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Stereoselective synthesis and antiviral activity of methyl-substituted cycloSal-pronucleotides.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 Aug 23; Vol. 55 (16), pp. 7245-52. Date of Electronic Publication: 2012 Aug 03. - Publication Year :
- 2012
-
Abstract
- Methyl-substituted cycloSal-pronucleotides of d4TMP were synthesized with high diastereoselectivities in satisfying chemical yields. The individual diastereomers were tested against HIV-1 and HIV-2 infected wild-type CEM/0 and HIV-2 infected thymidine kinase deficient CEM cells. All diastereomers tested showed significant antiviral activity in CEM/0 and strong activity in CEM/TK(-) cell cultures. The antiviral activities were strongly dependent on the chirality at the phosphate group and the position of the methyl-group(s) in the cycloSal moiety. In CEM/TK(-) cell cultures the difference in antiviral potency was found to be 7- to 20-fold. The stability of each diastereomer was studied in aqueous phosphate buffer and in CEM/0 cell extracts. Large differences in the half-lives were found. A comparison of the relative lipophilicity of the methyl-substituted cycloSal triesters was performed based on the retention times obtained by reversed phase HPLC. The results obtained clearly confirm the importance of a diastereoselective synthesis of cycloSal-pronucleotides.
- Subjects :
- Anti-HIV Agents chemistry
Anti-HIV Agents pharmacology
Cell Line
Dideoxynucleotides chemistry
Dideoxynucleotides pharmacology
Drug Stability
HIV-1 drug effects
HIV-2 drug effects
Humans
Hydrolysis
Mutation
Solvents chemistry
Stavudine chemical synthesis
Stavudine chemistry
Stavudine pharmacology
Stereoisomerism
Structure-Activity Relationship
Thymidine Kinase genetics
Thymine Nucleotides chemistry
Thymine Nucleotides pharmacology
Anti-HIV Agents chemical synthesis
Dideoxynucleotides chemical synthesis
Stavudine analogs & derivatives
Thymine Nucleotides chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22827702
- Full Text :
- https://doi.org/10.1021/jm3008085