Toward the Development of a Cephalosporin-Based Dual-Release Prodrug for Use in ADEPT
| Autor: | Timothy P. Smyth, Jonathan W. Grant |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Alkylation
Molecular Structure Dual release medicine.drug_class Chemistry Stereochemistry Organic Chemistry Cephalosporin Stereoisomerism Adept biochemical phenomena metabolism and nutrition Prodrug Antibody-Directed Enzyme Prodrug Therapy Cephalosporins polycyclic compounds medicine Combinatorial Chemistry Techniques Prodrugs |
| Zdroj: | The Journal of Organic Chemistry. 69:7965-7970 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/jo048970i |
| Popis: | In previous work we have shown that a cephalosporin structure bearing an S-aminosulfenimine at the 7-position behaved as a beta-lactamase-dependent dual-release prodrug. Scission of the beta-lactam ring of such a structure led to the rapid loss of the sulfur-attached side chain moiety via an intramolecular displacement, while the 3'-group was lost via the well-established elimination process at that position. In the present work we report on an evaluation of the scope and limitations of exploiting the S-aminosulfenimine functionality to generate a cephalosporin-based prodrug incorporating two biologically active components. Starting from 7-ACA, a viable synthetic cycle was put in place that avoided formation of the Delta(2) isomer throughout and that allowed incorporation of aminoglutethimide at the 3'-position and of a tosyl S-aminosulfenimine at the 7-position. The direct incorporation of a biologically active sulfonamide (ethoxzolamide) or a sulfamate (coumate) at this latter position was not achieved as a result of the difficulty of generating the corresponding sulfur diimides. An indirect route for the formation of an S-aminosulfenimine was put in place, as was a general method of alkylation (Mitsunobu reaction) of the tosyl S-aminosulfenimine following its incorporation. |
| Databáze: | OpenAIRE |
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