School of Pharmacy
Kinase, Benzimidazole, Cyclin dependent kinase, Alzheimer's disease, Tubulysin, Neurofibrillary tangles
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.
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