Matching Items (2)
Description
The 23-step total synthesis of dolastatin 16, a cyclic depsipeptide of marine origin, is presented. Included are syntheses of nonnatural amino acids dolamethylleuine and dolaphenvaline. The biological activity of the synthetic product differed from naturally isolated dolastatin 16, which may indicate the initial screening identified an inactive compound and the active one was not detected initially, or may be a result of the conformational dynamics induced by the proline residues. Additionally, a family of structural analogues to the bacillistatins, another cyclic marine depsipeptide, were synthesized. These were deemed the silstatins. 8 modifications were produced. The alterations aimed to introduce a heteroatomic residue for further derivatization, such as producing an antibody-drug conjugate. This introduction did in general decrease the neoplastic activity of these agents, as expected, but by modulating the lipophilicity of the compound we were able to salvage much of the potency of the bacillistatins while potentially allowing prodrug development.
ContributorsMacdonald, Christian B. (Author) / Pettit, George (Thesis director) / Wang, Xu (Committee member) / Melody, Noeleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Mathematical and Statistical Sciences (Contributor)
Created2015-05
Description
The purpose of this project is to explore the benefit of using prodrugs in chemotherapy, as well as to explain the concept of angiogenesis and the importance of this process to tumor development. Angiogenesis is the formation of new blood capillaries that are necessary for the survival of a tumor, as a tumor cannot grow larger than 1-2 mm3 without developing its own blood supply. Vascular disrupting agents, such as iodocombstatin, a derivative of combretastatin, can be used to effectively cut off the blood supply to a growing neoplasm, effectively inhibiting the supply of oxygen and nutrients needed for cell division Thus, VDAs have a very important implication in terms of the future of chemotherapy. A prodrug, defined as an agent that is inactive in the body until metabolized to yield the drug itself, was synthesized by combining iodocombstatin with a β-glucuronide linker. The prodrug is theoretically hydrolyzed in the body to afford the active drug by β-glucuronidase, an enzyme that is produced five times as much by cancer cells as by normal cells. This effectively creates a “magic-bullet” form of chemotherapy, known as Direct Enzyme Prodrug Therapy (DEPT).
ContributorsClark, Caroline Marie (Author) / Pettit, George Robert (Thesis director) / Melody, Noeleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2015-05