UC San Diego

Chapter 1. The first chapter discusses the background of peptides and their potential as drugs. The methodologies for peptide synthesis via solution and solid-phase as well as macrocyclization strategies for cyclic peptides. Cyclic peptides' biological activity and the challenges for peptide drug development. Chapter 2. This chapter emphasizes on the design, synthesis and Structural Activity Relationship (SAR) of San A derivatives. Six novel San A derivatives were designed based on the structural features of developed potent San A derivatives. The structural modifications of novel San A derivatives included : 1) D-amino acid incorporation, 2) insertion of N-Me-amino acid, and 3) Aliphatic size chain reduction. The cytotoxicity of synthesized San A derivatives were exanimated against pancreatic cancer cell line PL-45 using 3H-Thymidine incorporation assay. The biological results and SAR studies of six novel San A derivatives were discussed in this chapter. Chapter 3. Histone deacetylase (HDACs) are a class of enyzmes that are responsible for regulating the acetylation state of the histones. In many cancers, overexpression of HDACs is observed resulting hypoacetylation state of histones and improper gene transcriptions, which leads to tumor progression. Thus, the development of novel HDIs is critical for combating cancers. Chapter 3 focuses on the design and synthesis of novel Histone Deacetylase Inhibitors (HDIs) based on two cyclic tetrapeptide natural products: FR235222 and trapoxin B. The biological test results of developed novel HDIs and the discussion of structure-activity relationship are also presented. Chapter 4. Urukthepelstatin A (Ustat A) is a macrocyclic compound, which composed of a heterocyclic backbone and a peptide segment. Ustat A exhibits potent anti-tumor activity (GI₅₀ = 15.5 nM) and its biological mechanism varies from other structurally similar scaffolds. Thus, the development of Ustat A provides an opportunity to explore a novel cell-survival pathway. In chapter 4, a convergent synthetic approach for Ustat A and its derivatives was described. Ustat A derivatives were designed based on heterocycle placement strategy, which was never reported in literature. In this chapter, the synthesis of linear precursor and the cyclization attempt for Ustat A derivative Ustat A-2 were presented