Flucytosine synthesis

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

Flucytosine is converted in Candida fungi to 5-fluorouracil by the action of a specific cytosine deaminase. As an antimetabolite, this compound disrupts DNA and RNA synthesis (p. 298), resulting in a fungicidal effect Given orally, flucytosine is rapidly absorbed. It is well tolerated and often combined with amphotericin B to allow dose reduction of the lattet... 

Flucytosine is a fluorinated derivative of pyrimidine. Its spectrum of activity is narrower than that of amphotericin B. However, it exhibits a synergetic effect when used in combination with amphotericin B. In sensitive fungi, flucytosine is transformed into 5-fluorouracil, which in turn is turned into 5-fluorodeoxyuracilic acid, an inhibitor of thymidylate synthetase, and correspondingly, DNA synthesis. 5-Fluorouracil triphosphate, which causes the formation of defective RNA, may also be involved in this process. The mechanism is highly selective because mammahan cells are not able to turn a large amount of flucytosine into 5-fluorouracil. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively (Figure 48-1). Human cells are unable to convert the parent drug to its active metabolites, resulting in selective toxicity. 

Flucytosine Interferes with DNA and RNA synthesis selectively in fungi Synergistic with amphotericin systemic toxicity in host due to DNA and RNA effects Cryptococcus and chromoblastomycosis infections Oral duration, hours renal excretion Toxicity Myelosuppression... 

Mechanism of Action. Flucytosine is incorporated into susceptible fungi, where it undergoes enzymatic conversion to fluorouracil,7 which acts as an antimetabolite during RNA synthesis in the fungus. Fluorouracil is incorporated into RNA chains but acts as a false nucleic acid. This event ultimately impairs protein synthesis, thus disrupting the normal function of the fungus. 

Resistance Resistance can develop during therapy and is the reason that flucytosine is not used as a single antimycotic drug except for chromoblastomycosis. The rate of emergence of resistant fungal cells is lower with the combination of amphotericin B and flucytosine than it is with flucytosine alone. Decreased levels of any of the enzymes in the conversion of 5-FC to 5-FU and beyond, or increased synthesis of cytosine, can confer resistance. 

Pyrimidines, or antimetabolites (Flucytosine) Pyrimidines block thymidine synthesis in susceptible fiuigi, impairing DNA synthesis. Pyrimidines are fungistatic, and resistance can develop during treatment. 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

Biotransformation, especially phase I metabolic reactions, cannot be assumed to be synonymous with detoxification because some drugs (although a minority) and xenobiotics are converted to potentially toxic metabolites (e.g. parathion, fluorine-containing volatile anaesthetics) or chemically reactive intermediates that produce toxicity (e.g. paracetamol in cats). The term lethal synthesis refers to the biochemical process whereby a non-toxic substance is metabolically converted to a toxic form. The poisonous plant Dichapetalum cymosum contains monofluoroacetate which, following gastrointestinal absorption, enters the tricarboxylic acid (Krebs) cycle in which it becomes converted to monofluorocitrate. The latter compound causes toxicity in animals due to irreversible inhibition of the enzyme aconitase. The selective toxicity of flucytosine for susceptible yeasts (Cryptococcus neoformans, Candida spp.) is attributable to its conversion (deamination) to 5-fluorouracil, which is incorporated into messenger RNA. 

Flucytosine is used to treat some systemic fungal infections. It is an antimetabolite that is converted to 5-fluorouracil in fungal cells but not in human cells, which then inhibits an enzyme necessary for DNA synthesis. 

Fluorouracil is a pyrimidine analogue that substitutes for uracil in the synthesis pathway for thymidylate, a necessary step in the synthesis of DNA. Formation of a false nucleotide inhibits an enzyme necessary for DNA synthesis. This is similar to the mode of action of the antifungal drug, flucytosine (Chapter 9, page 167). 

Flucytosine is an antiinfective/antifungal agent that interferes with DNA and RNA synthesis. It is active against Candida and Cryptococcus. It is indicated in the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus. 

All susceptible fungi are capable of deaminating flucytosine to 5-fluorouracil, a potent antimetabolite that is used in cancer chemotherapy. Fluorouracil is metabolized fast to 5-fluorouracil-ribose monophosphate (5-FUMP) by the enzyme uracil phosphodbosyi transferase (UPRTase, also called uridine monophosphate pyrophosphorylase). As in mammalian cells, 5-FUMP then is either incorporated into RNA (via synthesis of 5-fluorouridine triphosphate) or metabolized to 5-fluoro-2 -5 deoxyuridine-5-monophos-phate (5-FdUMP), a potent inhibitor of thymidylate synthetase. DNA synthesis is impaired as the ultimate inhibition of this latter reaction. The selective action of flucytosine is due to the lack or low levels of cytosine deaminase in mammalian cells, which prevents metabolism to fluorouracil. 

Flucytosine (5-fluorocytosine), 6, is a synthetic nucleoside that is converted intracellularly to 5-fluorouracil which, consequently, interferes with protein synthesis [22]. Although this drug is indicated for disseminated cryptococcosis and disseminated candidiases, flucytosine is rarely used alone due to substantial resistance developed by many opportunistic fungal pathogens. It also has the side effect of suppressing bone marrow production which is particularly problematic in AIDS patients. Flucytosine is sometimes used in combination with amphotericin B to suppress the rapid development of resistance to the flucytosine, but the toxicity appears to increase dramatically in these circumstances [21]. 

Inhibitors of nucleic acid synthesis that include drugs that influence DNA template actions in eluding replication, inhibit RNA polymerase, and those that inhibit nucleotide metabolism (e.g., flucytosine (fungi), acyclovir (viruses), and quinolones) ... 

The major towback of Flucytosine is rapid development of resistance in fungi, either by mutations or by increased synthesis of pyrimidines this limits the use of 9 as a single antifungal agent. Monotherapy with Flucytosine is currently only used in some cases of chromoblastomycosis and in uncomplicated candidosis in all other cases, 9 is used together with other agents, usually Amphotericin B [173]. 

The first synthesis of Flucytosine (9) has been reported in 1957 [13, 14], The synthetic scheme is quite similar to that for Fluorouracil (1) in the case of 9, compound 27 was subjected to reaction with PCI5 and then - liquid ammonia to give 219, which was transformed to 9 upon hydrolysis (Scheme 52). In an alternative method, compound 70 (prepared from Fluorouracil) reacted with SOCI2 to give 220, which was transformed to 9 upon reaction with ammonia in methanol [84]. Another synthesis commenced from 2,5-difluoro-4-chloropyrimidine, which, however, is not readily accessible [178]. Flucytosine was also obtained by direct fluorination of cytosine using CF3OF (85 % yield) [179,180], fluorine [181, 182], and AcOF [20]. 

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