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In the everlasting battle against cancer the development of drugs targeting new therapeutic pathways is of crucial importance. In the attempt to develop new anticancer agents we have synthesized a library of anthraquinone compounds that show selectivity against leukemia. Mechanistic evaluation of the lead compound reveal that this class of compounds achieve their effects through inhibition of MDM2-MDM4 heterodimer and upregulation of the tumor suppressor p53. Computer aided rational design resulted in the development of a number of compounds with activities in the nanomolar range against various cancer cells. Analysis of the physicochemical properties of selected compounds allowed for their evaluation as potential drug candidates. The successful development of non-toxic formulations permits for the further in vivo investigation of the compounds. Click reactions have found wide spread applications in sensing, materials chemistry, bioconjugation, and biolabeling. A number of very useful click reactions have been discovered, which allow for various applications. In bioconjugation applications, the ability to conduct a secondary conjugation will be very useful in, e.g., protein pull down and binding site identification. Along this line, we describe a neighboring group-assisted facile condensation between an aldehyde and a vicinal aminothiol moiety, leading to the formation of benzothiazoles. The conversion is completed within 5 minutes at low micromolar concentrations at ambient temperature. The facile reaction was attributed to the presence of a neighboring boronic acid, which functions as an intramolecular Lewis Acid in catalyzing the reaction. The boronic acid group is compatible with most functional groups in biomolecules and yet can also be used for further functionalization via a large number of well-known coupling reactions.

The first section of this work describes the synthesis of a library of novel rhein analogues that are potential anticancer agents. The design of these compounds takes advantage of the ability for rhein to intercalate into DNA and as the incorporation of an alkylating agent, which serves to covalently modify DNA. In three cell lines, these compounds showed potent cytotoxicity with IC50 in the low to mid-μM range. The second project was focused on the development of an efficient synthesis of 6H-Isoindolo[2,1-α]indol-6-one (24), a core structure for a number of biologically active compounds. The approach is metal-free and uses a Beckmann rearrangement followed by an intramolecular cyclization.