Defense Date

10-1-2019

Graduation Date

Fall 12-20-2019

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Patrick Flaherty

Committee Member

Aleem Gangjee

Committee Member

Marc Harrold

Committee Member

Kevin Tidgewell

Committee Member

Jane E. Cavanaugh

Committee Member

Carl Anderson

Keywords

MEK5 CYCLOPHILIN SIGMA SMALL MOLECULES DESIGN SYNTHESIS

Abstract

Cyclophilin A are a class of peptidyl-prolyl isomerases that catalyzes isomerization of the proline residue within a protein. Cyclophilin A plays an instrumental role in the pathogenesis of HIV and HCV virus. Using structure-based drug we designed and synthesized small molecule inhibitors of cyclophilin A. These inhibitors were biologically evaluated for their ability to inhibit WT HIV-1 inhibition.

Mitogen-Activated Protein Kinase signaling cascades plays a critical role in cancer cell survival, metastasis, and chemo-resistance. The MEK5/ERK5 pathway, which is a member of MAPK signaling cascade, is involved in cell survival, anti-apoptotic signaling, angiogenesis, and cell motility. It is found to be significantly upregulated in breast cancers especially triple-negative breast cancers (TNBC). Despite its strong correlation with cancer, the MEK5/ERK5 pathway remains under-explored due to the lack of selective small-molecule inhibitors. Using the x-ray crystal structure of known MEK1/2 inhibitors bound to MEK1/2 (PDB ID: 3EQC and 3SLS) the homology model of MEK5 was built, and along with medicinal chemistry approaches, it was utilized for the design of diphenylamine and 2-amino-3-carboxythiophene derivatives as selective MEK5 inhibitors. During the development of 2-amino-3-carboxythiophene derivatives as MEK5 inhibitors, Ullmann couplings reactions were optimized for the installation of aryl ring on the 2-amino position.

Alzheimer’s disease (AD) is characterized by the buildup of amyloid plaques, accumulation of neurofibrillary tangles, inflammation of the neurons, and neuronal loss leading to cognitive decline. Current drugs provide only brief symptomatic relief without modifying the underlying disease pathology. Emerging data suggest that inhibition of sigma-2 receptors has the potential to deliver disease-modifying AD drugs. Using pharmacophore analysis and analog-based drug design, two novel series of piperazine derivatives were synthesized as sigma-2 receptor antagonists.

Language

English

Available for download on Sunday, December 20, 2020

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