Pyrimidine antimetabolites

Folate antagonists Purine antimetabolites Pyrimidine antimetabolites... 

Antimetabolites may be further classified as inhibitors of pyrimidine, purine, or glutamine metaboHsm. The compounds are cell cycle dependent. 

An important group of antimetabolites are the aza analogs of pyrimidine and purine bases which are theoretically derived by a replacement of the methine group of a pyrimidine or purine nucleus with a nitrogen atom. This replacement represents a relatively minor alteration of the structure of these substances as it does not change the functional groups, practically preserves the molecular weight, and produces almost isosteric compounds. The replacement of the methine... 

The 8-aza analogs of purine bases were the first to be studied among all the aza analogs of nucleic acid bases (as early as 1945). Before that time the chemistry of these substances had not been treated in detail from any aspect. Thus the entire chemistry of the u-triazolo [4,5-d]pyrimidines was developed only in connection with the study of antimetabolites of nucleic acid components. Therefore all the papers involved are largely of preparative character and only rarely discuss. theoretical points. 

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). 

Antimetabolites interfere with normal metabolic pathways. They can be grouped into folate antagonists and analogues of purine or pyrimidine bases. Their action is limited to the S-phase of the cell cycle and therefore they target a smaller fraction of cells as compared with alkylating agents. 

Capecitabine -converted to 5-FU preferentially by tumor cells pyrimidine analogue antimetabolite inhibits thymidylate synthase -mucocutaneous effects (stomatitis, mucositis) -diarrhea -bone marrow suppression -nausea and vomiting -palmar-plantar erythrodysethesias (hand-foot syndrome) -fatigue... 

Antimetabolites. This class of drugs includes purine, pyrimidine, and folic acid analogs that have been successfully used to treat various carcinomas, autoimmune diseases, and dermatological disorders such as psoriasis. Because of their structural similarities to normal components of DNA and RNA synthesis, they are capable of competing with the normal macromolecules and alkylating biological nucleophiles. 

Patients with partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity as DPD is responsible for detoxification of pyrimidine-based antimetabolite analogs, such as 5-FU and capecitabine. The onset of toxicity occurs, on average, twice as fast in patients with low DPD activity compared with patients with normal DPD activity (13-16). 

Antimetabolites (inhibition of purine and pyrimidine nucleotide synthesis) Methotrexate Folic acid antagonist, inhibits tetrahydrofolate reductase and therefore dTMP synthesis 6-Mercaptopurine Interferes with purine synthesis 5-Fluorouracil Inhibits dTMP synthesis ... 

Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. It inhibits the enzyme dihydrofolate reductase that is required for the synthesis of purines and pyrimidines. It is used in malignant disease, Crohn s disease, rheumatic disease and psoriasis. Folic acid is given with methotrexate to reduce the occurrence of side-effects particularly the risk of mucositis. 

The fact that many agents which interrupt the synthesis of pyrimidine nucleotides from orotic acid in animals can also inhibit the growth of experimental neoplasms suggests a search for additional antimetabolites whose locus of action is in this metabolic sequence. Two in vitro biological screening systems were developed for this purpose [202—207]. From a study of systems with oxidative energy sources, 5-bromo-[208—209] (Villa), 5-chloro-[210] (Vlllb) and 5-diazo-orotic acid [211] (IX) were found to inhibit the conversion of orotic acid to the uridine nucleotides by 40—100 per cent [202]. 

A variety of mammalian cell culture systems can be used to detect mutations induced by chemical substances. The L5178Y mouse l)nnphoma line, measuring mutation at the TK locus, is preferred. TK is an important enz)une involved in DNA synthesis. Cells are exposed to the test substance at various concentrations, in the presence and absence of a metabolic activation system, for a suitable period of time, and then subcultured to assess cytotoxicity and to allow phenotypic expression prior to mutant selection. Cells deficient in TK because of a forward mutation are resistant to the cytotoxic effects of pyrimidine analogues (antimetabolites), such as trifluorothymidine (TFT). This is because the antimetabolites cannot be incorporated into cellular nucleotides and kill the cell through inhibition of cellular metabolism. After treatment, cells are grown in a medium containing TFT mutant cells can proliferate in the presence of TFT, whereas normal cells containing TK are killed. This allows the detection of an increase in mutant... 

The pyrimidine 5-fluorouracil (64) is used extensively in the clinic as an antimetabolite antitumor agent. As a consequence of poor absorption by the oral route, the drug is usually administered by the intravenous route. A rather simple latent ated derivative, tegafur (66), has overcome this limitation by providing good oral absorption. Reaction of 5-fluorouracil with trimethylsilyl chloride in the presence of base gives the disilylated derivative (65). Reaction of this with dihydrofuran (obtained by dehydro-... 

Antimetabolites are structural analogs of ordinary cellular metabolites such as folic acid, pyrimidines and pyrines, which after being introduced in the body, begin to imitate the structure of ordinary metabolites. They compete with metabolites to block important reactions leading to formation of DNA/RNA. 

Antimetabolites are subdivided into three groups folic acid antagonists (methotrexate), purine antagonists (mercaptopurine, thioguanidine), and pyrimidine antagonists (fluo-rouracil, floxuridine, cytarabine). 

Cytarabine is an effective antimetabolite in treating leukemia. Like other pyrimidine antimetabolites, cytarabine must be activated by initially transforming into the corresponding nucleotide. The active form of the drag is cytarabine triphosphate. Cytarabine is used for all types of leukemia. Synonyms of this drug are cytosine, arabinoside, and ara-C. 

Gemcitabine, a new pyrimidine antimetabolite, is of substantial interest as a radiosensitizer in the treatment of pancreatic cancer. An ongoing multi-institutional Phase II study of preoperative EBRT and concomitant gemcitabine therapy for resectable adenocarcinoma will provide useful information (57-60). 

The answer is a. (Hardman, p 1302.) Cyclophosphamide, an alkylating agent, reacts with purine and pyrimidine bases of DNA to form bridges and dimers. These products interfere with DNA replication. 5-FU, methotrexate, and 6-thioguanine are antimetabolites, and the steroid prednisone has some tumor-suppressive effects. 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

Antimetabolite inhibitors of DNA synthesis act by the competitive or allosteric inhibition of a number of different enzymes participating in purine or pyrimidine biosynthesis. Actually, some such compounds interfere with as many as 10-12 different enzymes— although admittedly to a different degree. 

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... 

Fluorouracil, a fluorinated pyrimidine antimetabolite is used topically for the treatment of multiple actinic keratoses and intralesionally for keratoacanthomas. 

Fluorouracil is a fluorinated pyrimidine antimetabolite that resembles uracil, with a fluorine atom substituted for the 5-methyl group. Its systemic pharmacology is described in Chapter 54. Fluorouracil is used topically for the treatment of multiple actinic keratoses. 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

Cells are able to synthesize genetic material (DNA, RNA) from endogenous metabolites known as purine and pyrimidine nucleotides (Fig. 36-3). Certain anticancer drugs are structurally similar to these endogenous metabolites and compete with these compounds during DNA/RNA biosynthesis. These drugs are therefore called antimetabolites because they interfere with the normal metabolites during cellular biosynthesis.16,80... 

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