Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs.

A novel approach to the intracellular delivery of nucleotides using phosphoramidate-based prodrugs is described. Specifically, we have developed phosphoramidate prodrugs of the anticancer nucleotide 5-fluoro-2'-deoxyuridine-5'monophosphate (FdUMP). These phosphoramidate prodrugs contain an ester group that undergoes intracellular activation liberating phosphoramidate anion, which undergoes spontaneous cyclization and P-N bond cleavage to yield the nucleoside monophosphate quantitatively. In vitro evaluation of 5-fluoro-2'-deoxyuridine phosphoramidate prodrugs 2a and 3b against L1210 mouse leukemia cells show potent inhibition of cell growth (IC(50) 0.5-3 nM). Cell-based thymidylate synthase inhibition studies show that, in contrast to FUdR, the nitrofuran compound 2a is of comparable potency in wild type vs thymidine kinase deficient LM cells. This result indicates that the activation of this novel prodrug occurs via the proposed mechanism of intracellular delivery. However, naphthoquinone 3b has an IC(50) value for thymidylate synthase inhibition that is comparable to FUdR in thymidine kinase deficient cells. Further studies revealed that 3b rapidly decomposes to the nucleotide in cell culture medium, suggesting that the naphthoquinone analogue is not sufficiently stable to function as a nucleotide prodrug.

3-Iodothyronamine: a novel hormone controlling the balance between glucose and lipid utilisation.

3-Iodothyronamine is considered as a derivate of thyroid hormone as a result of enzymatic deiodination and decarboxylation. The physiological role of thyronamine (T1AM) is not known. The aim of this study was to analyze the metabolic response to T1AM in the Djungarian hamster Phodopus sungorus. We measured the influence of T1AM (50 mg/kg) on metabolic rate (VO(2)), body temperature (T (b)) and respiratory quotient (RQ) in this species and in BL/6 mice. T1AM treated hamsters as well as the mice showed a rapid decrease in VO(2) and T (b), accompanied by a reduction of RQ from normal values of about approximately 0.9 to approximately 0.70 for several hours. This indicates that carbohydrate utilisation is blocked by the injection of T1AM and that metabolic pathways are rerouted from carbohydrate to lipid utilisation in response to T1AM. This assumption was further supported by the observation that the treatment of T1AM caused ketonuria and a significant loss of body fat. Our results indicate that T1AM has the potential to control the balance between glucose and lipid utilisation in vivo.