This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Medicinal Chemistry / PhD / Dissertation
| Identifer | oai:union.ndltd.org:DUQUESNE/oai:digital.library.duq.edu:etd/154084 |
| Date | 16 December 2013 |
| Creators | Jain, Prashi |
| Contributors | Patrick T. Flaherty, Aleem Gangjee, Marc W. Harrold, David J. Lapinsky, Jeffry D. Madura, James K. Drennen |
| Source Sets | Duquesne University |
| Detected Language | English |
| Rights | One year embargo: no access to PDF file until release date by author request. |
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