Download or read book Design and synthesis of novel thienylpyridyl oligomers as alpha helix mimetics with protein protein interaction disrupting activity and possible biological applications written by Marcella De Giorgi and published by . This book was released on 2012 with total page 298 pages. Available in PDF, EPUB and Kindle. Book excerpt: Les interactions protéine-protéine (IPPs) représentent une classe importante de cibles thérapeutiques. En effet, la plupart des processus cellulaires sont composées ou influencés par les IPPs et leur disfonctionnement peut entraîner de nombreuses maladies. Même si les surfaces protéiques sont généralement larges, des éléments clés sont responsables de l'interaction et de la reconnaissance protéique (hot spots). La structure secondaire la plus commune dans les protéines naturelles est l’hélice alpha et les petites molécules semblent être des candidats intéressants pour perturber ces interactions protéine-protéine. Nous nous sommes particulièrement intéressés aux protéines de la famille Bcl-2 qui sont des régulateurs importants de l'apoptose. Elles sont surexprimées dans de nombreux cancers et contribuent à l'initiation tumorale, la progression et la résistance à la thérapie anticancéreuse. Le but de notre étude est de concevoir des petites molécules capables d'interagir avec les membres anti-apoptotiques et ainsi restaurer le mécanisme de l'apoptose mitochondriale. Nous avons synthétisé une chimiothèque d'oligomères de structure thiénylpyridine. Ces foldamères d’un genre nouveau imiteraient les éléments clés d'une surface protéique en mimant l'orientation spatiale des différents substituants d’une hélice alpha. La plupart de ces composés ont été engagée dans des étude.s de modélisation moléculaire associées à des résultats de radiocristallographie afin d'évaluer la capacité de mimes d’hélice alpha. Par ailleurs, l’évaluation biologique de ces composés a été réalisée et les premiers résultats montrent que nos composés sont capables de rompre les interactions protéine-protéine.
Download or read book Design and Synthesis of Alpha helix Mimetics for Protein protein Interactions written by Kajal A. Bhimani and published by . This book was released on 2010 with total page 150 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design and Synthesis of Substituted 1 4 hydrazine linked Piperazine 2 5 and 2 6 diones and 2 5 terpyrimidinylenes as alpha helical Mimetics written by Laura Anderson and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: ABSTRACT: The most common secondary structure of proteins is the alpha-helix. The alpha-helix can be involved in various protein-protein interactions (PPIs) through the recognition of three or more side chains along one face of the alpha-helix (Wells and McClendon, 2007). In recent years, there has been an increasing interest in the development of peptidic and non-peptidic compounds that bind to PPI surfaces. We focused on the design and synthesis of compounds that mimic the orientation of side chain residues of an alpha-helical protein domain. Although our scaffolds could potentially inhibit various PPIs, we focused mainly on the disruption of interactions among the Bcl-2-family of proteins and the Mdm-2-family of proteins to favor apoptosis in cancer cells. A summary of Bcl-2 and Mdm-2 structure and function relationships that focuses on the possibility of using peptidic and non-peptidic alpha-helical mimics as PPI inhibitors is described in Chapter One. Chapter Two discusses the design and synthesis of 3-substituted-2,6- and 2,5-piperazinedione oligomers as more hydrophilic scaffolds compared to previously reported alpha-helical mimetics (Yin, et al., 2005). A key feature of this design is the linkage of the units by a hydrazine bond. While we were able to prepare several monomers containing the hydrazine linkage, synthesis of the dimers and trimers is very challenging. Due to the difficulty of synthesizing oligomeric piperazine-diones in practical yields, we next focused on the design and synthesis of novel 2,5-terpyrimidinylene scaffolds as an alternative to obtain alpha-helical mimetics; this is discussed in Chapter Three. The main outcome of this project was the efficient preparation of a "first-generation" non-peptidic compound library via a facile iterative synthesis enabled by the key conversion of 5-cyanopyrimidine to 5-carboxamidine. Chapter Three also discusses our progress towards the synthesis of structurally similar substituted-2,5-terpyrimidinylenes, but with more drug-like properties as determined by QikProp calculations. Chapter Four describes an independent study on the synthesis of a guanidine derivative as an alkylating agent for the synthesis of cysteine peptide nucleic acids, CPNA, which is another current project in our lab.
Download or read book The Enzymes written by Edwin G. Krebs and published by Academic Press. This book was released on 1970 with total page 676 pages. Available in PDF, EPUB and Kindle. Book excerpt:
