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Synthesis and Structural Activity Relationship (SAR) of Novel Pyridazine-based Inhibitors for Inhibition of Amyloid Fibril Formation, and Biosynthesis and Optimization of L-AsparaginaseII Enzyme for Hydrolysis of Non-Native Substrate

Nazari Khodadadi, Alireza | 2017

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  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 50722 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Kalhor, Hamid Reza
  7. Abstract:
  8. After proteins, one of the important biological macromolecules, are synthesized by ribosomes,they automatically reach their own special 3-D structure. This native structur or better known as folded state is what determines the function of a protein. In some situations, the proteins become misfolded leading to its lack of biological function through aggregation or fibril formation known as "amyloid". The amyloid fibrils have been shown to be a causative factor in nerve decay such as Alzheimer's. Therefore, inhibition of amyloid formation using different approaches such as synthetic organic and natural compounds has, recently, been under spotlight. A pyridazine basedcompound (RS-0406) has been found to effectively inhibit amyloid formation, but no experimental evidence has been reported about its mechanism of inhibition. In the present work, 15 novel pyridazine-based compounds as analogues of RS-0406, were designed and synthesized. The results indicated that in addition to H-bonding, bulkiness, substituted position and solubility may have significant roles in amyloid inhibition. Moreover, by performing Quantitative Quantitative structure–activity relationship (QSAR) method, a carboxylic functional group was predicted to have a more effective inhibitory effect than the original lead compound. As L-asparaginase enzyme is the most important antileukemic drug; the enzyme by converting asparagine to aspartate mediates its anitlukemia function. In addition to the medicinal effect of this enzyme, its application as a biocatalyst has captured our attention. In this part of the thesis, the cloning and expression of L-asparginase were achieved and the enzyme will further be used to modify its active sites for novel organic reaction
  9. Keywords:
  10. Amyloid ; Cloning ; Pyridazine-Based Organic Compounds ; Quantitative Structure-Activity Relationship (QSAR)Model ; Asparaginase Enzyme ; Protein Misfolding ; Lysozyime

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