Design and Synthesis of Novel Benzodiazepines

Bivalent drug design is an efficient strategy for increasing potency and selectivity of many drugs. We devised a strategy to prepare agonist-benzodiazepine heterodimers that could simultaneously bind to agonist and BZD sites of the GABAAR. We synthesized a benzodiazepine-MPEG model compound that relied on physiological GABA to elicit flux. We established that a tether at the N1 position of the BZD would not prevent binding to the receptor. However, coupling of GABA amides with long chain PEG tethers studied by another group member resulted in complete loss of agonist activity. We therefore ceased research in this particular area. 1,4-Benzodiazepin-2,5-diones display a wide range of pharmacological activities. Compounds containing the tricyclic proline-derived subtype have received attention as potent anxiolytic agents and as starting materials for anthramycin-inspired anticancer agents. More recently enantiopure (S)-proline-derived 1,4-benzodiazepin-2,5-diones have been recognized as selective α5 GABAA receptor ligands. Despite the impressive diversity of 1,4-benzodiazepine-2,5-diones prepared to date, enantiopure examples possessing a quaternary stereogenic center have been largely unexplored. "Memory of chirality" (MOC) is an emerging strategy for asymmetric synthesis. This technique enables the memory of a sole chiral center in the substrate to be retained in a process that destroys that center. We have used this technique to prepare a library of quaternary proline-derived, thioproline-derived and hydroxyproline-derived 1,4-benzodiazepin-2,5-diones, in high ee. We have developed an efficient synthetic method for preparing oxaproline-derived 1,4-benzodiazepin-2,5-diones in high yields, and by applying the MOC strategy we have prepared quaternary derivatives in acceptable %ee. We envision oxaproline-derived 1,4-benzodiazepin-2,5-diones may exhibit similar or more potent pharmacological properties than proline-derived 1,4-benzodiazepin-2,5-diones. Using density functional theory (DFT) methods, we modeled the formation of an enantiopure, dynamically chiral enolate intermediate and the slow racemization of the enolate on the alkylation reaction time scale.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2005

Author dc:creator

• MacQuarrie, Stephanie Lee

Chair dc:contributor.committeechair

• Carlier, Paul R.

Committee members dc:contributor.committeemember

• Long, Timothy E.
• Kingston, David G. I.
• Deck, Paul A.
• Tanko, James M.

• 1,4-Benzodiazepin-1,5-dione
• Density Functional Theory
• Memory of Chirality
• Agonist
• Asymmetric Synthesis
• Benzodiazepine
• Bivalent Ligand
• GABA_A Receptor
• Heterodimer

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

etd-12212005-223136

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/30209