Fluorinated pyrimidines

Antifungal Agents - Synthesis and Drug Profile

Fluorinated pyrimidines

1. Flucytosine

Synthesis

Route I. From: 5-Fluorouracil

Route II. From: 5-Fluorouracil

Mode of action: Flucytosine is converted by cytosine deaminase into 5-flurouracil (5-FU), then, 5-fluoro deoxyuridylic acid is formed. This false nucleotide inhibits thymidylate synthetase, thus, depriving the organism of thymidylic acid, an essential DNA component. It is a potent antimetabolite, which replaces uracil in the pyrimidine pool and thus, disrupts protein synthesis. Mammalian cells do not convert flucytosine to fluorouracil. This fact is crucial for the selective action of this compound. In addition, 5-fluorouracil is metabolized into 5-fluoro uridylic acid by the enzyme uridine monophosphate (UMP) pyrophosphorylase. It is either incorporated into the DNA (via synthesis of 5-fluorouridine triphosphate) or would be metabolized into 5-fluoro deoxyuridylic acid, which is a potent inhibitor of thymidylate synthetase.

Metabolism: It is metabolized to 5-FU by fungal cytidine deaminase.

Then 5-FU is converted into 5-fluorodeoxyuridine, which is a thymidylate synthase inhibitor and interferes with both protein and RNA biosynthesis.

Properties and uses: Flucytosine is a white crystalline powder, sparingly soluble in water, and slightly soluble in ethanol. Flucytosine is the only available antimetabolite drug having antifungal activity.

Assay: Dissolve the sample in anhydrous acetic acid, add acetic anhydride, and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dosage forms: Flucytosine tablets B.P.