Synthesis and Evaluation of Novel Thymidine Analogs as Antitumor and Antiviral Agents

Abstract

Two series of thymidine analogs with a hydroxyalkylammonium(amine) moiety have been synthesized and evaluated for antitumor and antiviral activities. The hydroxyalkylammonium-(amine) group was introduced at the 5' position of the 2'-deoxyribose residue of thymidine or at a corresponding position in acyclic thymidine analogs. In order to increase the lipophilicity of these compounds and potentially enable them to cross the cell membrane, the free hydroxy group also was esterified with a long hydrocarbon chain. The hexadecanoyl analogs (compounds 1c, 1d, 7c, and 7d) showed moderate antitumor cytotoxicity against SV-28 and KB cell lines (IC50 approximately 20 microM). Compound 1d showed moderate anti-HIV activity (EC50 = 6.8 microM), while compound 5 showed weak anti-HIV activity (EC50 = 55 microM). None of the compounds showed antiherpes simplex virus activity.

The formation of thymidine-based T-tetramers with remarkable structural and metal ion size effects

“…Indeed, thymidine-based T-quartet structures may be of real significance. One hand, thymidine is more associated with DNA structures than thymine, in the other hand, thymidine and its derivatives have been used for the treatment of cancer 16, 17 and HIV/AIDS. 17,18 Many detection techniques such as NMR, 2,14,15,19 X-ray, 3,19 MS, 11,12,20 fluorescence, 19 CD spectra 8,21 and IR 22 have been developed to determine these supramolecular structures.…”

“…One hand, thymidine is more associated with DNA structures than thymine, in the other hand, thymidine and its derivatives have been used for the treatment of cancer 16, 17 and HIV/AIDS. 17,18 Many detection techniques such as NMR, 2,14,15,19 X-ray, 3,19 MS, 11,12,20 fluorescence, 19 CD spectra 8,21 and IR 22 have been developed to determine these supramolecular structures. In this regard, as a popular, minimally fragmenting tool for investigating supramolecular noncovalent interactions, matrix-assisted laser desorption/ionization (MALDI) time of flight (TOF) mass spectrometry and electrospray ionization (ESI) mass spectrometry, can provide various information for these possible supramolecular complexes present in solution.…”