Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2

Ashraf Al Madhoun, Jayaseharan Johnsamuel, Junhua Yan, Weihua Ji, Jianghai Wang, Jin Cong Zhuo, Anthony J. Lunato, Jeffrey E. Woollard, Andrew E. Hawk, Guirec Y. Cosquer, Thomas E. Blue, Staffan Eriksson, Werner Tjarks

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57 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4018-4028
Number of pages11
JournalJournal of Medicinal Chemistry
Volume45
Issue number18
DOIs
Publication statusPublished - 29 Aug 2002

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    Al Madhoun, A., Johnsamuel, J., Yan, J., Ji, W., Wang, J., Zhuo, J. C., Lunato, A. J., Woollard, J. E., Hawk, A. E., Cosquer, G. Y., Blue, T. E., Eriksson, S., & Tjarks, W. (2002). Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2. Journal of Medicinal Chemistry, 45(18), 4018-4028. https://doi.org/10.1021/jm020047q