Open AccessSynthesis of 4′-Ethynyl-2′-deoxy-4′-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI
Author(s) -
Kazuhiro Haraguchi,
Hisashi Shimada,
Keiogo Kimura,
Genta Akutsu,
Hiromichi Tanaka,
Hiroshi Abe,
Takayuki Hamasaki,
Masanori Baba,
Elizabeth A. Gullen,
Ginger E. Dutschman,
YungChi Cheng,
Jan Balzarini
Publication year - 2011
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml2001054
Subject(s) - chemistry , glycal , electrophile , nucleobase , stereochemistry , deoxyadenosine , deoxyguanosine , glycosyl , cytosine , combinatorial chemistry , dna , organic chemistry , stereoselectivity , biochemistry , catalysis
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 β-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: 32 (545) and 45 (458); 41 (>230) and 45 (1,630). In contrast, 4'-ethynyl-2'-deoxy-4'-thioguanosine 43 was found to possess a SI value of >18,200, which is twenty times better than that of 46 (933).