Fluorocytosines

Flucytosine. Flucytosine (17) or 5-fluorocytosine (4-amino-5-fluoro-2-pyrimidone, 5-FC), C H FN O, is a pyrimidine derivative, that is efficient against Candida albicans Cryptococcus neoformans and Torulopsis glabrata. 

A landmark scientific breakthrough resulted from the synthesis and metabohc studies of 5-fluorouracil (5) (fl ura or 5-FU), 5-fluoroorotic acid ( f) (fl oro), and 5-fluorocytosine (7) (fl cyt) by Heideiberger and co-workers [2] Several excellent recent reviews are available on this important field [9, 23, 24, 25, 26 ]. 

Therapeutic Function Antifungal Chemical Name 5-fluorocytosine Common Name —... 

Mycolic acid and arabinogalactan synthesis in mycobacteria 4.5 5-Fluorocytosine... 

Chromosome function Quinolones Metronidazole (also ) Nitrofu rantoin Rifampicin (also ) 5-Fluorocytosine Inhibit DNA gyrase DNA strand breakage DNA strand breakage Inhibits RNA polymerase Inhibits DNA synthesis No action on mammalian equivalent Requires anaerobic conditions not present in mammalian cells No action on mammalian equivalent Converted to active form in fungi... 

Many yeasts are inhibited by 5-fluorocytosine and a block in the synthesis of 5-fluorouridylic acid by loss of cytosine deaminase or of nracil phosphoribosyltransferase is sufficient to cause resistance. Mntational loss of pyrimidine salvage enzymes has been frequently observed. 

Hoeprich and Huston [117] assessed the stability of miconazole and three other antifungal agents under conditions encountered in bioassay and susceptibility testing in vitro. Although the amphotericins were labile as compared with other drugs, tests should be reliable with all four drugs in view of the rapid action of the polyenes and the relatively slow action of miconazole and 5-fluorocytosines. 

Traces (0.1%) of 2-l luoro-/)-alanine were also found in the urine of patients treated with the antifungal agent flucytosine (5-fluorocytosine, 4.239) [156], However, it appears that flucytosine, the amino analogue of 5-fluoro-... 

Flucytosine Flucytosine, 5-fluorocytosine (35.4.4), is synthesized from fluorouracil (30.1.3.3). Fluorouracil is reacted with phosphorous oxychloride in dimethylaniline to make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted with ammonia to make a product substituted with chlorine at the fourth position of the pyrimidine ring—4-amino-2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis of the chlorovinyl fragment of this compound in a solution of hydrochloric acid gives the desired flucytosine [52-55]. 

Huber BE, Austin EA, Richards CA, et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene Significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA 1994 91 8302-8306. 

Khil MS, Kim JH, Mullen CA, et al. Radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells in culture transduced with cytosine deaminase gene. Clin Cancer Res 1996 2 53-57. 

Also the preparation of the tumour imaging agents 5-[ F]fluorocytosine [108] (Scheme 28) and cytosine derivative [ F]capecitabine [109] can be considered as a direct /7eferoaromatic electrophilic dehydrogenation. 

The 5-fluorocytosine (flucytosine) is an inhibitor of sterol C-14 demethylase, an enzyme involved in the biosynthesis of ergosterol, an element of fungal wall. It is marketed as an anti-fungal agent, whereas nucleoside derivatives of the... 

Flucytosine (5-fluorocytosine) is also an inhibitor of lanosterol C-14 demethylase (Figure 8.3) with the same indications as fluoroazoles. 

It was previously thought that 5-FU inhibits the enzyme by classical competitive inhibition. However, it was found that 5-FU is a transition-state substrate, and it forms a covalent complex with tetrahydrofolate and the enzyme in the same way that the natural substrate does. The reaction, however, will not go to completion, since the fluoro-uridine derived from the antimetabolite remains attached to the enzyme, and the latter becomes irreversibly deactivated. Recovery can occur only through the synthesis of new enzyme. Fluorouracil is used in the treatment of breast cancer and has found limited use in some intestinal carcinomas. Unfortunately, this drug has the side effects usually associated with antimetabolites. Its prodrug, fluorocytosine (8.35, which is also an antifungal agent) is better tolerated. 

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... 

This field was recently reviewed [172]. Enzymes that have been used for ADEPT are, e.g., alkaline phosphatase, carboxypeptidase A, cytosine deaminase, -lactamase prodrugs and corresponding drugs were, e.g., adriamycin phosphate and adriamycin, methotrexate-alanine and methotrexate, 5-fluorocytosine and 5-fluorouracil, and vinca-cephalosporin and vinca alkaloid [172 and references therein]. 

Cunningham C, Nemunaitis J. A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Human Gene Ther 2001 12(12) 1594—1596. 

On the basis of the UV spectra of the neutral forms of cytosine and of the bathochromic and hypsochromic spectral shifts caused by protonation of cytosine and of its 1-methyl, 3-methyl, 5- and 6-halogeno derivatives, Wempen and Fox105 have concluded that 6-chloro and 6-fluorocytosine were best represented by the form 3 in which the dissociable proton was affixed to N-3. 5 - Ha I ogenocytosines by contrast occur mainly as form 2. 

Fluorocytosine, (nonaq. sol.) Aqueous solution Lactam-amine (2) UV spectroscopy text)... 

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