- 3′-Bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of mycobacterium tuberculosis
-
Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2′- or 3′-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3′-bromo-3′-deoxy- arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC 50 = 1 μg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC50 = 1-2 μg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 μg/mL concentration) than extracellular mycobacteria (75% reduction at 10 μg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC50 > 100-200 μg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
- Shakya, Neeraj,Srivastav, Naveen C.,Desroches, Nancy,Agrawal, Babita,Kunimoto, Dennis Y.,Kumar, Rakesh
-
experimental part
p. 4130 - 4140
(2010/09/04)
-
- Synthesis of 5'-phosphonate linked thymidine deoxyoligonucleotides
-
5'-Deoxy-5'-phosphonothymidine was synthesized and coupled with 3'-deoxy-3'-hydroxy-methylthymidine to yield a 3'-C-O-P-5' linked thymidine dinucleotide. This dimer as its 3'-phosphoramidite was used to synthesize deoxyoligonucleotides.
- Kofoed, Thomas,Caruthers, Marvin H.
-
p. 6457 - 6460
(2007/10/03)
-
- Intermolecular Radical C-C Bond Formation: Synthesis of a Novel Dinucleoside Linker for Non-anionic Antisense Oligonucleosides
-
An efficient, stereoselective synthesis of a thymidine (T) nucleoside dimer (T-3'-CH2-NH-O-5'-T) 1 has been accomplished via an intermolecular radical reaction.The new dimer and methodology is useful for the development of backbone modified antisense oligonucleosides.Key Words: antisense oligonucleotides, nonionic backbone, intermolecular radical reaction
- Debart, Francoise,Vasseur, Jean-Jacques,Sanghvi, Yogesh S.,Cook, P. Dan
-
p. 2645 - 2648
(2007/10/02)
-