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Small Organic Molecules as Tunable Tools for Biology


Unzue Lopez, Andrea. Small Organic Molecules as Tunable Tools for Biology. 2015, University of Zurich, Faculty of Science.

Abstract

Drug discovery and development is a very challenging interdisciplinary endeavor that needs the contribution of medical doctors, biologists, chemists, X-ray crystallographers, and computer scientists, among many others, in order to be successful.
The first part of this Ph. D. thesis focuses on the development of EphB4 receptor tyrosine kinase inhibitors. EphB4 has been linked to angiogenesis, which involves the formation of new blood vessels supplying tumor cells with the necessary nutrients. Protein kinases play a key role in cell signaling by phosphorylating specific proteins and thus, the inhibition of their enzymatic activity by small organic molecules has been widely explored in drug design. In this work, the biological properties of an EphB4 inhibitor identified by computer simulations were improved by the synthesis of several analogues. Their binding affinities were characterized by an array of biochemical and cell based assays, concluding with the validation of one of the most promising derivatives in an in vivo cancer xenograft model.
The second part of the thesis deals with the development of novel bromodomain ligands starting from a micromolar potent in silico discovered hit. Bromodomain proteins are epigenetic readers that constitute an emerging topic in the field of drug discovery and are thus considered as very attractive targets for the development of novel therapeutic drugs. A careful, structure-based design of analogues resulted in the discovery of nanomolar potent CREBBP ligands with an unprecedented selectivity profile among the bromodomain protein family. Moreover, the screening of the synthesized analogues against several cancer cell lines revealed leukemia as a possible therapeutical application for the developed compounds.
The third aspect of this work deals with actin: a very attractive, but yet unexplored target in medicinal chemistry. Actin is a cytoskeletal protein that participates in many important cellular functions and has been linked to key pathogenic cellular processes such as angiogenesis, cell adhesion, cytokinesis and metastasis. A new computational approach to discover novel actin leads targeting the ATP binding site of actin resulted in the selection of promising compounds, which were synthesized and tested. The developed small organic molecules constitute valuable tools for the study of actin dynamics as they are able to modify the actin cytoskeleton in cells and moderately inhibit actin polymerization in vitro; thus becoming promising starting hits for the development of more potent actin binders.
The last part of this Ph.D. thesis describes the synthesis of neuroprotective compounds by the development of fumaric acid and hydroxytyrosol conjugates, for which the corresponding receptor is unknown. The biological effects of the synthesized analogues are currently under investigation, but the synergistic effect of fumaric acid and hydroxytyrosol is expected to be beneficial in the context of neuroprotection.

Abstract

Drug discovery and development is a very challenging interdisciplinary endeavor that needs the contribution of medical doctors, biologists, chemists, X-ray crystallographers, and computer scientists, among many others, in order to be successful.
The first part of this Ph. D. thesis focuses on the development of EphB4 receptor tyrosine kinase inhibitors. EphB4 has been linked to angiogenesis, which involves the formation of new blood vessels supplying tumor cells with the necessary nutrients. Protein kinases play a key role in cell signaling by phosphorylating specific proteins and thus, the inhibition of their enzymatic activity by small organic molecules has been widely explored in drug design. In this work, the biological properties of an EphB4 inhibitor identified by computer simulations were improved by the synthesis of several analogues. Their binding affinities were characterized by an array of biochemical and cell based assays, concluding with the validation of one of the most promising derivatives in an in vivo cancer xenograft model.
The second part of the thesis deals with the development of novel bromodomain ligands starting from a micromolar potent in silico discovered hit. Bromodomain proteins are epigenetic readers that constitute an emerging topic in the field of drug discovery and are thus considered as very attractive targets for the development of novel therapeutic drugs. A careful, structure-based design of analogues resulted in the discovery of nanomolar potent CREBBP ligands with an unprecedented selectivity profile among the bromodomain protein family. Moreover, the screening of the synthesized analogues against several cancer cell lines revealed leukemia as a possible therapeutical application for the developed compounds.
The third aspect of this work deals with actin: a very attractive, but yet unexplored target in medicinal chemistry. Actin is a cytoskeletal protein that participates in many important cellular functions and has been linked to key pathogenic cellular processes such as angiogenesis, cell adhesion, cytokinesis and metastasis. A new computational approach to discover novel actin leads targeting the ATP binding site of actin resulted in the selection of promising compounds, which were synthesized and tested. The developed small organic molecules constitute valuable tools for the study of actin dynamics as they are able to modify the actin cytoskeleton in cells and moderately inhibit actin polymerization in vitro; thus becoming promising starting hits for the development of more potent actin binders.
The last part of this Ph.D. thesis describes the synthesis of neuroprotective compounds by the development of fumaric acid and hydroxytyrosol conjugates, for which the corresponding receptor is unknown. The biological effects of the synthesized analogues are currently under investigation, but the synergistic effect of fumaric acid and hydroxytyrosol is expected to be beneficial in the context of neuroprotection.

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Additional indexing

Item Type:Dissertation
Referees:Nevado Cristina, Caflish Amedeo, Brunner Damian
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2015
Deposited On:22 Jan 2015 13:32
Last Modified:05 Apr 2016 18:55

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