7239-42-1Relevant 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.
Conversion of Some Pyrimidine 2'-Deoxyribonucleosides into the Corresponding 2',3'-Didehydro-2',3'-dideoxynucleosides
Joshi, Bhalchandra V.,Rao, T. Sudhakar,Reese, Colin B.
, p. 2537 - 2544 (2007/10/02)
Thymidine 4b was converted into 2,3'-anhydro-1-(2'-deoxy-β-D-threo-pentofuranosyl)thymine 7b in ca. 65percent isolated yield by being heated at 155 deg C with an excess of diphenyl sulfite and 1-methylimidazole in N,N-dimethylacetamide solution. 2'-Deoxyuridine 4a, 2'-deoxy-5-ethyluridine 4c and 2'-deoxy-5-fluorouridine 4d were similarly converted into 2,3'-anhydronucleosides which were isolated as their 5'-O-(tert-butyldimethylsilyl) derivatives 8a, 8c and 8d in 51, 50 and 59percent yield, respectively.When the oxetane derivatives 5a-d, prepared by the literature procedure from the parent 2'-deoxynucleosides 4a-d, were heated with an excess of sodium hydride in N,N-dimethylacetamide solution at 100 deg C, they were converted into the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 6a-d in 68, 76, 69 and 74percent isolated yield, respectively.The latter compounds were similarly prepared from the 2,3'-anhydronucleosides 7a-d in 71, 81, 69 and 74percent isolated yield, respectively. 2,3'-Anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxy-5-(trifluoromethyl)- and -5-iodo-1-(β-D-threo-pentofuranosyl)uracil 8e and 8f, which were themselves prepared from the parent 2'-deoxynucleosides 4e and 4f, respectively, in ca. 60 and 50percent yield, were converted by a three-step procedure via the intermediate 2'-deoxy-3'-(phenylseleno) derivatives 10e and 10f into the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 6e and 6f in 52 and 49percent overall yield, respectively.Compound 8e was also converted into 2',3'-dideoxy-5-(trifluoromethyl)uridine 11b and 3'-azido-2',3'-dideoxy-5-(trifluoromethyl)uridine 11c in 49 and 66percent overall yield, respectively.
