翁啟惠臺灣大學：生化科學研究所邵奕鳴Shao, Yi-MingYi-MingShao2007-11-262018-07-062007-11-262018-07-062006http://ntur.lib.ntu.edu.tw//handle/246246/52756Severe acute respiratory syndrome (SARS) is a new viral infectious disease caused by a novel coronavirus (SARS-CoV). Currently, no effective antiviral agents exist against this type of virus. This thesis comprises the design, synthesis, biological activity, and complexed structures of two types of small molecules as inhibitors of SARS-CoV 3CL protease: (i) trifluoromethyl ketones and (ii) C2-symmetric diols. Trifluoromethyl ketones are known to be reversible inhibitors of some serine proteases, such as elastase and chymotrypsin. The best one of a series of trifluoromethyl ketones synthesized is a tetrapeptidyl trifluoromethyl ketone with Ki value of 0.286 μM against SARS-CoV 3CL protease, a cysteine protease. In addition, TL-3, a potent inhibitor of HIV protease, was previously found to show inhibition (Ki = 0.6 μM) against SARS-CoV 3CL protease. Without guidance of the crystal structure of this enzyme in complex with TL-3, optimization of this inhibitor was performed based on computational modeling prediction. Aided by modeling, two novel TL-3 derivatives 163 and 168 with indole instead of benzyl group as the core were synthesized. These two new compounds were proved to be more effective inhibitors (Ki = 0.340 and 0.073 μM, respectively) than TL-3 for SARS-CoV 3CL protease. The interactions between 163 and SARS-CoV 3CL protease were determined using the combination of X-ray crystallography and computer modeling, and an molecular insight of small molecule-biological target interactions was disclosed.Chapter 1 Introduction........................................................................................ 1 1.1 Severe Acute Respiratory Syndrome (SARS)…………………………...1 1.2 SARS-CoV……………………………………………………………... 1 1.3 SARS-CoV 3CL Protease and its Inhibitors…………………………….5 1.4 References……………………………………………………………...13 Chapter 2 Trifluoromethyl Ketones...............................................................16 2.1 History of Development…………………………………………........ 16 2.2 Synthesis of Trifluoromethyl Ketones………………………………...20 2.3 Biological Activity………………………………………………….....33 2.4 Crystal Structure Analysis & Computer Modeling…………………....41 2.5 Experimental Section……………………………………………….....42 2.6 References…………………………………………………………......67 Chapter 3 C2-Symmetric Diols……………………………………………… 70 3.1 History of Development……………………………………………….70 3.2 Synthesis and Activity of C2-Symmetric Diols………………………..77 3.3 Crystal Structure Analysis & Computer Modeling…………..............106 3.4 Experimental Section………………………………………………...108 3.5 References……………………………………………………………181 3.6 Thesis Summary……………………………………………………...184 Appendix Selected Spectra…………………………………………………. 18517869313 bytesapplication/pdfen-US蛋白酶抑制劑三氟甲基酮C2-對稱雙醇電腦模型X光結晶學protease inhibitorstrifluoromethyl ketonesC2-symmetric diolscomputer modelingX-ray crystallography[SDGs]SDG3otherhttp://ntur.lib.ntu.edu.tw/bitstream/246246/52756/1/ntu-95-R92b46018-1.pdf