Pelitrexol (also known as AG2037) was developed by Pfizer as a glycinamide ribonucleotide formyltransferase inhibitor. This drug was studied in phase II clinical trials in patients with metastatic non-small cell lung cancer and in patients with metastatic colorectal cancer who failed treatment. In addition, the drug participated in a phase I clinical trial in treating patients who have advanced, metastatic, or recurrent solid tumors. Information about the further development of pelitrexol is not available.

Edatrexate (10-ethyl-10-deazaaminopterin or 10-EDAM) is an analog of methotrexate with improved pre-clinical antitumor activity, more selective cellular uptake, and with the more extensive formation of intracellular polyglutamate metabolites. This drug is a new dihydrofolate reductase inhibitor, which was studied in phase II clinical trial for the patients with different cancers. The studies were discontinued, for example, in advanced renal cell carcinoma edatrexate in the investigated dose and schedule had minimal activity and was toxic. In case of non-small-cell lung cancer, the dosing schedule of edatrexate did not appear to be improved compared to other chemotherapeutic regimens. In addition, edatrexate was involved in the experiment for the treatemnt of rheumatoid arthritis, but this study was also discontinued.

Fialuridine, or 1-(2-deoxy-2-fluoro-1-D-arabinofuranosyl)-5-iodouracil (FIAU) is a thymidine nucleoside analog with activity against various herpesviruses and hepatitis B virus (HBV) in vitro and in vivo. Herpes virus thymidine kinase considered to be a target of FIAU. In a Phase II study, fialuridine induced a severe toxic reaction in chronic hepatitis B patients characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy. These clinical manifestations led to the hypothesis that the toxicity of FIAU was mediated through mitochondrial dysfunction, possibly as a result of the inhibition of mitochondrial DNA polymerase gamma and/or incorporation of FIAU into mitochondrial DNA.

Lobucavir is a new anti-cytomegalovirus infection agent, manufactered by Bristol Myers Squibb, Inc. Lobucavir is a cyclobutyl analog of guanine with broad spectrum antiviral activity against most herpes viruses and Hepatitis B. Lobucavir was shown to inhibit herpes simplex virus (HSV) DNA polymerase after phosphorylation by the HSV thymidine kinase. The drug was well tolerated with few side effects. Lobucavir had been in phase III clinical trial for the treatment of Hepatitis B, Herpes simplex virus infections and in phase II for the treatment of Cytomegalovirus infections. All these studies were discontinued.

CNDAC (TAK-109) is an analog of the nucleoside deoxycytidine with potential antineoplastic activity. CNDAC is incorporated into DNA and induces single-strand breaks, which are converted into double-strand breaks (DSBs) when cells go through a second S phase. This results in the cell cycle arrest in the S and G2/M phases, DNA fragmentation, and tumor cell apoptosis. Sapacitabine, a prodrug of CNDAC, is being developed by the US biotechnology company Cyclacel for the treatment of hemalogical cancers and solid tumors.

Gemcitabine elaidate is an ester of anticancer drug gemcitabine and elaidic fatty acid. The motivation to make an ester was to facilitate gemcitabine uptake and prolong retention in the cell. The drug is converted to parent compound gemcitabine both inside and outside the cell. Gemcitabine elaidate was developed by Clavis Pharma for treatment of solid tumors, including non-small cell lung cancer and pancreatic cancer, but its development was discontinued after product missed the primary endpoint in the Phase II LEAP trial to treat metastatic pancreatic cancer.

Triciribine is a purine analogue which inhibits DNA and protein synthesis, it is a synthetic tricyclic nucleoside which acts as a specific inhibitor of the Akt signaling pathway. It selectively inhibits the phosphorylation and activation of Akt1, -2 and -3 but does not inhibit Akt kinase activity nor known upstream Akt activators such as PI 3-Kinase and PDK1. It inhibits cell growth and induces apoptosis preferentially in cells that express aberrant Akt1. In whole cells triciribine is phosphorylated by adenosine kinase which may be necessary for its activity. Triciribine is a cancer drug which was first synthesised in the 1970s and trialled clinically in the 1980s and 1990s without success. Following the discovery in the early 2000s that the drug would be effective against tumours with hyperactivated Akt, it is now again under consideration in a variety of cancers. As PTX-200, the drug is currently in two early stage clinical trials in breast cancer and ovarian cancer being conducted by the small molecule drug development company Prescient Therapeutics.

Tezacitabine is a cytidine derivative patented by Merrell Dow Pharmaceuticals, Inc. as an antineoplastic and antiviral agent. Tezacitabine acts as irreversible ribonucleotide reductase inhibitor and DNA chain terminator. Tezacitabine shows as potent activity in a broad spectrum of tumor cell lines and in vivo tumor models, including human colon, prostate, and breast tumor xenografts, In clinical trials combination of Tezacitabine and 5-Fluorouracil exerts favor influences in patients with advanced solid tumors particularly in patients with esophageal and other gastrointestinal carcinomas.

8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action remains poorly understood, however, it is known that the drug inhibits RNA synthesis. It has significant cytotoxic activity against lymphoid and myeloid malignant cells. The nucleoside analog 8-Cl-Ado is phosphorylated into its cytotoxic triphosphate 8-Cl-ATP. The accumulation of the cytotoxic metabolite results in a parallel decrease of the ATP cellular pools. 8-Cl-Ado gets incorporated into RNA during transcription, hindering this process. In addition, this triphosphate inhibits ATP-dependent poly(A) tail synthesis, and, as a consequence, mRNA processing is inhibited, resulting in vitro cytotoxicity in several solid and hematological malignancies. This agent is currently in clinical trials for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia.