UC San Diego

The American Cancer Society estimates that there will be 97,000 new cases of colon cancer and 51,000 deaths in the United States in 2023Approximately 30% of these diagnoses are in patients under the age of 55. These numbers have been declining slightly in recent years as methods of detection are improving and people are making efforts to live healthier lifestyles. If detected early, the 5 year survival rate is approximately 90%; however, if detected late, the survival rate decreases significantly (14% in stage IV disease). With people being diagnosed at earlier ages, and with only approximately 51% of people being up to date on the colorectal cancer screening, it is imperative that we have as many tools as possible at our disposal for treatment of the disease. While palmyramide A is a promising new drug candidate that may potentially help in the treatment of this disease, availability from natural sources is extremely low (471 g of dry bacteria used to isolate 6.1 mg palmyramide A). To aid in having enough of the compound available, we are proposing the first highly convergent total synthesis that will produce enough material for further testing. Part I of this dissertation describes the first total synthesis of palmyramide A, the biological evaluation of the natural product, and modification of the natural product to use as a probe that can determine its molecular mechanism of action.The World Health organization estimates there are approximately 71 million people worldwide living with hepatitis C virus (HCV), with 15-30% of those developing advanced liver diseases such as cirrhosis or liver cancer. While current treatments can be effective, they are extremely cost prohibitive, limiting access for many people. Another issue is that most commercially available drugs target the same viral protein, non-structural protein 5B (NS5B), an RNA dependent RNA polymerase. Because HCV is a positive-sense RNA virus, its genome is translated and replicated with little proofreading, rendering it prone to mutations, and a mutation in NS5B could render these therapeutics ineffective. However, a small segment of the 5’ non-coding RNA, known as the internal ribosome entry site subdomain IIa, is extremely highly conserved, and is an attractive target for therapeutics. Part II of this dissertation describes the design and synthesis of new classes of therapeutics targeting the HCV IRES.