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[摘要]：A new class of d4TMP-cycloSal-pronucleotides bearing enzymically cleavable amino acid esters is reported. These compds. are designed to trap the pronucleotide inside the cell by a fast conversion of a nonpolar ester group into a charged carboxylate. This should prevent efficient diffusion equil. across the cell membrane to the extracellular environment, leading to an intracellular accumulation of the compds. This initial conversion is followed by a slow release of the nucleoside monophosphate (i.e., d4TMP). The concept is proven by hydrolysis studies in phosphate buffer, cell exts., and human serum. These investigations revealed a high sensitivity of some amino acid ester modifications to conversion by cellular exts., resulting in the fast release of a charged intermediate, whereas no cleavage of the modification is found in phosphate buffer. In addn., antiviral activities against HIV are presented. |
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