The synthesis and biochemical evaluation of thymidine analogues substituted with nido carborane at the N-3 position.
Several thymidine analogues substituted with closo- and nido-carborane at the N-3 position were synthesized. The nido-carboranyl thymidine analogues were designed to be effective substrates for human thymidine kinase 1 in combination with an increased water solubility sufficient for clinical application in boron neutron capture therapy. This was done because N-3 substituted closo-carboranyl thymidine analogues previously synthesized in our laboratories were good TK1 substrates but were poorly water-soluble. Newly synthesized zwitterionic amino nido- and the corresponding neutral closo-m-carboranyl thymidine analogues exhibited excellent TK1 phosphorylation rates up to 75% relative to thymidine, indicating that these compounds were good substrates for thymidine kinase 1. Thin layer chromatographic studies were indicative of increased hydrophilicity of the synthesized nido-carboranyl thymidine analogues compared with their closo-carboranyl counterparts and previously reported closo-carboranyl thymidine analogues.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, 422, Parks Hall, 500, West 12th Avenue, The Ohio State University, Columbus, OH 43210, USA.
Youngjoo
Y
Byun
Junhua
J
Yan
A S Ashraf S
AS
Al-Madhoun
Jayaseharan
J
Johnsamuel
Weilian
W
Yang
R F Rolf F
RF
Barth
Staffan
S
Eriksson
Werner
W
Tjarks
D016754:Boron Neutron Capture Therapy; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D013379:Substrate Specificity; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism
D011994:Recombinant Proteins; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine