Hydrophilically enhanced 3-carboranyl thymidine analogues (3CTAs) for boron neutron capture therapy (BNCT) of cancer.
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.
Narayanasamy
Sureshbabu
S
College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Thirumamagal
B T S
BT
Johnsamuel
Jayaseharan
J
Byun
Youngjoo
Y
Al-Madhoun
Ashraf S
AS
Usova
Elena
E
Cosquer
Guirec Y
GY
Yan
Junhua
J
Bandyopadhyaya
Achintya K
AK
Tiwari
Rohit
R
Eriksson
Staffan
S
Tjarks
Werner
W
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
D011994:Recombinant Proteins; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine