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A series of pro-nucleotide phosphoramidates and phosphorodiamidates of the antiviral lead compound 3′-deoxy-3′-fluorothymidine (FLT) have been designed and synthesized. In vitro antiretroviral and cytostatic studies revealed potent (sub-micromolar) inhibition of HIV-1 and HIV-2 replication, with retention of activity in thymidine kinase-negative cell models, as predicted by the ProTide concept.

Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC(50) values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.

Inoculation of cynomolgus monkeys with simian immunodeficiency virus (SIVSM) results in an acute infection with circulating viral antigen. The time for appearance of the viral antigen peak was dependent on the dose of virus given, a reduced dose of virus resulting in a later peak. 3′-Fluorothymidine (FLT) was given at a dose of 3 × 5mg kg−1 day−1 starting 8 h before virus inoculation and then every 8 h for 10 days. In monkeys inoculated with 500–2500 infectious doses of SIVSM no significant effect of treatment with FLT was seen. When the amount of virus was reduced to 100 infectious doses or less, treatment with FLT resulted in a significant delay in the appearance of viral antigen. At an inoculum of 2–10 infectious doses per monkey, FLT treatment showed a prophylactic effect.