5′-O-Alkyl and Acyl Prodrugs of 1-β-D-Arabinofuranosyl-E-5-(2-Bromovinyl)Uracil
| Autor: | Fumitaka Kano, Yohko Watanabe, Shinji Sakata, H. Machida, Noriyuki Ashida, Katsushi Ijichi |
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| Rok vydání: | 1994 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Stereochemistry 030106 microbiology Uracil General Medicine Prodrug Alkylation 01 natural sciences Chemical synthesis 0104 chemical sciences Acylation 010404 medicinal & biomolecular chemistry 03 medical and health sciences Hydrolysis chemistry.chemical_compound chemistry Oral administration lipids (amino acids peptides and proteins) Alkyl |
| Zdroj: | Antiviral Chemistry and Chemotherapy. 5:74-82 |
| ISSN: | 2040-2066 |
| DOI: | 10.1177/095632029400500203 |
| Popis: | Summary 5' -O-Alkyl derivatives of 1-[3-D-arabinofuranosyl-E-5 (2-bromovinyl)uracil (BV-araU) were synthesized by selective alkylation and deprotection of 2' ,3' -bis-O tetrahydropyranyl BV-araU to enhance metabolic sta bility and evaluated for efficacy as oral prodrugs of BV-araU. For comparison, their acyl congeners, and 3'-0- and 2'-0-ethyl BV-araU, were also prepared by direct acylation of BV-araU and by selective protec tion, alkylation, and deprotection, respectively. The 5' -O-alkyl prodrugs were stable in acidic solutions, whereas the 5' -O-acyl analogues were unstable under the same conditions. When incubated with enterobac teria, the 5' -O-acyl derivatives resulted in the for mation of BV-uracil through non-enzymatic hydrolysis of BV-araU, but the 5' -O-alkyl prodrugs did not. 5' -0 Short-chain aliphatic alkyl (not longer than butyl) and generally acyl prodrugs gave higher blood concentra tions of BV-araU than the aromatic derivatives. Plasma concentrations of BV-araU were equal or slightly higher than those after equivalent oral doses of BV araU. 5'-0-Ethyl BV-araU was effective against intracerebral, intraperitoneal, and cutaneous infec tions with herpes simplex virus type 1 in mice. 5'-0 Short-chain aliphatic alkyl derivatives may prove to be useful oral prodrugs of BV-araU because of increased metabolic stability. |
| Databáze: | OpenAIRE |
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