Ue, w re Not so dependent Ngig of the activation. Zus Involved tzlich to all the enzymes GDC-0879 in anabolic activation of nucleoside analogs, there are many catabolic enzymes that interact with these compounds and these enzymes can can Have profound effects on its biological activity T and play an R Important in the activity T of all purine and pyrimidine antimetabolites of. The compound should be a good selective inhibitor of DNA replication and minimal effects on RNA and protein synthesis, inhibition of the activity Th leads to toxicity t. The main intracellular Ren objectives of the purine and pyrimidine antimetabolites are available DNA polymerases, ribonucleotide reductase and thymidylate synthase.
Although some agents are currently approved and are converted into ribonucleotides metabolites widespread in RNA, the Head T Installed ACTION these compounds is that the results of its antitumor activity T their AZD1152-HQPA inhibition of DNA synthesis or St is Tion function of the DNA. Without a selective activation in tumor cells, the nucleoside analogs that target RNA synthesis or function must be highly cytotoxic, since all cells require RNA for vitality. Herk As with most Mmlichen antitumor agents is the inhibition of DNA replication, the most important action of purine and pyrimidine metabolites of the antitumor activity of t. St Tion of purine biosynthesis de novo or secondary Rer effects of RNA in activity Th, DNA replication and DNA beautiful competent st Ren. However, the inhibition of DNA synthesis is not sufficient to produce a tumor cell to t Ten.
For example, an agent such as aphidicolin, a potent inhibitor of DNA replication, well synchronizer cells since it inhibits the synthesis of DNA and in contrast to nucleoside analogues, it causes no permanent inhibition. Once it is removed from the cell takes DNA synthesis easily sustainable without toxicity t. Nucleoside analogues have two attributes that sustained inhibition of DNA replication after drug withdrawal due to natural processes in your body. First, the active metabolites of these agents nucleotide analogues that penetrate cell membranes and are therefore not easily maintained in the cell after the drug was withdrawn, which is an attribute that is unique for this class of antitumor agents.
Be the half-life abduction of triphosphate of cells k Can very long, leading to further use by the polymerases, and therefore continued inhibition of Parker Page 15 Chem Rev Author manuscript, reached in PMC 2010 1 July. PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript NIH DNA replication. The retention time of intracellular Ren active metabolites may fluctuate significantly analogues, and this can have a significant effect on the activity t of an agent against solid tumor cells. The half-life significantly l singer is as dFdC araCTP TP believed to be a prime Rer factor in solid tumor activity t of gemcitabine and the lack of solid tumor activity t of ARAC. Second, the nucleosides are incorporated into the DNA, resulting in a DNA molecule that are not easily expanded and repaired, can the synthesis can be continued. Therefore, an agent that is DNA-Sch Caused ending, which is difficult to repair or lead to a slow ridiculed Ngerten DNA-Sch To which the importer