Total Synthesis of an Analog of Hydramycin and Derivatization of Thiol-terminated Carbohydrates and Development of a Glycoconjugate Too Set for the Assembly and Presentation of Carbohydrate Ligands on Surfaces

2-(1,2-Dihydroxy-1-(oxiran-2-yl)ethyl)-11-hydroxy-5-methyl-1Hnaphtho[ 2,3-h]chromene-4,7,12-trione (1), a pyranoanthraquinone isolated from Streptomyces violaceus P950-4, showed a potent antibacterial and cytotoxic activity. A model synthesis for analogs 2-(1,2-dihydroxy-1-(oxiran-2-yl)ethyl)-4H-chromen- 4-one (2) and2-(1-hydroxy-1-(oxiran-2-yl)ethyl)-1H-naphtho[2,3- h]chromene-4,7,12-trione (3) was developed by Dr. David White and Dr. Sarah Headrick. A new analog, 2-(1,2-dihydroxy-1-(oxiran-2-yl)ethyl)-1H-naphtho[2,3- h]chromene-4,7,12-trione (4), was designed to be structurally more similar to hydramycin with –CH2OH functionality on the pyranone ring and anthraquinone skeleton. Therefore, it is expected to have greater anticancer activity than either analogs 2 or 3. This dissertation will cover developments, challenges and solutions in the total synthesis of the analog 4.

Both eukaryotic and prokaryotic cell surfaces present a complex set of glycoconjugates. Glycoconjugates contain carbohydrates covalently linked to another building block of nature, such as an amino acid (peptide) or a lipid. Since most glycans, which are complex arrays of covalently attached sugar chains, are on the outer surface of cellular and secreted macromolecules, they are in a position to modulate or mediate a wide variety of events in cell–cell, cell–matrix, cell–surface, cell–virus and cell–molecule interactions. These interactions mediate cell adhesion, cell motility, and cell–cell communication and recognition of toxins. This dissertation is focused on the development of a glycoconjugate“tool set”, that will facilitate a modular approach to glycoarrays. The development consists of a derivatization of thiol-terminated mannose and galactose that will mimic the glycans on the cell surfaces, creation of nano-patterned microarray surfaces for the introduction of carbohydrates, and examination of the arrays by interrogation with fluorescently labeled probes.