Pyrimidines analogs

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU) 

FdUMP inhibits thymidylate synthetase, and this is in turn inhibits the essential formation of dTTP, one of the four precursors of DNA. In addition, 5-FU is sequentially converted to 5-FUTP, which becomes incorporated into RNA, thus inhibiting its processing and functioning. Fluorouracil is used for the following types of cancer  

Resistance of 5-FU occurs as the result of one or a combination of the following factors  

Because 5-FU is metabolized rapidly in the liver, it is administered intravenously and not orally. 5-FU causes myelosuppression and mucositis. 

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Some newly introduced pyrimidine analogs (e.g., azacitidine and decitabine) differ in their mechanism of action to such a degree from the other antimetabolites that they are subgrouped under the heading DNA de- or hypomethylating agents (see below). 

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

Certain Pyrimidine Analogs Are Substrates for Enzymes of Pyrimidine Nucleotide Biosynthesis... 

Figure 11-11. The structures of pyrimidine analogs described in the text, along with the general structure of C4- and C5 -substituted 2P derivatives...

Kistler KA, Matsika S (2007) The fluorescence mechanism of 5-methyl-2-pyrimidinone an ab initio study of a fluorescent pyrimidine analog. Photoch Photob 83 611-624... 

Acyclic C-nucleoside analogs of imidazo[l,2-a]pyrimidine analogs were prepared (95MI2). Regioisomeric analogs of HEPT were prepared as shown in Scheme 238 (94MI9) and possessed activity against HIV-1. 

Cyclacel described thiazolo-pyrimidine analogs, exemplified by 104 [268, 269], and a related series of 2-aminophenyl-4-phenylpyrimidines, exemplified by 105a,b [270] with activity against PLK-1. These compounds were derived... 

Kinsella TJ, Dobson PP, Mitchell JB, et al. Enhancement of X ray induced DNA damage by pretreatment with halogenated pyrimidine analogs. Int J Radiat Oncol Biol Phys 1987 13(5) 733-739. 

Nucleic-acid-related molecules (nucleotides, nucleosides, purines, pyrimidines) may also be used as dmgs themselves (and not only as dmg receptors). Once again, as discussed in chapters 7 and 9, this is most relevant in the areas of cancer and infectious disease, with purine/pyrimidine analogs being exploited as antimetabolites. 5-Fluorouracil is a well-described antineoplastic agent. Analogously, 5-fluorocytosine is used as an antifungal... 

Flucytosine (5-FC) was discovered in 1957 during a search for novel antineoplastic agents. Though devoid of anticancer properties, it became apparent that it was a potent antifungal agent. Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B. 

Sjoberg, A.H. Wang, L. Eriksson, S. Substrate specificity of human recombinant mitochondrial deoxyguanosine kinase with cytostatic and antiviral purine and pyrimidine analogs. Mol. Pharmacol., 53, 270-273 (1998)... 

Antiviral actions of purine and pyrimidine analogs. Acyclovir and ganciclovir (top) are phosphorylated first by viral kinase to the monophosphate. This intermediate and the drugs shown on the left are then phosphorylated by host cell kinases to the nucleotide analogs that inhibit viral replication. (Modified and reproduced, with permission, from Trevor AT, Katzung BG, Masters SM Pharmacology Examination Board Review, 6th ed. McGraw-Hill, 2002.)... 

A variation of the use of standards is the method in which predetermined quantities of a standard radioactive compound are added to the solution. The fractions are collected, and, by plotting the counts of the fractions, the peak of interest can be identified. This method is especially useful in following cell metabolism of purine and pyrimidine analogs. A plot of the nucleotides in a cell extract of schistosomes containing 14C-labeled adenine and guanine nucleotides is shown in Figure 7.3.5... 

In a study aimed at the treatment of Pneumocystis carinii and Toxoplasma gondii infections in AIDS patients, several 2,4-diaminothieno[2,3-pyrimidine analogs 49b of the potent dihydrofolate reductase inhibitors trimetrexate and piritrexim were tested. Although several compounds... 

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