Expanding the Heterocyclic Repertoire of DNA Minor Groove Binding Polyamides PDF Download
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Author: Khalid Aman
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Chapter 1 introduces the regulation of gene expression using MGB small molecules.Chapter 2 describes the synthesis of hairpin polyamides, starting with the building blocks and then the solid phase synthetic protocol for constructing 8-ring hairpin polyamides.Chapter 3 showcases the thermal UV melt data, and examines the polyamide binding kinetics with DNA duplexes. Further insight into the binding was obtained with switchSENSE® technology, which allowed the generation of kinetic rate maps. The data outlined in this chapter enabled the profiling of the kinetic parameters that govern PA-dsDNA binding.Chapter 4 provides a structural view of a novel iPr-Im-containing polyamide-DNA complex, highlighting the closer proximity of the N-terminal iPr-Im N2 to the exocyclic amine of G5 compared with the N-terminal iPr-Nt analogue. Furthermore, the 3D NMR-restrained molecular dynamics (MD) structure indicated the major groove compression was greater for polyamide with the terminal iPr-Im monomer compared with the Me-Im analogue, highlighting the importance of a seemingly subtle change in steric bulk facing away from the minor groove for augmenting structural distortion of the DNA duplex.Chapter 5 takes the key findings of this thesis and uses them as a lens for looking to the future direction that this research may take. Namely, the potential of this novel iPr-Im monomer unit to replace imidazole as a G-selective residue that can induce greater structural distortion of the DNA duplex by polyamides.
Author: Khalid Aman
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Chapter 1 introduces the regulation of gene expression using MGB small molecules.Chapter 2 describes the synthesis of hairpin polyamides, starting with the building blocks and then the solid phase synthetic protocol for constructing 8-ring hairpin polyamides.Chapter 3 showcases the thermal UV melt data, and examines the polyamide binding kinetics with DNA duplexes. Further insight into the binding was obtained with switchSENSE® technology, which allowed the generation of kinetic rate maps. The data outlined in this chapter enabled the profiling of the kinetic parameters that govern PA-dsDNA binding.Chapter 4 provides a structural view of a novel iPr-Im-containing polyamide-DNA complex, highlighting the closer proximity of the N-terminal iPr-Im N2 to the exocyclic amine of G5 compared with the N-terminal iPr-Nt analogue. Furthermore, the 3D NMR-restrained molecular dynamics (MD) structure indicated the major groove compression was greater for polyamide with the terminal iPr-Im monomer compared with the Me-Im analogue, highlighting the importance of a seemingly subtle change in steric bulk facing away from the minor groove for augmenting structural distortion of the DNA duplex.Chapter 5 takes the key findings of this thesis and uses them as a lens for looking to the future direction that this research may take. Namely, the potential of this novel iPr-Im monomer unit to replace imidazole as a G-selective residue that can induce greater structural distortion of the DNA duplex by polyamides.
Author: Giacomo Padroni
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Pyrrole-Imidazole (Py-Im) hairpin polyamides are a programmable class of compounds that bind in the minor groove of double-stranded DNA (dsDNA). The hairpin conformationenables sufficient flexibility to form a side-by-side arrangement within the minor groove of target dsDNA sequences. An Im-Py pair discriminates G over C, A and T, whereas a Py-Pypair binds A and T over C and G. The possibility to target specific dsDNA sequences enables polyamides to modulate gene expression by the disruption of transcription factors such as the androgen receptor, over expressed in prostate cancer. A current limitation of the biological applications of Py-Im polyamides is their variable cell permeability profile. Im-richpolyamides tend to have reduced cellular and nuclear uptake in eukaryotic cells. Although modifications to the periphery of the polyamide scaffold have been explored at length, there has been limited studies on tuning the physicochemical properties of the G-recognising Imunit. This thesis describes the preparation and the evaluation of the binding mode of hairpin polyamides with Im units replaced by a series of 5-substituted 2-amino-4-carboxylic thiazole(Nt) building blocks. Chapter 1 introduces the endogenous and exogenous DNA recognition by protein and small molecules, the modulation of gene expression using Py-Im polyamides and the limitations of this approach. Chapter 2 describes the preparation of the building blocks and the optimisation of the solid phase synthesis of hairpin polyamides containing Nt units. These optimised conditions were used for the preparation of a suite of 8-ring polyamides incorporating Nt in different positions of the polyamide scaffold. Expanding the DNA binding repertoire of Pyrrole-Imidazole polyamides Chapter 3 describes the evaluation of the binding mode of Nt-containing polyamides using a combination of biophysical and biochemical methods. The 5-isopropyl substituted Nt (iPrNt) building block was identified as an alternative to Im for targeting G when incorporated at theN-terminus of the polyamide scaffold. Chapter 4 describes the structural characterisation of three selected polyamides binding to their dsDNA target sequence using NMR spectroscopy and molecular dynamics. This study reveals that the polyamide containing iPrNt at the N-terminus induces a greater compression of the major groove compared to the Im-containing analogue. Finally, Chapter 5 reflects on the work of this thesis and offers some perspective of the future development of Py-Im polyamides as gene expression modulators.
