I. Selective Probes for Cytochrome P450 17A1 Suggest a Design Strategy Toward Improved Breast and Prostate Cancer Agents II. Spatiotemporal Control of Reactivity via Visible Light-Mediated C-H Activation Creates Patterned Carbohydrate Surfaces III. Toward Catalytic Intramolecular Schmidt Reactions

Abstract

Selective Probes for Cytochrome P450 17A1 Suggest a Design Strategy Toward Improved Breast and Prostate Cancer Agents. Sex steroids stimulate the growth of hormone-responsive breast and prostate tumors, the two most commonly diagnosed cancers in America. Inhibiting the sex steroid biosynthetic pathway is a promising strategy to halt the progression of these cancers. Cytochrome P450 17A1 (CYP17A1) is a validated target in prostate cancer, but clinical agents fail to achieve selectivity over the highly similar CYP21A2, involved in mineralocorticoid production and blood pressure regulation. In this work, we devised and confirmed a strategy to allow the selective blockade of sex steroidogenesis with the continued production of corticosteroid hormones. To rationally achieve this aim, several co-crystal structures were solved and an assay to evaluate CYP17A1/CYP21A2 selectivity was developed to guide the synthesis of new compounds. A class of these probes achieved significant gains in selectivity over the currently marketed drug abiraterone and galaterone and orteronel, still in clinical trials. This design strategy represents a step toward selectively targeting sex steroidogenesis as a chemotherapeutic tactic for prostate and possibly breast cancers. Spatiotemporal Control of Reactivity via Visible Light-Mediated C-H Activation Creates Chemically Patterned Carbohydrate Surfaces. Reactivity in photochemistry can be restricted to a desired area of a reaction medium by controlling the exposure of reagents to light. This can create patterned surfaces of chemical functionality, which can be used in numerous applications in chemical biology. To demonstrate this utility, we formulated a light-mediated photo-Meerwein arylation reaction to occur on a surface encoded with the reaction substrate. In this proof-of-concept study, reactants were chosen that would undergo a visible color change upon successful reaction. Potential surfaces to display these reactants were then tested. Paper sheets proved optimal for visualization, in which the cellulose C6-position was covalently modified by functionalized coumarin reactants. Use of a photomask allowed these surfaces to be selectively modified by exposure to visible light in the presence of various aryl diazonium reagents and a photocatalyst. These reactions resulted in a strikingly visible color change over the target area. This represents a rapid, cost-effective strategy to selectively encode desired chemical functionality on cellulose medium. This technology could be applied toward surfaces bearing protein capture resins, biosensors, or other agents for chemical biology. Studies Toward Overcoming Product Inhibition in Catalysis of the Intramolecular Schmidt Reaction. Transformations that efficiently generate molecular complexity are useful in drug design, polymer chemistry, and natural product synthesis. The intramolecular Schmidt reaction allows access to amides and lactams from ketone starting materials, and has seen extensive use in the above applications. This reaction is promoted by strongly acidic conditions. Since the reaction creates amide products with increased Lewis basicity over the ketone reactants, most acids are readily sequestered upon successful reaction. In this chapter, we describe the optimization of conditions that promote the intramolecular Schmidt reaction with substoichiometric Sc(OTf)3, which turns over to allow a catalytic cycle in response to heat. The scope, temperature dependence, and kinetics of this transformation were characterized. Additionally, several strategies to expand this strategy were screened. This work, with additional results from a co-worker, ultimately led to the development of vastly improved conditions and scope for catalytic Schmidt reactions.