Design and Synthesis of Benzimidazoles as CDK5 Inhibitors and Progress toward the Total Synthesis of Tubulysin D

This thesis describes the design and synthesis of 1,4,6-trisubstituted benzimidazoles as CDK5 inhibitors and the progress toward the total synthesis of tubulysin D.</p><p> Tubulysin is a natural product with potential anti-cancer activity. The two gamma-amino acids in the Tuv and Tup fragments of tubulysin were synthesized. Evans' oxazolidinone chemistry was employed for the stereoselective synthesis of Cbz-beta-homovaline in Tuv fragment. A crystal structure of the Tup fragment was obtained.</p><p> Cyclin dependent kinase 5 (CDK5) is one of the kinases that can hyperphosphorylate tau. Selective inhibition of the CDK5/p25 complex may be a useful component for Alzheimer's disease therapy. Benzimidazole based analogs of the known non-selective CDK5 inhibitor (R)-Roscovitine were designed. Synthesis of 6-benzyl substituted benzimidazole analogs was developed and two compounds were synthesized in this series. Two methods of the synthesis of 6-(2-hydroxy-1-alkyl)amino substituted benzimidazole analogs were developed.

Name thesis:degree_name

MS

Level thesis:degree_level

Immediate Access

Discipline thesis:degree_discipline

Medicinal Chemistry

Year dc:date.available

2009

Author dc:creator

• Yi, Shuyan

Contributors dc:contributor

• Patrick Flaherty
• Aleem Gangjee
• Marc Harrold
• David Lapinsky

• Kinase
• Benzimidazole
• Cyclin dependent kinase
• Alzheimer's disease
• Tubulysin
• Neurofibrillary tangles

Language dc:language

English

Repository record dc:identifier

https://dsc.duq.edu/etd/1392

OAI identifier oai:identifier

oai:dsc.duq.edu:etd-2408