本論文主旨在研究設計與合成新穎組織蛋白酶S抑制劑，探討結構與活性的關係（structure-activity relationship，SAR），並進一步應用於抗癌症轉移之研究。研究方向分為二部分：第一部分係探討α-酮醯胺胜肽系列化合物之合成與抗癌轉移的研究；第二部分係探討醛基胜肽系列化合物之合成與抗癌轉移的研究。

首先我們利用Passerini multicomponent reaction(MCR)合成一系列α-酮醯胺胜肽化合物，建立一系列P3位置衍生物，進行芳香環取代基效應、脂環族骨架結構、提昇選擇性和氨基甲酸酯置換醯胺四個方向進行結構與活性關係的探討。

接著我們利用兩次醯胺偶合反應建構醛基胜肽系列化合物之主要片段方法，合成一系列組織蛋白酶S彈頭(warhead)位置衍生物，增加彈頭結構的多元性與新穎性，並進行結構與活性關係的探討。

總結本論文藉由建立α-酮醯胺胜肽系列和醛基胜肽系列兩系列衍生物之結構活性關係，尋找抑制組織蛋白酶S的最佳結構化合物，進行抗癌症轉移生理活性之研究。

This dissertation focuses on the design and synthesis of novel Cathepsin S inhibitors used as anticancer agents in metastasis research. For further detailed studies on structure-activity relationships (SARs), the research is subdivided into two parts: a) dipeptide synthesis of α-ketoamide series and it’s anticancer activity discussion; b) dipeptide synthesis of aldehyde series and it’s anticancer activity discussion.
Passerini multicomponent reaction is the key step for the synthesis of α-ketoamide. To construct structure-activity relationships, we focus on modifying analogues of P3 site series. Our strategy is divided into the following four parts: a) aromatic ring substitution effect; b) aliphatic ring size effect to compare it to the aromatic ring; c) enhancing selectivity for cathepsin S; and d) changing amide moiety to urea or thiourea.
The peptides of aldehyde series were constructed by double amide coupling to synthesize the main skeleton. We synthesized a series of warhead analogues to enhance the diversity and novelty and discovered the SARs of the aldehyde series.
We constructed the SARs for α-ketoamide peptide series and aldehyde peptides series in order to search the best cathepsin S inhibitor for further research on their role as anticancer agent in metastasis.

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