Synthesis of a Small Library of 3-(Carboranylalkyl)thymidines and Their Biological Evaluation as Substrates for Human Thymidine Kinases 1 and 2
| Autor: | Anthony J. Lunato, J Woollard, Weihua Ji, Junhua Yan, Thomas E. Blue, Staffan Eriksson, Andrew E. Hawk, Guirec Y. Cosquer, Jianghai Wang, Ashraf S. Al-Madhoun, Jayaseharan Johnsamuel, Jin-Cong Zhuo, Werner Tjarks |
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| Rok vydání: | 2002 |
| Předmět: |
Boron Compounds
Kinase Stereochemistry Substituent Thymidine Kinase Chemical synthesis Substrate Specificity Structure-Activity Relationship chemistry.chemical_compound chemistry Thymidine kinase Drug Discovery Combinatorial Chemistry Techniques Humans Molecular Medicine Carborane Methylene Thymidine kinase 1 Thymidine |
| Zdroj: | Journal of Medicinal Chemistry. 45:4018-4028 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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