MEDI 97 |
| Nucleoside reverse transcriptase inhibitors often face two challenges that limit their anti-HIV activity: limited cellular uptake because of their hydrophilic nature and the rate-limiting monophosphorylation step. Herein, we designed bis(fatty acyl-glycol) phosphate triester derivatives of 3'-fluoro-2',3'-dideoxythymidine (FLT) to circumvent these problems. 5'-Hydroxyl group of FLT was linked to two fatty acyl groups through a phosphate triester linker to enhance the lipophilicity. Furthermore, it was expected that the prodrugs release the FLT-monophosphate intracellularly upon cellular uptake. Fatty acyl-glycol ester conjugates were reacted with diisopropylphosphoramidous dichloride to afford diisopropylphosphoramidous bis(fatty acyl-glycol) conjugates. Replacement of diisopropylamino group with FLT in presence of 5-ethyl-1H-tetrazole followed by oxidation with t-butyl hydroperoxide produced the final products. The anti-HIV activities of the products were significantly lower (12.5 to >100 μg/mL) than that of FLT (0.2-0.3 μg/mL) against lymphocytotropic and monocytotropic HIV strains (R5 virus). This suggests that the compounds had very limited cellular uptake, possibly due to extracellular hydrolysis to FLT-monophosphate.
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |
