Plant-derived natural products continue to be a valuable source of useful therapies for cancer as well as other diseases. As part of a continuing mission to obtain anticancer agents from natural sources, researchers at the National Cancer Institute (NCI) established the 60 human tumor cell line anticancer screen. The schweinfurthins are one family of unique natural products discovered through this screening process. Most of these natural compounds exhibit potent and differential activity in the 60-cell screen. Importantly, the pattern of activity displayed by the schweinfurthins shows no correlation to any clinically used anticancer drug, indicating that this family of natural products probably acts via a novel mechanism or at a novel target. Our group has conducted extensive structure-activity relationship studies in an effort to illuminate the mechanism of action of the schweinfurthins. In this thesis, the preparation and biological activity of a number of new schweinfurthin F analogues possessing variations in the D-ring alkyl chain and stilbene moiety will be discussed. These studies have clarified the importance of the D-ring to the schweinfurthins' pharmacophore. Based on the results obtained from the exploration of the structural requirements of these natural products, it was determi-ned that the right-half of the schweinfurthins would be an appropriate site for attachment of a molecular probe to be used in affinity experiments. The synthesis of these biotinylated probes will be examined in detail, and their use in pull-down assays will be summarized. The preparation of key schweinfurthin intermediates has involved the extensive use of Lewis acid-mediated cationic cascade cyclizations terminated by MOM-protected phenols. Those successes have inspired investigations of additional applications of these cyclizations. In particular, a variant of these cyclizations using "MOM-protected" enol ethers as reasonable substitutes for β-keto ester terminating moieties has been studied. These interrelated studies involving the synthesis of schweinfurthin analogues and the exploration of cascade cyclizations will be discussed in detail.

Schweinfurthins are intriguing natural product chemotherapeutics due to their potent yet selective activity and their unknown mechanism of growth inhibition in cancer. Much progress has been made in characterizing the intracellular effects of the schweinfurthins since they were first isolated from Macaranga schweinfurthii in 1986. Here, the L-type calcium channel and P- glycoprotein (Pgp) inhibitor verapamil has been found to enhance schweinfurthin- induced growth inhibition. Verapamil induces an increase in the intracellular concentration of a fluorescent schweinfurthin. However, the synergistic relationship between the schweinfurthins and verapamil is complex and not obvious in that verapamil fails to increase the intracellular concentration of a schweinfurthin analogue that is a known substrate of Pgp. Schweinfurthins are also found to induce alterations to cholesterol homeostasis by increasing the expression of the cholesterol efflux pump ABCA1 in an apparent liver X receptor- independent fashion. In addition, schweinfurthin treatment blunts epidermal growth factor downstream activation and phosphorylation of Akt. Lastly, a schweinfurthin-resistant cell line has been created and characterized for resistance to schweinfurthin-induced growth inhibition. The variety of intracellular effects characteristic of schweinfurthin treatment described here provide mechanistic framework for identifying the potential target and mechanism of growth inhibition for the schweinfurthins.

Natural products are a rich source of lead compounds for treatment of cancer as well as other diseases. Researchers at the National Cancer Institute, as part of their continuing effort to discover anticancer agents from natural sources, created the 60 human tumor cell-line anticancer screen to test natural products for their potential against various types of cancer. Through this screening process a family of natural products called schweinfurthins was discovered to possess potent and differential activity. Of potentially great significance, the pattern of activity that the schweinfurthins displayed in the screen does not correlate with any currently used anticancer drug, indicating that the schweinfurthins likely act via a previously unknown mechanism or on a novel target. Our group has synthesized many of the natural schweinfurthins as well as numerous analogues in an effort to probe the pharmacophore and gain understanding of the key features that are important for potency as well as differential activity. During the course of these studies, it was discovered that the right-half of the molecule is most amenable for modifications. One potential modification to the schweinfurthins is to replace the resorcinol substructure seen in the right-half of the natural product with a heteroaromatic moiety such as a benzofuran or indole system. This change may produce analogues that are potentially more active, that contain motifs that are seen in many therapeutic drugs, and that have improved chemical stability relative to the natural products. With this goal in mind benzofuran and indole containing schweinfurthin analogues were synthesized. Once these compounds were prepared, it was found that such modifications were welltolerated, and in the case of the indole analogues activity in the 60 cell-line screen was equivalent to the corresponding natural product. In an effort to improve that activity, prenyl and geranyl side chains were added to the indole system, at both the C-2 and C-3 positions, to better match the structure of the natural schweinfurthins. In addition, analogues methylated selectively on the indole nitrogen or phenol were synthesized to improve stability. The impact of those modifications on the activity was tested, and potent compounds were found. The left-half of the schweinfurthins is prepared via a Lewis acid mediated cascade of a geranyl epoxide. The protecting group that is typically employed on the terminating phenol, a methoxymethyl ether or MOM group, is cleaved during the reaction. In the past preparation of an analogue that lacked a substituent at the C-5 position, it was found that the MOM cation released during the cyclization would participate in an electrophilic aromatic substitution reaction at the neighbouring position which resulted in the formation of a benzyl methyl ether. In order to probe the scope of this reaction and its potential utility in the synthesis of natural products, several geranyl epoxides with various "protecting groups" on the phenol were prepared and subjected to the cyclization conditions. These investigations have established that stabilization of the liberated cation determines the likelihood and regioselectivity of a tandem electrophilic aromatic substitution reaction.

Cancer is a serious family of disease that continues to cripple and claim those afflicted. For the last several decades, America has invested in a national program to alleviate cancer and cancer related suffering, ultimately seeking a cure. As part of this goal, the National Cancer Institute (NCI) has spent significant effort scouring the globe with the hope of finding naturally occurring compounds that can successfully combat cancer. Presently, this effort has uncovered many natural products with chemotherapeutic potential and many of the lead agents used in the fight against cancer are either natural products themselves or are compounds inspired by a natural product. This work describes one family of natural products uncovered by the NCI that is being explored for chemotherapeutic applications, namely the schweinfurthins. The schweinfurthins were isolated by the NCI; however the natural source, Macaranga schweinfurthii, did not provide these compounds in ample quantity to permit further study. The paucity of natural material indicated that a chemical synthesis of these compounds would be the most reliable method to provide meaningful amounts of schweinfurthins. The present work describes the chemical synthesis of four of the most potent schweinfurthins, describes the synthesis of numerous structural analogues, and details advances to the field of cascade cyclizations which makes their synthesis possible.