A Method for Quantitating the Intracellular Metabolism of AZT Amino Acid Phosphoramidate Pronucleotides by Capillary High-Performance Liquid Chromatography−Electrospray Ionization Mass Spectrometry

A methodology has been developed for the analysis of the intracellular metabolism of 3‘-azido-3‘-deoxythymidine (AZT) amino acid phosphoramidates utilizing reverse-phase high-performance liquid chromatography interfaced with negative ion electrospray ionization mass spectrometry (LC/ESI- -MS). The presented work demonstrates the potential of capillary LC/MS and LC/MS/MS to identify and quantitate the cellular uptake and metabolism of nucleoside phosphoramidate. Significant intracellular amounts of d- and l-phenylalanine methyl ester or d- and l-tryptophan methyl ester AZT phosphoramidates were observed for human T-lymphoblastoid leukemia (CEM) cells incubated for 2 and 4 h with the prodrugs. AZT-MP was the primary metabolite observed for human T-lymphoblastoid leukemia (CEM) cells. In this paper, the details of using LC/MS to analyze AZT amino acid phosphoramidates in biological samples are discussed. LC/MS is an efficient method for analyzing multiple samples containing several analytes in a short period of time. The method also provides high selectivity and sensitivity, and requires minimal sample preparation. This approach should be broadly applicable for the analysis of the intracellular metabolism of nucleoside prodrugs and pronucleotides. Keywords: Prodrugs; antiviral agent; AZT; phosphoramidat

Initial incidence of HS-PDA, HIS-PDA, and early closure at the end of the first postnatal week according to gestational age subgroup.

GA, gestational age; HS-PDA, hemodynamically significant patent ductus arteriosus; HIS-PDA, hemodynamically insignificant patent ductus arteriosus.</p

Adjusted odds ratios for risk of adverse outcomes by presence of HS PDA.

Adjusted odds ratios for risk of adverse outcomes by presence of HS PDA.</p

Cumulative incidence rate of ductal patency during hospitalization in infants with initial HS PDA according to gestational age group.

PDA, patent ductus arteriosus; GA, gestational age.</p

Adjusted odds ratios for risk of adverse outcomes by duration (per week) of HS PDA.

Adjusted odds ratios for risk of adverse outcomes by duration (per week) of HS PDA.</p

Characteristics of HS PDA according to gestational age subgroup.

Characteristics of HS PDA according to gestational age subgroup.</p

Demographic and outcomes data of the study population.

Demographic and outcomes data of the study population.</p

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)–fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1–3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC

Comparison of the nutritional characteristics between Periods I and II.

Comparison of the nutritional characteristics between Periods I and II.</p

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)–fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1–3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC