Pyrimidine analogues

5- fluorouracil by cytosine deaminase in the fungal cells. Idoxuridine (iododeoxyuridine), another halogenated pyrimidine derivative, is used in viral infections. It is a competitive inhibitor (via phosphorylated derivatives) of the incorporation of thymidylic acid into DNA. 

Cytarabine (cytosine arabinoside) is an analogue of 2 -deoxycytidine. The 2 -hydroxyl group of the arabinose moiety is in a trans position with respect to the 3 -hydroxyl group (instead of in a cis position, as in the ribose) and causes steric hindrance to rotation of the base around the nucleoside bond (Chapter 23). Phosphorylated derivatives of cytarabine inhibit nucleic acid synthesis as well as being incorporated into nucleic acids. 

6-Azauridine and its triacetyl derivative, azaribine, inhibit pyrimidine biosynthesis. Azaribine is better absorbed than 6-azauridine, but it is converted in the blood to 

5-Azacytidine, after conversion to a phosphorylated derivative, arrests the DNA synthesis phase of the cell cycle. It also affects methylation of certain bases, which leads to hypomethylation (Chapter 26). 

Azathymidine, 3 -azido-3 -deoxythymidine (AZT), after conversion to the corresponding 5 -triphosphate, inhibits viral reverse transcriptase. Hence, AZT is used in the treatment of AIDS (Chapter 25). 

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ErHistidine C. glutamicum 2-thiazole-3-Ala triazole-Ala purine and pyrimidine analogues 15... 

The first pyrimidine analogues of sulfanilamide were introduced in 1942, some five years after the start of the bacterial chemotherapy revolution. Sulfadiazine (1018 R = R = H) and sulfamerazine (1018 R = Me, R = H) may be made by treatment of pyrimidin-2-amine or its 4-methyl derivative, either with p-acetamidobenzenesulfonyl chloride followed by... 

Enzymic oxidations at the 7-position of pyrido[2,3-oxygenated derivatives and of the 8-N-oxide have been observed in the metabolism of the pyrido[2,3-e/]pyrimidine analogues of the antiepileptic drug methaqualone (75MI21502, 74MI21500). 

Methanol, l-isoquinolyl(phenyl)-confonnation, 2, 110 Methanol, pyrimidinyl-synthesis, 3, 113 Methanol, tetrahydropyran-2-yl-microwave spectra, 3, 625 Methantheline as neurotransmitter, 1, 175 therapeutic properties, 3, 882 Methaphenilene biological activity, 4, 911 Methapyrilene biological activity, 4, 911 toxicity, 4, 912 Methaqualone, 3, 150 as anticonvulsant, 1, 166 pyrido[2,3-d]pyrimidine analogues metabolism, 3, 205 as sedative, 1, 166 Metharbitone as anticonvulsant, 1, 166 Methazolamide... 

Thomsen, A. E., Friedrichsen, G., Sorensen, A. H., Andersen, R., Nielsen, C. U., Brodin, B., Begtrup, M., Frokjaer, S., Steffansen, B., Prodrugs of purine and pyrimidine analogues for the intestinal di/ tripeptide transporter PepTl affinity... 

S., Steffansen, B., Prodrugs of purine and pyrimidine analogues for oligopeptide transporter, AAPS Pharm. Sci. 2001, 3 suppl. 

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... 

Acid and base extractions from this material have been shown to form spontaneous structures in solution termed coercevates that could easily form the basis for protypical membranes (more of this in Chapter 9). Hydrocarbons with chain lengths C15-C30 (both straight and branched chains) and of course PAHs, predominantly pyrene and fluoranthrene, polar hydrocarbons such as aromatic ketones, alkyl and aryl ketones, nitrogen and sulphur heterocycles and most intriguingly purine and pyrimidine analogues have all been observed from this rich carbonaceous cocktail of compounds. Why ... 

Cytotoxic agents Since proliferation of cells is essential for the immune response, agents that inhibit DNA synthesis have been used as immunosuppressive agents for many years. The first were used in the 1960s, particularly to prevent rejection of a transplanted organ, for example purine and pyrimidine analogues. These agents are not now used in autoimmune diseases but are stiU used in cancer chemotherapy (Chapter 21). 

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... 

Daher GC, Harris BE, Diasio RB. Metabolism of pyrimidine analogues and their nucleosides. Pharmacol Ther 1990 48 189-222. 

Fluorouracil is a pyrimidine analogue (see Chapter 27, Section II.b.3). Topical application may be used for malignant and premalignant skin conditions, including actinic keratosis. Adverse effects include local inflammatory and allergic reactions. Photosensitivity reactions during and for up to 2 months after treatment may become manifest. 

Schneider and coworkers investigated the capability of the tetraazonia cyclophane 51 to bind nucleosides and nucleotides in water [72]. Its two diphenylmethane units border a lipophilic cavity for the uptake of likewise lipophilic molecules or subunits. As evidenced by HNMR studies of the complexes, only in the case of the purine derived nucleosides and nucleotides (A, G, AXP, GMP) the base moiety is included inside the host cavity but not in the case of the pyrimidine analogues (U, C, UMP, CMP, TMP). Due to their hydrophilic nature, the sugar and phosphate groups remain outside the niche. 

About 2 years later, a Stanford Research Institute group described the synthesis of the first true pyrimidine analogue of FA (303) which incorporated all of the structural features of FA except the pyrazine ring (see Scheme 3.55) [159], They envisioned that (303) could be assembled from appropriately protected derivatives of isocytosine, glyoxal and p-aminobenzoyl L-glutamic... 

An interesting series of extended pyrimidine analogues was described by Davoll and Johnson Scheme 3.59) [164]. Reductive animation of an appropriately substituted benzonitrile (323a-c) with p-aminobenzoyl aspartic acid followed by saponification gave (324a-c). The m-substituted compound (326) was prepared analogously starting with (325). 

The doubling of resonances in the racemate is characteristic of the 2-CCSiMe3 pyrimidine analogue, and also for both substrates in toluene,... 

The point arose as to the actual site of action of moniliformin in plants. Earlier, it had been stated that the geometrical criteria of hydrogen bond formation suggested that MH could be regarded as either a purine or pyrimidine analogue and, therefore, could substitute as one of the base pairs in nucleic acid.11 And the fact that it had shown plant growth regulatory activity had led an industrial company to become interested in the product as a potential herbicide. 

Several dozen patents have been granted for work in the pyrimidopyrimidine series. Most of them have been reported in the review by Delia and Warner folic acid (111) have been prepared and screened for antitumor activity... 

Coupling diazotized 3-aminoisothiazolo[2,3- >]pyridines with arenes, especially anilines, gives dyes (162) for polyester fibers (79BRP1550828). Pyrimidine analogues and pyrimidinedione analogues (163) are similarly claimed as dyes (75GEP2336978). 

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