Defense Date
3-3-2009
Graduation Date
Spring 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
Language
English
Recommended Citation
Yi, S. (2009). Design and Synthesis of Benzimidazoles as CDK5 Inhibitors and Progress toward the Total Synthesis of Tubulysin D (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1392