Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2.
A small library consisting of two series of thymidine derivatives containing o-carboranylalkyl groups at the N-3 position was prepared. In both series, alkyl spacers of 2-7 methylene units were placed between the o-carborane cage and the thymidine scaffold. In one series, an additional dihydroxypropyl substituent was introduced at the second carbon atom of the carborane cage. In the series of N-3-substituted carboranyl thymidines without additional dihydroxypropyl substituent, three steps were required to obtain the target compounds in overall yields as high as 75%, while in the series of N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituent, 9-10 steps were necessary with significantly lower overall yield. All target compounds were good substrates of human cytosolic thymidine kinase 1 while they were, if at all, poor substrates of the mitochondrial thymidine kinase 2. There was only a minor difference in phosphorylation rates between N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituents with thymidine kinase 1 (range: 13-49% relative to thymidine) and their counterparts lacking this group (range: 11-57% relative to thymidine). Tether lengths of two and five methylene groups in both series gave the highest enzyme activities in the present study. A hypothesis for this result is presented.
Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Center, SE-75123 Uppsala, Sweden.
Ashraf S
AS
Al-Madhoun
Jayaseharan
J
Johnsamuel
Junhua
J
Yan
Weihua
W
Ji
Jianghai
J
Wang
Jin-Cong
JC
Zhuo
Anthony J
AJ
Lunato
Jeffrey E
JE
Woollard
Andrew E
AE
Hawk
Guirec Y
GY
Cosquer
Thomas E
TE
Blue
Staffan
S
Eriksson
Werner
W
Tjarks
D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D013937:Thymidine Kinase / Q000737:chemistry*
D001896:Boron Compounds; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine