Synthesis of Fluorosugar Analogues of 2,5,6-Trichloro-1-(β-d -ribofuranosyl)benzimidazole as Antivirals with Potentially Increased Glycosidic Bond Stability
| Autor: | John C. Drach, George Andrew Freeman, Kristjan Gudmundsson, Leroy B. Townsend |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Benzimidazole
Stereochemistry Human immunodeficiency virus (HIV) Cytomegalovirus Enzyme-Linked Immunosorbent Assay Herpesvirus 1 Human Viral Plaque Assay medicine.disease_cause Antiviral Agents Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Tumor Cells Cultured medicine Humans Cells Cultured Skin chemistry.chemical_classification Bicyclic molecule Chemistry Glycosidic bond Fluorine Fibroblasts Xyloside Yield (chemistry) Molecular Medicine Benzimidazoles Ribonucleosides Nucleoside Cell Division |
| Zdroj: | Journal of Medicinal Chemistry. 43:2473-2478 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The metabolic instability in vivo of the glycosidic bond of 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole , 2,5, 6-trichloro-1-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole, and 2-bromo-5, 6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3',5'-ditrityl derivatives, which were fluorinated with DAST and deprotected to yield 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole and 2,5, 6-trichloro-1-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low overall yield (5%) of 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5, 6-trichlorobenzimidazole was condensed with 1-bromo-3, 5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|