221156-18-9Relevant academic research and scientific papers
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
Shi, Junxing,McAtee, J. Jeffrey,Wirtz, Susan Schlueter,Tharnish, Phillip,Juodawlkis, Amy,Liotta, Dennis C.,Schinazi, Raymond F.
, p. 859 - 867 (2007/10/03)
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.
