Eniluracil (5-ethynyluracil, GW 776, 776C85) is a potent irreversible inhibitor of dihydropyrimidine dehydrogenase, the first enzyme in the catabolic pathway of 5-fluorouracil (5-FU), the most widely used drug in cancer chemotherapy. Eniluracil increases the oral bioavailability of 5-FU to 100%, facilitating uniform absorption and predictable toxicity. Eniluracil was being developed as a novel modulator of 5-FU for the treatment of cancer.

Galocitabine is an orally available 5-fluorouracil (5-FU) prodrug with potential antineoplastic activity. Upon administration, galocitabine is converted to 5’-deoxy-fluorocytidine (5’-DFCR) by acylamidase in the liver and is then converted to 5’-DFUR by cytidine deaminase. Efficient conversion of galocitabine to 5-FU is necessary for galocitabine to have a therapeutic effect. 5-FU is further metabolized into other cytotoxic metabolites that interfere with RNA and DNA synthesis via inhibition of thymidylate synthase. As a result, this agent eventually inhibits tumor cell growth.

Navuridine (AzddU) is a nucleoside analogue which demonstrated significant anti-HIV activity and low toxicity in preclinical studies. The drug was originally developed by University of Georgia. Navuridine is a dideoxyuridine inhibitor of HIV reverse transcriptase that is related to zidovudine. Navuridine exhibits a relatively short half-life and incomplete oral bioavailability and has not been developed into a clinical drug.

Metoprine is a diaminopyrimidine folate antagonist with potential antineoplastic activity. Metoprine inhibits dihydrofolate reductase, resulting in decreased cellular folate metabolism and cell growth. Metoprine shows potent in vitro antitumor activity against several experimental tumors including methotrexate-resistant tumors. Metoprine inhibits the enzyme dihydrofolate reductase, much less effectively than methotrexate but it also inhibits histamine-N-methyltransferase, resulting in decreased histamine catabolism. S phase cells are most sensitive, whilst cells in G2 and M are least sensitive to the lethal effects of Metoprine, and a prolonged exposure to a high Metoprine concentration produces maximum cytotoxic effects. After oral administration, Metoprine has a widespread distribution and concentration in all tissues examined with the highest tissue/plasma ratios found in brain, lung, pancreas, and skin. Phase I and early Phase II clinical trials in various centers have shown activity in hypernephroma, epidermoid carcinoma arising in bronchus or head and neck, central nervous system leukemia, malignant melanoma, and mycosis fungicides. Metoprine had been in some phase II clinical trials but further studies were discontinued due to CNS and hematological toxicity.

Fiacitabine, also known as FIAC, is a pyrimidine nucleoside, which had been in phase II clinical trilas for the treatment Cytomegalovirus infections and Herpes simplex virus infections. However, these researches have been discontinued. It was also shown the inhibitor activity of FIAC against the DNA polymerase of hepadnaviruses.

Pyrazofurin (PF) (3,β-D-ribofuranosyl, 4-hydroxyprazole-5-carboxamide) is a C-nucleoside antibiotic, one in which the ribose joins the base-ring carbon instead of a base-ring nitrogen. Pyrazofurin potently inhibits orotidine 5'-monophosphate (OMP) decarboxylase, thereby interfering with de novo synthesis of uridine nucleotides and resulting in cytotoxicity. This agent also causes a rapid depletion of the pyrimidine deoxynucleotide pool, thereby inhibiting DNA synthesis and cell replication. PF was isolated from fermentation filtrate of Strepomyces candidus. This compound was initially found to have inhibitory activity against the vaccinia, herpes simplex, rhino and measles viruses in vitro and the vaccinia virus in vivo. More recently the antiviral spectrum has been extended to include the polio, Coxsackie, Sindbis and vesicular stomatitis viruses.

Dezaguanine is a broad spectrum guanine antimetabolite. This compound differs from guanine only in the substitution of a carbon for the 3-nitrogen of guanine. Dezaguanine must be converted to its nucleotides to be active. Dezaguanine nucleotides inhibit synthesis of guanine nucleotides, and can be incorporated into nucleic acids in place of guanine nucleotides; incorporation into DNA may be particularly important in the cytotoxicity of this compound. Addition of certain purines or purine nucleosides can prevent dezaguanine cytotoxicity in vitro. It has exhibited sufficient preclinical antitumor activity, particularly against rat and mouse mammary adenocarcinomas, slow and fast growing mammary tumors in mice and the human breast xenograft subrenal capsule implant system. It has completed one phase I trial.

Thiamiprine is a cytotoxic purine derivative patented by Wellcome Foundation Ltd. as an immunosuppressive and antineoplastic agent. In preclinical models, Thiamiprine is active against a variety of transplantable rodent tumors and in the rat adjuvant arthritis model.

Tetrahydrouridine is a potent competitive reversible inhibitor of cytidine deaminase. Tetrahydrouridine can inhibit cell proliferation by regulation of the cell cycle independent of cytidine deaminase (CDA) expression levels. Tetrahydrouridine may be useful for researching potential treatments for high CDA-expressing tumors. Tetrahydrouridine use, alone or in combination with the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycytidine, is being evaluated in animal models and clinical trials for diseases, including cancer and mitochondrial DNA depletion syndrome.