Synthesis and Biological Evaluation of 2‘,3‘-Didehydro-2‘,3‘-dideoxy-5- fluorocytidine (D4FC) Analogues: Discovery of Carbocyclic Nucleoside Triphosphates with Potent Inhibitory Activity against HIV-1 Reverse Transcriptase

Authors:
Publisher website
Google Scholar
Abstract
The discovery of a novel cytosine nucleoside, β-d-2‘,3‘-didehydro-2‘,3‘-dideoxy-5-fluorocytidine (d-D4FC), as a potent antihuman immunodeficiency virus (HIV) agent led us to synthesize a series of analogues and derivatives of β-d-D4FC that could be more selective and also possess increased glycosidic bond stability. The synthesized d-D4FC analogues were evaluated for anti-HIV-1 activity, anticancer activity, and cytotoxicity in various cells. The biological data demonstrated that the 5-substitution of β-d-D4FC with bromine (6c) and iodine (6d) resulted in the loss of antiviral activity, and the α-d anomer (7a) of d-D4FC was also devoid of activity. The 5-fluorouracil analogues (6b and 7b) of d-D4FC were less potent and more cytotoxic than the parent compound, whereas the β-l-D4FU (11) showed both potent anti-HIV-1 activity and cytotoxicity. N4- and 5‘-O-acyl derivatives (17, 15a−c) of β-d-D4FC exhibited comparable antiviral activity to β-d-D4FC. In contrast, the N4-isopropyl derivative (20) of β-d-D4FC was not active against HIV-1, even at 100 μM. The carbocyclic analogues (26a,b) of D4FC demonstrated weak activity against HIV-1 and no toxicity in various cells. The triphosphates (27a,b) of the carbocyclic nucleosides demonstrated potent inhibitory activity against recombinant HIV-1 reverse transcriptase at submicromolar concentrations. Of the compounds tested as potential anticancer agents, β-d-, α-d-, and β-l-D4FU (6b, 7b, 11) showed inhibitory activity against rat glioma and modest activity against human lung carcinoma, lymphoblastoid, and skin melanoma cells.

This publication has 6 references indexed in Scilit: