University of Groningen
Target-based drug discovery: from protein structure to small-molecules by MCR chemistry Wang, Yuanze
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Publication date: 2018
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Wang, Y. (2018). Target-based drug discovery: from protein structure to small-molecules by MCR chemistry. University of Groningen.
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Summary
In Chapter 1, we give an overview of target-based drug discovery. High throughtput screening, fragment-based drug discovery, protein as drug target, protein expression, purification, refolding and crystallization are briefly introduced. Meanwhile, “privileged scaffolds” synthesized by MCR chemistry, especially Ugi reaction and its post-cyclization, are concluded by Scheme.
In Chapter 2, we established a systematic protein refolding method which contains a primary pH-refolding screening and a secondary additive screening. Four different proteins: HA-RBD, MDM2, IL-17A and PD-L1 were used to validate our refolding approach. Our systematic protocol evaluates the impact of the “helper” molecules, the pH, buffer system and time on the protein refolding process in a high-throughput fashion. In addition, we demonstrated that refolding time and a secondary thermal shift assay buffer screen are critical factors for improving refolding efficiency.
In Chapter 3, two positional isomeric monosubstituted tetrazole libraries was prepared in a convenient and fast procedure. This new method has several advantages: mild reaction conditions, short reaction time, easy work up and broad substrate scope. With more and more drug candidates originated from fragment-based lead discovery have been progressed into clinical trials, the efficient build-up of fragment libraries containing ‘drug-like’ fragments like tetrazole is of great importance.
In Chapter 4, the application of mono-Boc-protected hydrazine in the Ugi-terazole synthesis and its post-cyclization has been explored. By using α-amino acid derived isocyanides as starting material, 7-aminotetrazolopyrazinones and tetrazolotriazepinones were afforded in one-pot under acidic conditions. In addition, Boc-protected 7-aminotetrazolopyrazinones were obtained under basic
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condition in good to excellent yield. Moreover, the exposed free primary amine could be further used as the building block to synthesize more complex compounds.
In Chapter 5, the isoquinoline derivatives and benzo[d]azepine derivatives were successfully constructed by new Ugi/Pomeranz-Fritsch reaction. Meanwhile, this methodology has also been applied to the Ugi-tetrazole reaction to afford the isoquinoline-tetrazole derivatives.
In Chapter 6, isoquinoline drivatives and heterocyclic compounds were constructed by Ugi/Schlittler–Müller reaction in good yield.
