Author:

Keywords:

esterase-cleavable sites, 2nd-generation, chemistry, Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, ESTERASE-CLEAVABLE SITES, 2ND-GENERATION, CHEMISTRY, DESIGN, Anti-HIV Agents, Chemistry, Pharmaceutical, Chromatography, High Pressure Liquid, Circular Dichroism, Dideoxynucleotides, Drug Design, Electrons, HIV-1, HIV-2, Humans, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Models, Chemical, Nucleotides, Stavudine, Thymine Nucleotides, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

In our attempt to further develop the cycloSal pronucleotide concept, we report oil 5-(1-acetoxyvinyl)-cycloSal-d4TMPs as a new type of enzyme-activated pronucleotides. These compounds were converted into 5-acetyl-cycloSal-d4TMPs by (carboxy)esterase cleavage inside the cells. The enzymatic reaction led to the formation of a strong electron-withdrawing substituent that strongly accelerates the chemical hydrolysis of the cycloSal nucleotide to give d4TMP. For some cycloSal-d4TMPs a separation into the diastereomers was achieved. The absolute configuration was assigned by correlation of circular dichroism spectra with similar compounds. Most of the compounds showed complete retention of antiviral activity in TK-deficient CEM/TK- cells, which proves the TK-bypass potential of this approach. Interestingly, (S-p)-isomers of cycloSal phosphate triesters showed better antiviral activity in HIV-2-infected thymidine-kinase deficient CEM/TK- cells than their (R-p)-counterparts.