Design and synthesis of CDK-5 and MEK-5 inhibitors and synthesis towards tubulysin analogs.

摘要

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 nonselective 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.