Synthesis of 2',3'-dideoxynucleoside 5'-alpha-P-borano-beta,gamma-(difluoromethylene)triphosphates and their inhibition of HIV-1 reverse transcriptase.
The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'-alpha-R(P)-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaB-betagammaCF(2)TP) has been identified as a potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT). This work was aimed at confirming that 5'-alphaB-betagammaCF(2)TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-alphaB-betagammaCF(2)TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alphaB-betagammaCF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alphaB-betagammaCF(2)TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alphaB-betagammaCF(2)TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents.
Boyle
Nicholas A
NA
Research Laboratories, Biota, Inc., 2232 Rutherford Road, Carlsbad, California 92008, USA.
Rajwanshi
Vivek K
VK
Prhavc
Marija
M
Wang
Guangyi
G
Fagan
Patrick
P
Chen
Fu
F
Ewing
Gregory J
GJ
Brooks
Jennifer L
JL
Hurd
Tiffany
T
Leeds
Janet M
JM
Bruice
Thomas W
TW
Cook
P Dan
PD
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D003854:Deoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D066298:In Vitro Techniques; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D001896:Boron Compounds; D003854:Deoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase