Jennifer L. Brooks

Synthesis of azole nucleoside 5'-monophosphate mimics (P1Ms) and their inhibitory properties of IMP dehydrogenases.

IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5′‐MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient. In order to bypass cellular phosphorylation, a series of azole nucleoside 5′‐MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises. P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with Ki values in low micromolar range. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

2′,3′-Dideoxynucleoside 5′-β,γ-(Difluoromethylene) Triphosphates With α-P-Thio or α-P-Seleno Modifications: Synthesis and Their Inhibition of HIV-1 Reverse Transcriptase

Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5′-α-R p -borano-β,γ-(difluoromethylene) triphosphate (5′-αBCF 2 TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT.[1] [2] Herein we report the synthesis and activity against HIV-1 RT of several ddN 5′-α-modified-β,γ-(difluoromethylene) triphosphate mimics with either a non-bridging α-P-thio (5′-αSCF 2 TP) or α-P-seleno (5′-αSeCF 2 TP) modification. One compound, namely, AZT-5′-α-P-seleno-β,γ-(difluoromethylene) triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (K i = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an α-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.

Synthesis of 5′-Triphosphate Mimics (P3Ms) of 3′-Azido-3′,5′-Dideoxythymidine and 3′,5′-Dideoxy-5′-Difluoromethylenethymidine as HIV-1 Reverse Transcriptase Inhibitors

3′-Azido-3′,5′-dideoxythymidine 5′-phosphonate and 3′,5′-dideoxy-5′-difluoromethylenethymidine 5′-phosphonate were prepared by multistep syntheses. The nucleoside 5′-phosphonates were converted to their triphosphates and triphosphate mimics (P3Ms) containing β,γ-difluoromethylene, β,γ-dichloromethylene, or β,γ-imodo by condensation with pyrophosphate or pyrophosphate mimics, respectively. Inhibition of HIV-1 reverse transcriptase by the nucleoside P3Ms is briefly discussed.