Abstract
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.