The Syntheses Of6-(p-Tolyl)Benzo[f]Pyrido[2,3-b][1,4]Thiazepine11,11-Dioxide Derivatives As Molecular Probes And Their Anti-Cancer Activity

This thesis deals with the syntheses of6-(p-tolyl)benzo[f]pyrido[2,3-b][1,4]thiaz-epine11,11-dioxide derivatives and their anti-cancer activity. Based on the leadcompounds, activity-based probes (ABP) were designed and synthesized. It consistsof three chapters.The first chapter summarized the biological activity of pyrido[2,3-b][1,4]thiazepi-nes. CDS2086was identified in cell based assays as a lead compound with goodanti-proliferative activities against several cancer cell lines through the screening ofour in-house compound library. The mechanism-of-action of CDS2086is notknown. In our follow up study, CDS2086and its derivatives also showed lowaqueous solubility. This thesis focuses on the development of structure activityrelationship around CDS2086to improve their solubility, as well as the design andsyntheses molecular probes for target identification.Two general approaches for enhancing aqueous solubility of drug candidateswere described with literature examples.In addition, this chapter also summarized the methods for target discovery,including the concept, structure, mechanism and the synthesis of activity-basedprobes(ABP). The ABPs were classified according to their target enzyme classes.Recent researches in the area of ABP from other laboratories were also summarized. In the second chapter, the syntheses of6-(p-tolyl)benzo[f]pyrido[2,3-b][1,4]thiaz-epine11,11-dioxide derivatives were described, which can be divided into three parts:further study of the structure-activity relationship of CDS2086analogs; the selectionof proper linker to form a ABP precursor; enhancing the aqueous solubility ofCDS2086via the incorporation of polar functionalities at various positions.In the third chapter, the syntheses of ABPs based on CDS2086were described, inwhich a fluorescent probe and a biotin probe were incorporated, respectively.The ABP precursors synthesized by us have similar biological activity in the cellbased assays, therefore we selected the derivative whose preparation is the moststreightforward as the final ABP precursor. This precursor underwent hydrolysis,acylation, deprotection, and react with activated intermediates of biotin andfluorescein to furnish the ABPs in the end.The research work represented above laid the foundation for further study of thestructure-activity relationship and solubility of CDS2086analogs. We successfullysynthesized two ABPs of CDS2086which can be used for the studymechanism-of-action of CDS2086.