The proposed research program reflects the interest of the Principal Investigator, John A. Porco, Jr., and his group in new chemical reaction development and the synthesis of biorelevant molecules using efficient approaches. Their overall goal is to develop and refine new synthetic methodologies for the asymmetric syntheses of diazobenzofluorene natural products, the epidithiidiketopiperazine (ETP) natural products, and the recently isolated kibdelones, three classes of complex natural products with demonstrated antitumor activity. They will apply the methodologies developed to the chemical synthesis of complex targets including FL-120B', lomaiviticin B, and the ambewelamides/scabrosin esters, and kibdelones A, B, and C. In collaborative studies with investigators at Boston University, the NIH Chemical Genomics Center (NCGC), and the National Cancer Institute (NCI), Porco and colleagues will assay the biological activity of natural and unnatural compounds produced during the course of this research. Their proposal is organized into three core projects reflecting their fundamental interest in new reaction methodology development, mechanistic studies, and applications towards the synthesis of biologically active molecules. The aims of the proposed project are: To develop an efficient asymmetric synthesis of the diazobenzofluorenes FL-120B'and lomaiviticin B and evaluate the DNA cleavage properties of synthetic compounds. To complete the syntheses of the epidithiodiketopiperazine (ETP) natural products vertihemiptellide A, the ambewelamides/scabrosin esters, and rostratin A. To complete the asymmetric syntheses and absolute configuration assignment of the polycyclic xanthone antitumor agents kibdelones A , B, and C. PUBLIC HEALTH RELEVANCE: Organic synthesis is an important discipline which continues to play a key role in drug discovery and in the allied fields of medicine and biology. As part of our laboratory's interest in new chemical reaction methodology, we continue to develop enabling approaches to bioactive natural products including antitumor natural products. The relevance to public health of the planned asymmetric syntheses of complex natural products entails identification of novel, biologically active antitumor agents. Such agents should be useful as novel pharmacological tools and in drug discovery related to various pathologies, including a variety of human cancers.