Sugar-Based Enantiomeric and Conformationally Constrained Pyrrolo[2,1-c][1,4]-Benzodiazepines as Potential GABAA Ligands
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- 作者：Ana C. Arau虂jo ; Ame虂lia P. Rauter ; Francesco Nicotra ; Cristina Airoldi ; Barbara Costa ; Laura Cipolla
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：March 10, 2011
- 年：2011
- 卷：54
- 期：5
- 页码：1266-1275
- 全文大小：983K
- 年卷期：v.54,no.5(March 10, 2011)
- ISSN：1520-4804
文摘
Synthesis of a library of pyrrolo[2,1-c][1,4]-benzodiazepines derived from spiro bicyclic d- or l-proline analogues containing a d- or l-fructose moiety was developed. The l-fructose moiety was obtained by using a new synthetic pathway starting from l-arabinose through a six steps synthesis in 18% overall yield. Molecular modeling calculations and DNMR studies showed that d- and l-fructose-based pyrrolobenzodiazepines exhibit a rigid (P)- and (M)-helical conformation, respectively, in which the C-11a substituent was always pseudoequatorial. Additionally, pyrrolobenzodiazepines functionalized with a chloride, bromide, nitro, or amino group in the benzene ring, with or without N-methylation and with or without protection of sugar alcohol groups, allowed a relationship between the molecular structure and biological activity to be established. The conformation of the diazepam ring was not the sole key player influencing binding affinities, and the sugar moiety can in some cases increase the binding activity, possibly by participating in the binding event. Finally, these compounds have increased the understanding of the differential recognition of (M)-/(P)-helical benzodiazepines on GABAA receptor.