Studies on orally active cephalosporin esters. III. Effect of the 3-substituent on the chemical stability of pivaloyloxymethyl esters in phosphate buffer solution
| Autor: | Fujimoto Koichi, Masao Miyauchi, Junya Ide, Isao Kawamoto, Hideo Nakao, Hideshi Kurihara |
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| Rok vydání: | 1989 |
| Předmět: |
Chemical Phenomena
Stereochemistry Substituent Administration Oral Esters General Chemistry General Medicine Buffer solution Buffers Pivaloyloxymethyl Medicinal chemistry Cephalosporins Phosphates Delta II chemistry.chemical_compound Chemistry Reaction rate constant chemistry Drug Stability Drug Discovery Chemical stability Pentanoic Acids HOMO/LUMO Isomerization |
| Zdroj: | Chemicalpharmaceutical bulletin. 37(9) |
| ISSN: | 0009-2363 |
| Popis: | The effect of substituents at the C-3 position on the degradation kinetics of the pivaloyloxymethyl (POM) ester of delta 3 cephalosporin in phosphate buffer solution (pH 6-8) was investigated. In the degradation, the isomerization process to the delta 2 ester was the rate-determining step. In this study, the logarithm of the isomerization rate to the delta 2 ester (log k12) correlated with the carbon-13 nuclear magnetic resonance chemical shift difference value at C-3 and C-4 of the delta 3 ester (delta delta (4-3)). The energy level of the lowest unoccupied molecular orbital (LUMO) of the delta 3 esters also correlated with log k12. The electronic properties at the C-2 position had no effect on the isomerization reaction. On the other hand, the logarithm of the isomerization rate back to the delta 3 ester (log k21) correlated with the van der Waals volume (MV) of the 3-substituent. These results show that the substituent at the C-3 position influences mainly the electronic structure of the conjugated pi-bond system (C3 = C4 - C4 = O) and consequently affects the feasibility of isomerization to the delta 2 ester, i.e., the stability to degradation. |
| Databáze: | OpenAIRE |
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