Synthesis and biological activity of 7-deaza-7-ethynyl-2'-deoxy-2'-fluoro-2'-C-methyladenosine and its 2'-C-methyl-ribo analogue.
In our search for improved therapeutic agents against HCV we synthesized 7-deaza-7-ethynyl-2'-C-methyladenosine (1) and its 2'-deoxy-2'-fluoro analogue 2. The corresponding nucleoside triphosphates were efficient chain terminators of the HCV NS5b polymerase with IC(50)'s of 0.75 microM and 0.4 microM respectively. However, only the ribo-nucleoside 1 exhibited activity in a Huh7 cell based replicon assay with an EC(50) of 0.09 microM. In order to overcome the lack of activity of the fluoro analogue 2 we synthesised several phosphoroamidate prodrugs.
Prhavc
Marija
M
Genelabs Technologies, Inc., 505 Penobscot Drive, Redwood City, CA 94063, USA. marijap@genelabs.com
Dyatkina
Natalia
N
Keicher
Jesse
J
Liehr
Sebastian
S
Koo-McCoy
Samantha
S
Latour
Derek
D
Fung
Kevin
K
Dunlop
Kevin
K
Pouliot
Jeffrey
J
Wang
Ting
T
Li
Wenbao
W
Lou
Lillian
L
Roberts
Christopher
C
Griffith
Ronald
R
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D011355:Prodrugs; D014372:Tubercidin; D017361:Viral Nonstructural Proteins; C541642:7-deaza-7-ethynyl-2'-C-methyladenosine; C541637:7-deaza-7-ethynyl-2'-deoxy-2'-fluoro-2'-C-methyladenosine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase