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Synthesis of Selected Pyridazine-based Organic Compounds and Investigation of Their Inhibitory Effects Against Amyloid Formation

Ghasemi, Elham | 2015

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  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 47794 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Kalhor, Hamid Reza
  7. Abstract:
  8. At the molecular level, proteins control almost all the biochemical reactions in the cells. In order for proteins to function, they must be able to fold into their unique 3D structure. Deformation of protein structure due to some environmental phenomena such as pH, high temperature, and stress may cause unfolding of proteins and finally result in formation of protein fibrils called "amyloid". Amyloid has been found in a number of human diseases such as Alzheimer, type II diabetes, and Parkinson. Recently pyridazine has been under spotlight due to its unique chemical properties such as high dipole moment and higher solubility in biological solvents. In this study, we aim at using a pyridazine derivative as electrophile and using at a number of different nucleophiles, containing aromatic groups in order to synthesis novel anti- amyloid compounds. Our target synthses aim to produce products that are symmetric, flat molecules which contain hyrdoxyl groups. The products were synthesized in various conditions (temprature, solvent, base,…), and the major products were identified using 1HNMR, 13CNMR, CHN, IR techniques. Hen egg white lysozyme (HEWL) was used as a model protein to investigate the effects of novel compounds. HEWL was chosen because of its known unfolding pathway under low pH, and high temprature. The synthetic were examined against HEWL fibril formation. To invesigate the effects of pyridazine-based compounds on HEWL a number of biochemical methods were employed. These approches include dye specific binding (ThT) to β-sheet secondry structures in order to quantify fibril formation, gel electrophoresis to observe different kinetic steps protein fibrilation, FTIR to detect conformational changes during amyloid formation. The initial results shows that some of the synthesized compounds have inhibitory effects and prevented the lysozyme amyloid formation. In addition, synthesis of symmetrical compounds turned out to be difficult, and hydroxyl groups seem to be crucial for quantitative synthesis of symmetrical compounds
  9. Keywords:
  10. Amyloid ; Inhibitor ; Pyridazine-Based Organic Compounds ; Lysozyime Protein

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