Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties.
Eleven 3-carboranyl thymidine analogues (3CTAs) containing highly hydrophilic and flexible ethyleneoxide moieties were synthesized as potential agents for boron neutron capture therapy (BNCT) and their biochemical and physicochemical properties were evaluated. Based on specific structural features, this library of 3CTAs was divided into three subgroups. The first group contained 3CTAs with 1-4 ethyleneoxide units between the thymidine (Thd) scaffold and a carborane cluster. The second group of 3CTAs contained a pentylene spacer between Thd and the carborane and 2-4 ethyleneoxide units additionally attached to the carborane cluster. The third group contained three 3CTAs all with pentylene spacers and four ethylene units but with different carborane cages. The ethyleneoxide modified 3CTAs were good substrates of thymidine kinase 1 (TK1) and poor substrates of human mitochondrial thymidine kinase 2 (TK2) as determined in phosphoryl transfer assays. In the first group of 3CTAs, all the compounds were efficiently phosphorylated regardless of varying spacer lengths (37-42% of the activity of Thd). The second group of 3CTAs was less effectively phosphorylated (17-26% of the activity of Thd) probably due to a less favorable sterical orientation of Thd within the active site of TK1 and/or an increased lipophilicity compared with the first group. In the third group of structural isomers, no significant differences in phosphorylation rates were observed (17-25%). A structure-function hypothesis explaining these results is presented.
Johnsamuel
Jayaseharan
J
College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Lakhi
Nisha
N
Al-Madhoun
Ashraf S
AS
Byun
Youngjoo
Y
Yan
Junhua
J
Eriksson
Staffan
S
Tjarks
Werner
W
D001896:Boron Compounds / Q000032:analysis / Q000138:chemical synthesis*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005027:Ethylene Oxide / Q000032:analysis / Q000138:chemical synthesis*; D006801:Humans; D013936:Thymidine / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis*
D001896:Boron Compounds; D005027:Ethylene Oxide; D013936:Thymidine