Part I. Isolation of natural product inhibitors and synthesis of inhibitors of signal transduction. Part II. Structure-activity relationship for a series of glycosidase inhibitors

Normal cell growth and division is controlled by a very delicate and elaborate regulatory mechanism balancing growth promoting and growth suppressing signals, about which relatively little is known. Cancer (the uncontrolled proliferation of cells) is believed to be caused by a breakdown in this growth regulatory system. Part I of this thesis describes the bioassay directed isolation of natural product inhibitors of several enzymes involved in this growth regulatory system. The targets studied include PKC (protein kinase C), TPK (tyrosine protein kinase), PI-3-Kinase (phosphatidylinositol-3-kinase), PIPLC (phosphoinositide specific phospholipase C), Calcium signaling, and MAP-Kinase (mitogen-activated protein kinase). Plant material under investigation was collected in the Southeastern United States. Jacaranone ethyl ester was isolated from Senecio anonymus as a calcium signaling inhibitor. Physcion, a naturally occurring anthraquinone, was isolated from Polygonum cuspidatum as an inhibitor of PKC. (+)-Pinoresinol monomethyl ether, a rarely observed lignan, was isolated from Asclepias tuberosa via separations directed by the assay for PKC; however, (+)-pinoresinol monomethyl ether is not responsible for the activity of the extract. Also, a series of anthraquinone (both naturally occurring and synthetic) inhibitors was studied with four kinases. The structure-activity relationship is discussed.; For several years, the biological significance of the interactions between proteins and sugars has been recognized. Carbohydrate binding proteins have been demonstrated to play a major role in biological recognition in both plant and mammalian systems. GP120, a glycoprotein which forms the outer surface of the HIV viral coat, interacts with the CD4 protein, an interaction which is required for initiation of infectivity. A method of interrupting or interfering with glycoprotein processing would be an effective method of chemotherapy against HIV. There is also evidence that cell surface oligosaccharides play a role in tumor metastasis; known glycoprotein processing inhibitors have been found to inhibit tumor metastasis. Oligosaccharide processing inhibitors, then, are potential anti-cancer agents. Part II discusses the structure-activity relationship for a series of flavonoid inhibitors of {dollar}alpha{dollar}-glucosidase, an enzyme involved in oligosaccharide processing. Structural features necessary for activity are described. The mechanism of binding to the enzyme is unknown; however, the flavonoid compounds, because of their rigid structure, are not able to bind in the manner suggested for other glycosidase inhibitors.