brivudine and phosphoramidic-acid

Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD

Topics: Amides; Animals; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Cell Line, Tumor; Cell Proliferation; Humans; Mice; Neoplasms; Phosphoric Acids

We report the synthesis of a series of novel 2'-deoxy-2',2'-difluoro-5-halouridines and their corresponding phosphoramidate ProTides. All compounds were evaluated for antiviral activity and for cellular toxicity. Interestingly, 2'-deoxy-2',2'-difluoro-5-iodo- and -5-bromo-uridines showed selective activity against feline herpes virus replication in cell culture due to a specific recognition (activation) by the virus-encoded thymidine kinase.

Topics: Amides; Animals; Antineoplastic Agents; Antiviral Agents; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Floxuridine; Hepacivirus; Humans; Mice; Microbial Sensitivity Tests; Molecular Conformation; Phosphoric Acids; Stereoisomerism; Structure-Activity Relationship; Virus Replication

The aim of the present work is to investigate through molecular modelling the possible role of the human enzyme Hint1 in the final P-N bond cleavage of phosphoramidate ProTides, which would lead to the intracellular delivery of unmasked nucleoside analogue monophosphates. Herein, we report our preliminary analysis based on docking studies of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) related aminoacyl phosphates with Hint1 and the effect of the amino acid moiety on the enzyme-substrate binding affinity.

Topics: Amides; Bromodeoxyuridine; Catalytic Domain; Humans; Models, Molecular; Nerve Tissue Proteins; Phosphoric Acids; Protein Conformation; Substrate Specificity

The phosphoramidate technology we have developed has been recently applied to BVdU, leading to NB1011 (NewBiotics Inc., California), a novel potential anticancer compound recently entered into phase 2 of the clinical trials for colon cancer. We report in this work a new series of derivatives containing naphthol as aryl masking group on the phosphate moiety, which has shown a significant increase in anticancer activity in preliminary biological evaluations.

Topics: Amides; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Cell Line, Tumor; Colonic Neoplasms; Female; Humans; Male; Models, Chemical; Phosphoric Acids

We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), designed to act as membrane soluble prodrugs of the free nucleotide. The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains. The phosphoramidate derivative bearing the amino acid alpha,alpha-dimethylglycine showed poor activity in all cell lines tested. It appears that successful kinase bypass by phosphoramidates is highly dependent on the nucleoside analogue, amino acid and ester structure, as well as the cell line to which the drugs are exposed.

Topics: Acyclovir; Amides; Antiviral Agents; Bromodeoxyuridine; Cell Line; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Fibroblasts; Herpesvirus 3, Human; Humans; Lung; Molecular Structure; Phosphoric Acids; Simplexvirus; Structure-Activity Relationship; Vaccinia virus; Vesicular stomatitis Indiana virus