title: Sugar-based enantiomeric and conformationally constrained pyrrolo[2,1-c][1,4]-benzodiazepines as potential GABAA ligands.
abstract: 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 GABA(A) receptor.
authors.affiliation: Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Centro de Química e Bioquímica, Lisboa, Portugal. acaraujo@kth.se
authors.forename: Ana C
authors.initials: AC
authors.lastname: Araújo
authors.forename: Amélia P
authors.initials: AP
authors.lastname: Rauter
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicotra
authors.forename: Cristina
authors.initials: C
authors.lastname: Airoldi
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Laura
authors.initials: L
authors.lastname: Cipolla
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005632:Fructose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D008024:Ligands; D011758:Pyrroles; D011963:Receptors, GABA-A; D013141:Spiro Compounds; D001569:Benzodiazepines; D005632:Fructose