"Lock-in" modified CycloSal nucleotides - The second generation of CycloSal prodrugs
ABSTRACT A new generation of cycloSal-pronucleotides is presented. CycloSal-d4TMPs have been modified by introduction of an esterase-cleavable site in order to trap them inside cells. Hydrolysis studies in different media (PBS, CEM/0- and liver extracts) and anti-HIV evaluation of separated diastereomers revealed unexpected differences between the isomers.
- Journal of Medicinal Chemistry 05/2008; 51(8):2328-45. DOI:10.1021/jm701260b · 5.48 Impact Factor
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ABSTRACT: Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy for many viruses. However, the requirement for intracellular activation and side-effects caused by distribution to off-target sites of toxicity still limit the efficacy of the current generation of drugs. Kinase bypass strategies, where phosphorylated nucleosides are delivered directly into cells, thereby, removing the requirement for enzyme catalyzed phosphorylation steps, have already changed the face of antiviral therapy in the form of the acyclic nucleoside phosphonates, cidofovir, adefovir (given orally as its dipivoxil prodrug) and tenofovir (given orally as its disoproxil prodrug), currently used clinically. These strategies hold further promise to advance the field of antiviral therapy with at least 10 kinase bypass and tissue targeted prodrugs, representing seven distinct prodrug classes, currently in clinical trials. This article reviews the history of kinase bypass strategies applied to nucleoside antivirals and the evolution of different tissue targeted prodrug strategies, highlighting clinically relevant examples.Antiviral research 08/2011; 92(2):277-91. DOI:10.1016/j.antiviral.2011.08.015 · 3.94 Impact Factor
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ABSTRACT: The development of cancer and fibrotic diseases has been shown to be highly dependent on disregulation of cap-dependent translation. Binding protein eIF4E to N7-methylated guanosine capped mRNA has been found to be the rate-limiting step governing translation initiation; and therefore represents an attractive target for drug discovery. Our group has found that 7-benzyl guanosine monophosphate (7Bn-GMP) is a potent antagonist of eIF4E cap binding (Kd = 0.8 uM). Recent X-ray crystallographic studies have revealed that the cap-dependent pocket undergoes a unique structural change in order to accommodate the benzyl group. Unfortunately, 7Bn-GMP is not cell permeable. Recently, we have prepared a tryptamine phosphoramidate prodrug of 7Bn-GMP, 4ei1, and shown that it is a substrate for human histidine triad nucleotide binding protein (hHINT1) and is inhibit eIF4E initiated epithelial-mesenchymal transition (EMT) by Zebra fish embryo cells. To assess the intracellular uptake of 4ei1 and conversion to 7Bn-GMP by cancer cells, we developed a sensitive assay using LC-ESI-MS/MS for the intracellular quantitation of 4ei1 and 7Bn-GMP. When incubated with the breast cancer cell line MDA-231; or lung cancer cell lines H460, H383 and H2009, 4ei1 was found to be rapidly internalized and converted to 7Bn-GMP. Since oncogenic mRNAs are predicted to have the highest eIF4E requirement for translation, we carried out chemosensitization studies with 4ei1. The prodrug was found to chemosensitize both breast and lung cancer cells to non-toxic levels of gemcitabine. Further mechanistic studies revealed that the expressed levels of eIF4E were substantially reduced in cells treated with 4ei1 in a dose dependent manner. The levels of eI4E could be restored by treatment with the proteasome inhibitor MG-132. Taken together, our results demonstrate that 4ei1 is likely to inhibit translation initiation by eIF4E cap binding by both antagonizing eIF4E cap binding and initiating eIF4E proteasomal degradation.Molecular Pharmaceutics 01/2013; 10(2). DOI:10.1021/mp300699d · 4.79 Impact Factor