N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase

A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil (19) exhibited the highest activity (EC₅₀ = 0.27 μM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs.     

Ester derivatives of nucleoside inhibitors of reverse transcriptase: I. Molecular transport systems for 3'-azido-3'-deoxythymidine and 2',3'-didehydro-3'-deoxythymidine

The methods of synthesis of the derivatives of nucleoside analogues esterified with various aliphatic, aromatic, and heteroaromatic acids and the construction from them of molecular transport systems that involve lipids, carbohydrates, peptides, and amino acids are discussed. The characteristics of the biological activity of a number of such systems are described.     

Telomere shortening in human HL60 cells by treatment with 3'-azido-2',3'-dideoxynucleosides and telomerase inhibition by their 5'-triphosphates

Telomerase is thought to play an important role in the mechanism of tumor cell immortalization by maintenance of telomere length. To obtain information on the susceptibility of telomerase to nucleoside analogues, the effects of base-modified 3'-azido-2',3'-dideoxynucleoside triphosphates on the enzyme were investigated. It is suggested that the 2-amino group of the nucleotide purine nucleus is important for the inhibitory activity. Telomere shortening caused by long-term treatment with these nucleosides is also described.     

Ester derivatives of nucleoside inhibitors of reverse transcriptase: II. Molecular systems for combined therapy with 3'-azido-3'-deoxythymidine and 2',3'-didehydro-3'-deoxythymidine

The methods of synthesis of conjugates of anti-HIV nucleosides with various compounds, such as protease inhibitors, peptides, polysaccharides, and bicyclames, are considered; they are designated for the combined therapy of HIV.