8-Azaguanine is a purine analog which resembles guanine close enough to compete with it in the metabolism of living organisms. It has been widely studied and has shown to cause retardation of some malignant neoplasms when administered to tumors in animals. It has been used for the treatment of patients with leukemia.

Piritrexim is a synthetic antifolate agent with antiparasitic, antipsoriatic and antitumor properties. Piritrexim inhibits the enzyme dihydrofolate reductase, thereby disrupting folate metabolism and DNA synthesis and cell division. A theoretical advantage of piritrexim over trimetrexate is a lack of any known effects on histamine metabolism, which may lower the risk of hypersensitivity reactions. Piritrexim is a nonclassical antifolate for antitumor and parasitic chemotherapy that passively diffuses into cells and hence do not have to depend on folylpoly-gamma-glutamate synthetase or the reduced folate carrier. Because piritrexim is not a substrate for polyglutamation, the drug is not selectively retained within cells for prolonged periods. Piritrexim has a reliably high oral bioavailability of about 75%, which has led to its development as an oral lipophilic antifolate. Most commonly, it has been administered in oral daily doses of 75 to 150 mg bid or tid every 5 days, with cycles repeated every 3 weeks. Oral absorption is rapid, with peak plasma levels appearing at 1.5 hours after ingestion. Elimination occurs primarily via hepatic metabolism of the drug to active metabolites, and the terminal half-life of the parent compound is about 1.5 to 4.5 hours. Single-agent oral piritrexim has clinical activity in melanoma, urothelial cancers, and head and neck cancers. Tolerable combinations of piritrexim with cisplatin, fluorouracil, and leucovorin have been tested, with promising results achieved in head and neck cancer. An interesting attempt to alternate piritrexim with methotrexate did not have any greater activity than methotrexate alone.

Raluridine (also know as 935U83) is a nucleoside analog reverse transcriptase inhibitor patented by Wellcome Foundation Ltd. for the treatment of HIV infection. Raluridine has demonstrated selective anti-human immunodeficiency virus (HIV) activity in vitro and favorable safety profiles in monkeys and mice. When tested in phytohemagglutinin-stimulated normal human peripheral blood lymphocytes against fresh clinical isolates of HIV type 1 Raluridine inhibited virus growth with an average 50% inhibitory concentration of 1.8 microM. Importantly, Raluridine retained activity against HIV strains that were resistant to zidovudine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytosine. The anabolic profile of Raluridine was similar to that of zidovudine, and Raluridine triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. In clinical trials systemic exposure to Raluridine at levels exceeding its average in vitro antiretroviral 50%, inhibitory concentration (approximately 1.8 microM) can be achieved after a single oral dose.

Thiarabine (also known as OSI-7836) is a new-generation deoxycytidine nucleoside analog with potent anticancer activity. As with other nucleoside analogs, Thiarabine is a prodrug and requires intracellular phosphorylation by deoxycytidine kinase to the active form (Thiarabine-triphosphate), which then competes with deoxycytidine for incorporation into DNA resulting in cell death. In xenograft studies using lung, colon, pancreatic, breast, and melanoma models, Thiarabine shows superior antitumor activity in most of these tumors, particularly in lung and pancreatic models, compared with gemcitabine, cisplatin, and paclitaxel. Thiarabine seems to be less schedule dependent than gemcitabine, showing antitumor activity with a variety of schedules in preclinical studies. In clinical trials, Thiarabine administration was associated with excessive fatigue, and despite changes in its schedule and duration of administration.

1-(2-DEOXY-2-FLUORO-β-D-ARABINOFURANOSYL)URACIL (FAU) is a thymidine analog. In several cancer cell lines, FAU was phosphorylated intracellularly to its monophosphate, 1-(2-deoxy-2-fluoro--Darabinofuranosyl) uracil monophosphate (FAUMP), by thymidine kinase and methylated in the 5-position by thymidylate synthase to form the product, 1-(2-deoxy-2-fluoro- -D-arabinofuranosyl) 5-methyluracil monophosphate (FMAUMP). FAU strongly inhibits the growth of tumor cells with high thymidylate synthase activity. FAU had been in phase I clinical trial for the treatment of advanced solid tumors.

Lometrexol, formerly known as DDATHF; LY 264618; T-64 was the first glycinamide ribonucleotide formyl transferase (GARFT) inhibitor to be investigated clinically. Lometrexol had been in phase II clinical trial for the treatment non-small cell lung cancer (NSCLC). However, the studies have been discontinued by Tularik Inc, because Company had suggested, that drug would face competition from other companies in the indication

3'-C-ethynylcytidine (Ethynylcytidine, TAS-106) is a synthetic cytidine nucleoside containing a covalently bound ethynyl group with potential antineoplastic and radiosensitizing activities. 3'-C-ethynylcytidine is metabolized in tumor cells to ethynylcytidine triphosphate (ECTP), which inhibits RNA synthesis by competitive inhibition of RNA polymerases I, II and III; subsequently, RNase L is activated, resulting in apoptosis. RNase L is a potent antiviral and antiproliferative endoribonuclease that cleaves singled stranded RNA, causes 28s rRNA fragmentation, and activates Janus Kinase (JAK), a mitochondrial-dependent apoptosis signaling molecule. Development of a cytosine derivative of 3'-ethynyl ribonucleoside, TAS-106, as an intravenously administered treatment for solid tumours was discontinued. A phase II trial in patients with head and neck cancer was terminated in the US.

THIOINOSINE (Methylmercaptopurine riboside, NSC- 40774) is a purine derivative with antineoplastic and anti-angiogenic properties. THIOINOSINE is readily converted in cells to its active form, 6-methylmercaptopurine ribonucleoside 5'- monophosphate (MMPR-P), by the enzyme adenosine kinase. THIOINOSINE inhibits amidophosphoribosyltransferase, the first committed step in de novo purine synthesis, and inhibits fibroblast growth factor-2 (FGF2)-induced cell proliferation. It has been used similarly to Mercaptopurine in the treatment of Leukemia. It has being tested in clinical trials for advanced pancreatic cancer.

Folitixorin, a thymidylate synthase inhibitor is a substrate used by the enzyme methylenetetrahydrofolate reductase (MTHFR) to generate 5-methyltetrahydrofolate. Folitixorin was studied in clinical trials for the treatment of breast cancer, metastatic colorectal cancer and for the treatment of advanced pancreatic cancer. Folitixorin had been granted orphan drug status for the treatment of pancreatic cancer in both the U.S. and EU. However, further development of this drug was discontinued.

Talotrexin (also known as PT-523) was developed as a nonpolyglutamatable antifolate drug for the treatment of various types of tumors. It is known that antifolates are a class of cytotoxic or antineoplastic agents, which inhibit or prevent the maturation and proliferation of malignant cells. Talotrexin was studied in clinical trials for the treatment of brain and central nervous system tumors, leukemia, lymphoma, unspecified childhood solid tumor. However, this study was withdrawn because of toxicity. In addition, was studied in phase I/II multicenter clinical trial in patients with non-small-cell Lung carcinoma, this study was also withdrawn. The withdrawal was related to incidences of dose-limiting mucositis and myelosuppression. However, on May 22, 2006, was announced that the U.S. Food and Drug Administration has granted orphan drug designation for talotrexin in patients with acute lymphoblastic leukemia (ALL).