Synthesis and Biological Evaluation of Flavonoid Natural Products as Potential Anticancer Agents

• Main Author: Farmer, Rebecca Leigh
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2012
• Subjects: Biochemistry; Cancer; Chemical synthesis; Drug therapy; Molecular biology; Oncology; Organic chemistry
• ISBN: 9781267339584; 1267339586

The flavonoids are a family of small molecules derived from plants that are known for their structural diversity and potent biological activity. A great deal of attention has been focused on these compounds as potential cancer therapeutics due to their known antiproliferative, antiangiogenic and antioxidant activity. Despite this promising biological activity, there still remains a lack of effective and selective chemical methods to access the more complicated members of the flavonoid family, limiting the additional studies that can be performed to develop potent and selective anticancer agents. Our work has focused on developing new approaches to synthesize the flavonoids and their analogs and evaluating these compounds in relevant biological assays for their anticancer potential. A major focus of our work has been the design and synthesis of analogs of the natural product, genistein, a flavonoid found in soy that is known to inhibit the metastasis of prostate cancer. One of our analogs, KBU2046, has comparable anti-metastatic activity to genistein, but significantly reduced estrogenic side effects when compared to the natural product. This analog has shown promise in preclinical animal models and is currently being studied for its translational potential in human subjects. In addition, utilizing a new chemical reaction that we have developed, we have been able to complete the asymmetric total synthesis of a number of anticancer flavonoids, including abyssinones I-IV 4´-OMe, deguelin and tephrosin. Because we can access either stereoisomer of the abyssinone natural products, we have demonstrated that the natural (S) isomers of abyssinones III and IV 4´-OMe have potent antiproliferative activity, while the unnatural (R) isomers show promising anti-metastatic activity. We are also undertaking similar studies with deguelin and tephrosin. These interdisciplinary investigations that integrate catalysis, chemical synthesis, medicinal chemistry and cell biology may have a significant impact on public health, since we are able to generate novel anticancer agents with improved activity and attenuated side effects. The molecules that we synthesize in our laboratory could be used to both prevent and treat advanced cancer, thereby significantly reducing the mortality associated with one of the leading causes of death in the United States.