Author: Scott Reynolds Carter
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 396
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Book Description
Author: Stephen Neidle
Publisher: Elsevier
ISBN: 0080553524
Category : Science
Languages : en
Pages : 302
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Book Description
This unique and practical resource provides the most complete and concise summary of underlying principles and approaches to studying nucleic acid structure, including discussion of x-ray crystallography, NMR, molecular modelling, and databases. Its focus is on a survey of structures especially important for biomedical research and pharmacological applications. To aid novices, Principles of Nucleic Acid Structure includes an introduction to technical lingo used to describe nucleic acid structure and conformations (roll, slide, twist, buckle, etc.). This completely updated edition features expanded coverage of the latest advances relevant to recognition of DNA and RNA by small molecules and proteins. In particular, the reader will find extensive new discussions on: RNA folding, ribosome structure and antibiotic interactions, DNA quadruplexes, DNA and RNA protein complexes, and short interfering RNA (siRNA). This handy guide ends with a complete list of resources, including relevant online databases and software. - Completely updated with expanded discussion of topics such as RNA folding, ribosome structure and antibiotic interactions, DNA quadruplexes, DNA and RNA protein complexes, and short interfering RNA (siRNA) - Includes a complete list of resources, including relevant online databases and software - Defines technical lingo for novices
Author: George W. Gokel
Publisher: Elsevier
ISBN: 0128031999
Category : Science
Languages : en
Pages : 4627
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Book Description
Comprehensive Supramolecular Chemistry II, Second Edition, Nine Volume Set is a ‘one-stop shop’ that covers supramolecular chemistry, a field that originated from the work of researchers in organic, inorganic and physical chemistry, with some biological influence. The original edition was structured to reflect, in part, the origin of the field. However, in the past two decades, the field has changed a great deal as reflected in this new work that covers the general principles of supramolecular chemistry and molecular recognition, experimental and computational methods in supramolecular chemistry, supramolecular receptors, dynamic supramolecular chemistry, supramolecular engineering, crystallographic (engineered) assemblies, sensors, imaging agents, devices and the latest in nanotechnology. Each section begins with an introduction by an expert in the field, who offers an initial perspective on the development of the field. Each article begins with outlining basic concepts before moving on to more advanced material. Contains content that begins with the basics before moving on to more complex concepts, making it suitable for advanced undergraduates as well as academic researchers Focuses on application of the theory in practice, with particular focus on areas that have gained increasing importance in the 21st century, including nanomedicine, nanotechnology and medicinal chemistry Fully rewritten to make a completely up-to-date reference work that covers all the major advances that have taken place since the First Edition published in 1996
Author: American Chemical Society
Publisher:
ISBN:
Category : Chemistry
Languages : en
Pages : 1450
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Book Description
Author: Michael J Waring
Publisher: Royal Society of Chemistry
ISBN: 1788014286
Category : Science
Languages : en
Pages : 432
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Book Description
There have been remarkable advances towards discovering agents that exhibit selectivity and sequence-specificity for DNA, as well as understanding the interactions that underlie its propensity to bind molecules. This progress has important applications in many areas of biotechnology and medicine, notably in cancer treatment as well as in future gene targeting therapies. The editor and contributing authors are leaders in their fields and provide useful perspectives from diverse and interdisciplinary backgrounds on the current status of this broad area. The role played by chemistry is a unifying theme. Early chapters cover methodologies to evaluate DNA-interactive agents and then the book provides examples of DNA-interactive molecules and technologies in development as therapeutic agents. DNA-binding metal complexes, peptide and polyamide–DNA interactions, and gene targeting tools are some of the most compelling topics treated in depth. This book will be a valuable resource for postgraduate students and researchers in chemical biology, biochemistry, structural biology and medicinal fields. It will also be of interest to supramolecular chemists and biophysicists.
Author:
Publisher:
ISBN:
Category : Dissertations, Academic
Languages : en
Pages : 782
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Book Description
Author: American Chemical Society. Committee on Professional Training
Publisher:
ISBN:
Category : Biochemistry
Languages : en
Pages : 1932
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Book Description
Faculties, publications and doctoral theses in departments or divisions of chemistry, chemical engineering, biochemistry and pharmaceutical and/or medicinal chemistry at universities in the United States and Canada.
Author: Wolfram Saenger
Publisher: Springer Science & Business Media
ISBN: 1461251907
Category : Science
Languages : en
Pages : 574
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Book Description
New textbooks at all levels of chemistry appear with great regularity. Some fields like basic biochemistry, organic reaction mechanisms, and chemical ther modynamics are well represented by many excellent texts, and new or revised editions are published sufficiently often to keep up with progress in research. However, some areas of chemistry, especially many of those taught at the grad uate level, suffer from a real lack of up-to-date textbooks. The most serious needs occur in fields that are rapidly changing. Textbooks in these subjects usually have to be written by scientists actually involved in the research which is advancing the field. It is not often easy to persuade such individuals to set time aside to help spread the knowledge they have accumulated. Our goal, in this series, is to pinpoint areas of chemistry where recent progress has outpaced what is covered in any available textbooks, and then seek out and persuade experts in these fields to produce relatively concise but instructive introductions to their fields. These should serve the needs of one semester or one quarter graduate courses in chemistry and biochemistry. In some cases the availability of texts in active research areas should help stimulate the creation of new courses. CHARLES R. CANTOR New York Preface This monograph is based on a review on polynucleotide structures written for a book series in 1976.
