Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Peng George Wang

Second Advisor

Jun Yin

Third Advisor

Gangli Wang


O-glycosylation is a common and complex post-translational modification of many biomolecules. While this dissertation will focus on the glycosylation with proteins, other types of biomolecules are also known to couple with glycans, most notably lipids. Protein glycosylation is usually divided into three different kinds of groups based on the first atom which links the glycan with the protein: N-type, O-type and the rare C-type. O-Glycosylation, the subject of this dissertation, is the glycans attached to the oxygen of the hydroxyl group on serine (Ser) or threonine (Thr) residue.

Chapter 1 describes a strategy for the synthesis of O-mannosyl glycan. O-Mannosylation is a vital protein modification involved in brain and muscle development, whereas the biological relevance of O-mannosyl glycans remains largely unknown, due to the lack of structurally defined glycoforms. An efficient scaffold synthesis/enzymatic extension (SSEE) strategy was thus developed to prepare such structures, by combining gram-scale convergent chemical synthesis of 3 scaffolds and strictly controlled sequential enzymatic extension catalyzed by glycosyltransferases. Totally, 45 O-mannosyl glycans were obtained, covering majority of identified mammalian structures. Subsequent glycan microarray analysis revealed fine specificities of glycan-binding proteins and specific antisera.

In chapter 2, we try to develop a new method to achieve O-GalNAc glycan from cell. Protein O-glycosylation is a universal post-translational modification that plays an essential role in many biological regulations. Recently we reported a technology termed Cellular O-Glycome Reporter/Amplification (CORA) to amplify and profile mucin-type O-glycans from living cells. However, the application and development of the CORA method is litmted by the precursor function. Here we described a rapid parallel synthesis of cellular O-glycome precursors via microwave assisted reaction. In total, 26 Ac3GalNAc-α-Bn derivatives, including fluorescent and other reactive functional groups, were successfully synthesized. Furthermore, subsequent activity screening and evaluation of these precursor toward living cell and T-synthase were performed.

In chapter 3, the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC was reported. Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. In this study, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in a low micro-molar range in cell based assays.

Available for download on Wednesday, December 02, 2020