Further Evidence on the Favorable Role of the Anomeric Effect on the Cleavage of HepDirect and Cyclophosphamide Prodrugs

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• 作者：Fernando Sartillo-Piscil ; Leticia Quintero ; Silvano Cruz-Gregorio ; Javier Espinosa-Aguirre ; Carmen M. Elinos-Baez ; Herbert H枚pfl ; Abel Serrano
• 刊名：Journal of Organic Chemistry
• 出版年：2014
• 出版时间：October 17, 2014
• 年：2014
• 卷：79
• 期：20
• 页码：9647-9654
• 全文大小：473K
• ISSN：1520-6904

文摘

On the basis of previous conformational and configurational studies of 4-aryl-substituted cyclophosph(on)ates derived from d-xylofuranose derivatives, wherein it was proposed that the anomeric effect is involved in the spontaneous isomerization of the P atom and the C4 carbon, and consequently, this unusual behavior was associated with the cleavage of the HepDirect prodrugs. We synthesized an analogous series of 2-amino-2-oxo-1,3,2-dioxaphosphorinanes and performed a conformational and configurational analysis in solution and the solid state followed by an examination of their mutagenic activity. The results showed that the 2-amino-2-oxo-1,3,2-dioxaphosphorinanes with the largest mutagenic activity contain either a 4-methoxyphenyl or 4-fluorophenyl group at C4 carbon and presented a major chair conformation, which is prone to weaken the C4鈥擮3 bond via the anomeric effect and facilitates the cleavage for the release of the biologically active metabolite.