Author

Shuyan Yi

Defense Date

3-3-2009

Graduation Date

2009

Availability

Immediate Access

Submission Type

thesis

Degree Name

MS

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Patrick Flaherty

Committee Member

Aleem Gangjee

Committee Member

Marc Harrold

Committee Member

David Lapinsky

Keywords

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

Abstract

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.

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.

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.

Format

PDF

Language

English

Share

COinS