| Summary: | 博士 === 國立臺灣大學 === 化學研究所 === 93 === This thesis is composed of two parts: the first part is to develop the novel organic synthetic methodology, such as the preparation of polysubstituted thiophenes, benzothiophenes and transformation of organic aldehydes in aqueous solution. The second part is to design and synthesize the SARS-CoV 3CL protease inhibitors.
Part I. Development of novel synthetic methodology
First, we describe the comparative study of TmI2, SmI2, and SmI2/ HMPA in the cross-coupling reactions of 2-acetylthiophene with carbonyl compounds. The reaction mode of TmI2 is found to be similar to that of SmI2/HMPA, but different from that of SmI2.
By a similar procedure, we have developed a three-step procedure for the preparation of polysubstituted benzothiophenes and the related sulfur-containing polycyclic aromatic compounds. By the promotion of SmI2/HMPA or TmI2, thiophene-2-carboxylate underwent a double- electrophilic reaction effectively with a variety of ketones, followed by acid-catalyzed dehydration and oxidative aromatization, to give a series of sulfur-containing polycyclic aromatic compounds that are not easily prepared by other approaches. This method is also applicable to the preparation of a novel photochromic system of 4,5-dialkenylthiophenes.
In another study, we have explored a new methodology using one-pot tandem reactions for the direct conversion of aldehydes to amides, tetrazoles, and triazines, via addition of H2O2, NaN3/ZnBr2, and dicyandiamide/KOH to the intermediate nitriles. These reactions are conducted smoothly by an initial treatment with iodine in aqueous ammonia, and the desired products are obtained simply by extraction or filtration.
Part II. Design and synthesis of SARS-CoV 3CL protease inhibitors
Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel variant of coronavirus (SARS-CoV). Currently, no effective drug exists to treat SARS-CoV infection.
In this study, we have explored efficient methods to synthesize nearly 700 compounds, including AG7088 and its analogs. Although the previous reports in the literature have predicted AG7088 may show antiviral activities against SARS 3CL protease, it turns out to be inactive by the cell-based assay. However, by our primary screening using fluorescence assay, we have found a number of potent 3CL protease inhibitors with various core structures, such as conjugated ester, indanol amide, aniline amide, thiazine, C2-symmetric diol and benzotriazole.
On the basis of these results, we thus set the specific aims to discover more potent 3CL protease inhibitors, such as peptidomimetic, unsaturated esters and anilide compounds. The most potent inhibitor 92 is an anilide derived from 2-chloro-4-nitroaniline, L-phenylalanine and 4-(dimethylamino)benzoic acid. This anilide is a competitive inhibitor of the SARS-CoV 3CL protease with Ki = 0.03 μM. Another protease
inhibitor 68o with an inhibition constant of 0.52 μM is obtained by
condensation of the Phe-Phe dipeptide α,β-unsaturated ester with
4-(dimethylamino)cinnamic acid. The cell-based assays also indicate that
68o is a nontoxic anti-SARS agent with an EC50 value of 0.18 μM.
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