Defense Date
3-17-2010
Graduation Date
2010
Availability
Immediate Access
Submission Type
thesis
Degree Name
MS
Department
Medicinal Chemistry
Committee Chair
Patrick Flaherty
Committee Member
Aleem Gangjee
Committee Member
Marc Harrold
Committee Member
David Lapinsky
Committee Member
Jane Cavanaugh
Keywords
Benzimidazoles, Diphenylamine, Flavones, MEK-5, Ortho-Carboxyamide, Tubulysin
Abstract
CDK-5 is associated with hyperphosphorylation of the microtubule-associated protein tau, formation of neurofibrillary tangles, and possibly an acceleration of the neurodegenerative progression of Alzheimer's disease. C6-O linked benzimidazoles and C-4 benzamide and phenylacetamide benzimidazoles based on (R)-Roscovitine, a non-selective inhibitor of CDK-5 were designed and synthesized.
MEK-5, a member of the MAPK family, phosphorylates ERK-5 permitting cells to survive oxidative stress. MEK-5 is upregulated in tumor cells and activated by mitogens; inhibition of this enzyme is a potential anti-cancer strategy. Scaffolds from the following classes--benzimidazole, diphenylamine, flavones, and ortho-carboxyamide were examined for their capacity to be developed into potent and selective MEK-5 inhibitors.
Tubulysin is a natural product that disrupts microtubule dynamics, blocks mitosis, and induces cell death. It has been examined as a potential anti-cancer agent in hollow fiber assays. Simple and reliable procedures were developed for the gram-scale synthesis of Mep-Ile dipeptide and Tup fragments of tubulysin.
Format
Language
English
Recommended Citation
Chopra, I. (2010). Design and Synthesis of CDK-5 and MEK-5 Inhibitors and Synthesis towards Tubulysin Analogs (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/404