title: Stereoselective synthesis and antiviral activity of methyl-substituted cycloSal-pronucleotides.
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.
authors: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
authors: Edwuin H
authors: EH
authors: Rios Morales
authors: Jan
authors: J
authors: Balzarini
authors: Chris
authors: C
authors: Meier
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054306:Dideoxynucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D009154:Mutation; D012997:Solvents / Q000737:chemistry; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000235:genetics; D013942:Thymine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; C415254:Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate; D054306:Dideoxynucleotides; D012997:Solvents; D013942:Thymine Nucleotides; D018119:Stavudine; D013937:Thymidine Kinase