IC-87114 dFdU MP is formed in the cells

Are IC-87114 activated to cytotoxic Rly nucleotides by thymidine kinase. The monophosphates deoxycytidine analogs, especially dFdC MP are substrates for dCMP deaminase, and can also be detoxified by this enzyme. , but there is little evidence for its interaction with thymidylate synthetase. There is no evidence of TP dfdt in cells, indicating that MP dFdU not a substrate for thymidylate synthetase. There is some evidence that the aza-, an inhibitor of thymidylate synthetase dump, 36, and this k nnte On the cytotoxicity t the aza dCyd contribute at high concentrations. Due to the r Of the deaminases in the detoxification of these cytosine analogues, the design of new analogues usually studied compounds, which are poor substrates for these enzymes.
Fdeoxycytidine 5 is an example of an analog of deoxycytidine that is activated by deamination, and it has been proposed as a prodrug of F dUrd use, 37, but it was not approved for human beings. 2.3.2. Purine deoxynucleoside 2.3.2.1. Fludarabine and nelarabine: There are five approved similar purine deoxynucleosides, INO-1001 which were for cancer treatment since 1991. Two of these funds Are similar arabinoside and nelarabine and therefore has the same structural basis for the anti-cancer activity of t the ARAC. FaraAMP deoxy AMP is an analogue that for the treatment of lymphocytes Chronic leukemia.38 is allowed is 39 F, a prodrug of araA and F araAMP is clinically because of the low L Used solubility of F araA. F araAMP is rapidly converted by plasma phosphatases Faraa, which is the active form of the drug.
Adenosine deaminase is expressed in fa Is omnipresent Ships and is an important enzyme detoxifies deoxyadenosine analogues. A few years ago it was found that the replacement of the hydrogen atom of the adenosine-2 with a halogen atom in a molecule leads, which is against deamination, 40,41 and this feature has been incorporated in all approved anti-cancer deoxyadenosine analogues, to prevent its inactivation by adenosine deaminase. Nelarabine is a prodrug of 9 D-arabinofuranosyl guanine and was recently approved for the treatment of T-cell adenosine deaminase malignancies.42 is also an important enzyme in the metabolism of nelarabine. However, in the case of nelarabine, adenosine deaminase is essential for the activation in cytotoxic metabolites, replacing the 6-methoxy substituent to form with oxygen ARAG.
Since F araA, instead of nelarabine is ARAG, due to the low solubility L Of ARAG, the 196 443 was synthesized and used as a good activity T against T-cells in T-cells vitro.44 It was shown that more that araGTP B cells, 45,46 and it is this Anh ufung applies to the selective activity accumulate t Arag in malignant T cells The reason that T-cells h here levels of purine nucleotides that most cells are not well understood, but the obtained hte sensitivity t of T cells to accumulate inhibitors of purine nucleoside phosphorylase keywords. Page 8 Parker, Chem Rev Author manuscript, increases available in PMC 2010 1 July. PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript NIH araA and two F Arag substrates for deoxycytidine kinase, the key enzyme responsible for converting these compounds into the active metabolite, although Arag is al