862179-59-7Relevant articles and documents
Inhibition of hepatitis C viral RNA-dependent RNA polymerase by α-P-boranophosphate nucleotides: Exploring apotential strategy for mechanism-based HCV drug design
Cheek, Marcus Adrian,Sharaf, Mariam L.,Dobrikov, Mikhail I.,Shaw, Barbara Ramsay
, p. 144 - 152 (2013)
Improved treatments for chronic HCV infections remain a challenge,and new chemical strategies are needed to expand the current paradigm. The HCV RNA polymerase (RdRP) has been a target for antiviral development. For the first time we show that the boranophosphate (BP)modification increases the sub-strate efficiency of ATP analogs into HCV NS5B Δ55 RdRP-catalyzed RNA. Boranophosphate nucleotides contain a borane (BH3) group substituted for anon-bridging phosphoryl oxygen of a normal phosphate group, resulting in a class of modified isoelectronic DNA and RNA mimics capable of modulating the reading and writing of genetic information. We determine that HCV NS5B Δ55, being a stereo specific enzyme, incorporates the Rp isomer of both ATP αB and the two boranophos phate analogs:2'-O-methyladenosine5'-(α-P-borano) triphosp hate (2'-OMe ATP αB, 5a) and 3'-deoxyadenosine 5'-(α-P-borano) triphosphate(3'-dATPaB, 5b). The Rp3 diastereomer of ATP αB (6), having noribose modifications, was found to be a slightly better substrate than natural ATP, showing a42%decrease inthe apparent Michaelis-Mentenconstan t (Km). The IC50 of both 2'-O-Me and 3'-deoxy ATP was decreased with the boranophosphate modification upto16-fold. This ''borano effect''was further confirmed by determining the steady-state in hibitory constant (Ki), showing a comparable potency shift (21-fold). These experiments also indicate that the boranophosphat eanalogs 5a and 5b inhibit HCV NS5B through a competitiv emode of inhibition. This evidence, together with previous crystal structure data, further supports the idea that HCV NS5B (in a similar manner toHIV-1 RT)discriminates against the 3'-deoxy modification via lost interactions between the 3'-OH on the ribose and the active site residues, or lost intramolecular hydrogen bonding interactions between the 3'-OH and the pyrophosphate leaving group during phosphoryl transfer. To our knowledge, these data represent the first time a phosphate modified NTP has been studied as a sub-strate for HCV NS5B RdRP.
Phosphorus pentachloride promoted gem-dichlorination of 2′- and 3′-deoxynucleosides
Da Paixao Soares, Fabio,Groaz, Elisabetta,Herdewijn, Piet
, (2018/06/29)
Halogen substitution at various positions of canonical nucleosides has generated a number of bioactive structural variants. Herein, the synthesis of two unique series of sugar modified nucleosides bearing a gem-dichloro group is presented. The synthetic plan entails the controlled addition of phosphorus pentachloride to suitably protected 2′- or 3′-ketodeoxynucleoside intermediates as the key step, facilitating the rapid construction of such functionalized molecules. Under the same reaction conditions, the highest chemoselectivity was observed for the formation of 2′,2′-dichloro-2′,3′-dideoxynucleosides, while a competing 2′,3′-elimination process occurred in the case of the 3′,3′-dichloro counterparts.
Nucleic acid related compounds. 101. S-adenosyl-L-homocysteine hydrolase does not hydrate (5'-fluoro)vinyl or (6'-halo)homovinyl analogues derived from 3'-deoxyadenosine or 3'-(chloro or fluoro)-3'-deoxyadenosine
Robins,Neschadimenko,Ro,Yuan,Borchardt,Wnuk
, p. 1205 - 1211 (2007/10/03)
S-Adenosyl-L-homocysteine (AdoHcy) hydrolase is crucial for the maintenance of biomethylation. The usual mechanistic sequence involves oxidation of AdoHcy at C3' followed by elimination of L-homocysteine, Michael addition of water, and reduction to give adenosine. A 6'- fluorohomovinyladenosine analogue (EDDFHA) undergoes hydration of the 5',6' double bond (hydrolytic activity) at a more rapid rate than oxidation at C3'. Three 4',5'-didehydro-5'-deoxy-5'-fluoro nucleoside analogues were prepared from 3'-deoxy- and 3'-(chloro and flouro)-3'-deoxyadenosine via generation of the vinyl fluorides by thermolysis of 5'-fluoro-5'-thioether sulfoxides. The 3'-deoxy analogues of 6'-halohomovinyladenosines were prepared by Wittig extension with a 3'-deoxy-5'-carboxaldehyde and halodestannylation of vinyl stannanes. The 3'-hydroxyl group appears to be essential for binding to AdoHcy hydrolase. No hydrolytic activity at C5', or C6' was observed with the nonoxidizable 3'-deoxy or 3'-(chloro or fluoro) analogues in contrast with their 3'-hydroxy counterparts (ZDDFA and EDDFHA). These 3'-modified analogues cannot reduce enzyme-bound NAD+ to NADH and do not produce time-dependent inhibition for AdoHcy hydrolase, but are weak competitive inhibitors (K(i) = 150-200 μM).
