Sep, 2011
Synthesis of 4 '-Ethynyl-2 '-deoxy-4 '-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI
ACS MEDICINAL CHEMISTRY LETTERS
- Volume
- 2
- Number
- 9
- First page
- 692
- Last page
- 697
- Language
- English
- Publishing type
- Research paper (scientific journal)
- DOI
- 10.1021/ml2001054
- Publisher
- AMER CHEMICAL SOC
The synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. Electrophilic glycosidation between 16 and the silylated nucleobases (N(4)-acetylcytosine, N(6)-benzoyladenine, and N(2)-acetyl-O(6)-diphenylcarbamoylguanine) was carried out in the presence of N-iodosuccinimide (NIS), leading to the exclusive formation of the desired beta-anomers 29, 33, and 36. Anti-HIV studies demonstrated that these 4'-thio nucleosides were less cytotoxic to T-lymphocyte (i.e., MT-4 cells) than the corresponding 4'-ethynyl derivatives of 2'-deoxycytidine (44), 2'-deoxyadenosine (45), and 2'-deoxyguanosine (46). Comparison of the selectivity indices (SI) was made between 4'-thionucleosides (32, 41, and 43) and the corresponding 4'-oxygen analogues 44-46 by using the reported CC(50) and EC(50) values. In the case of cytosine and adenine nucleosides, comparable SI values were obtained as follows: 32 (545) and 44 (458); 41 (>230) and 45 (1630). In contrast, 4'-ethynyl-2'-deoxy-4'-thioguanosine 43 was found to possess a SI value of >18200, which is 20 times better than that of 46 (933).
- Link information
- ID information
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- DOI : 10.1021/ml2001054
- ISSN : 1948-5875
- Web of Science ID : WOS:000294790100009