Linked Life Data

12383014

Source:http://linkedlifedata.com/resource/pubmed/id/12383014

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
2002-10-17
pubmed:abstractText
As 2',3'-didehydro-2',3'-dideoxy-2'-fluoronucleosides have exhibited interesting antiviral effects against HIV-1 as well as HBV, it is of interest to synthesize the isosterically substituted 4'-thionucleosides in which 4'-oxygen is replaced by a sulfur atom. To study structure-activity relationships, various pyrimidine and purine nucleosides were synthesized from the key intermediate (2R,4S)-1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-beta-D-ribofuranoside 8, which was prepared from the 2,3-O-isopropylidene-D-glyceraldehyde 1 in 13 steps. The antiviral activity of the synthesized compounds were evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which cytidine 17, 5-fluorocytidine 18, adenosine 24, and 2-fluoroadenosine 32 showed moderate to potent anti-HIV activities (EC(50) 1.3, 11.6, 8.1, and 1.2 microM, respectively). It is noteworthy that 2-fluoroadenosine analogue 32 showed antiviral potency as well as high cytotoxicity (IC(50) 1.5, 1.1, and 7.6 microM for PBM, CEM, and Vero, respectively) whereas no other compound showed cytotoxicity up to 100 microM. The cytidine 17 and 5-fluorocytidine 18 analogues showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)), whereas the corresponding D-2'-Fd4 nucleosides showed limited cross-resistance. Molecular modeling studies demonstrated that the larger van der Waals radius as well as the close proximity to Met184 of the 4'-sulfur atom of D-2'-F-4'-Sd4C (17) may be the reasons for the decreased antiviral potency of synthesized 4'-thio nucleosides against the lamivudine-resistant variants (HIV-1(M184V)).
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
24
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4888-98
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:12383014-Animals, pubmed-meshheading:12383014-Anti-HIV Agents, pubmed-meshheading:12383014-Antiviral Agents, pubmed-meshheading:12383014-Binding Sites, pubmed-meshheading:12383014-Cell Line, pubmed-meshheading:12383014-Cercopithecus aethiops, pubmed-meshheading:12383014-Drug Resistance, Viral, pubmed-meshheading:12383014-HIV Reverse Transcriptase, pubmed-meshheading:12383014-HIV-1, pubmed-meshheading:12383014-Humans, pubmed-meshheading:12383014-Lamivudine, pubmed-meshheading:12383014-Leukocytes, Mononuclear, pubmed-meshheading:12383014-Models, Molecular, pubmed-meshheading:12383014-Mutation, pubmed-meshheading:12383014-Purine Nucleosides, pubmed-meshheading:12383014-Pyrimidine Nucleosides, pubmed-meshheading:12383014-Quantum Theory, pubmed-meshheading:12383014-Stereoisomerism, pubmed-meshheading:12383014-Zalcitabine
pubmed:year
2002
pubmed:articleTitle
Stereoselective synthesis and antiviral activity of D-2',3'-didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides.
pubmed:affiliation
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.