylation; Protein Conformation; Protein Structure, Tertiary; Radiation therapy and radiosensitizing agent; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Stereoisomerism; Structure-Activity Relationship; Thymidine - analogs & derivatives; Thymidine - chemistry; Thymidine - therapeutic use; Thymidine Kinase - antagonists & inhibitors; Thymidine Kinase - chemistry; Thymidine kinase 1 (TK1); Treatment with physical agents; Treatment. General aspects; Tumors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.06.039

Several 3-carboranyl thymidine analogues (3CTAs), all of which are containing hydrophilicity-enhancing groups, were synthesized and their biochemical and physicochemical properties were evaluated. 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 μM. 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.