Sugar-Based Enantiomeric and Conformationally Constrained Pyrrolo[2,1-c][1,4]-Benzodiazepines as Potential GABA(A) Ligands
2011 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 5, 1266-1275 p.Article in journal (Refereed) Published
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 compounds have increased the understanding of the differential recognition receptor. participating in the binding event. Finally, these of (M)-/(P)-helical benzodiazepines on GABA(A) receptor.
Place, publisher, year, edition, pages
2011. Vol. 54, no 5, 1266-1275 p.
Central Benzodiazepine Receptors, Beta-D-Glucose, L-Fructose, Biological Evaluation, Practical Synthesis, Chimeric Scaffolds, Design; 1, 4-Benzodiazepin-2-Ones, Recognition, Derivatives
Chemical Sciences Medical and Health Sciences
IdentifiersURN: urn:nbn:se:kth:diva-100977DOI: 10.1021/jm101244nISI: 000287833300014OAI: oai:DiVA.org:kth-100977DiVA: diva2:545998
QC 201208222012-08-222012-08-222012-08-22Bibliographically approved