Inhibition of ABC transporters associated with multidrug resistance

The first part of this dissertation (chapters 1 and 2) deals with the inhibition of the ABC transporters ABCB1 (p-glycoprotein) and ABCG2 (breast cancer resistance protein). Less lipophilic and better water soluble analogues of the known ABCB1 inhibitor tariquidar were synthesized from one central building block via Cu(I)-catalyzed N/O-arylation reactions. These compounds were tested for their inhibitory activity against the ABCB1 transporter in a flow cytometric calcein-AM efflux assay and a correlation between their calculated log P values and their activities was observed. During this work it was discovered that slight structural modifications of the aromatic core resulted in potent ABCG2 inhibitors. Based on this finding a series of new ABCG2 inhibitors was prepared and found to be highly selective over ABCB1 and ABCC2. Such compounds, which are among the most potent and selective ABCG2 inhibitors known so far, might be useful for cancer treatment with respect to reversal of drug resistance, overcoming the blood brain barrier and targeting of tumor stem cells. The second part of this work (chapter 3) describes the synthesis of ketoalkenes from the pale purple coneflower (Echinacea pallida). These compounds contain diene or triene motifs with skipped conjugation and were synthesized from one common vinyl zinc chloride precursor via Pd-catalyzed allylation reactions. The synthetic route developed at the same time allowed to prepare non-natural conjugated analogues via Suzuki and Sonogashira cross coupling reactions. Both the natural products and their analogues were tested for their ability to activate the human cannabinoid receptors 1 and 2 to find out whether such compounds might be responsible for the observed immunostimulatory effects of Echinacea extracts. While no significant activity of the natural products was observed at either receptor the new analogues showed micromolar potency at both cannabinoid receptors. The last part (chapter 4) finally deals with the preparation of new tetracyclic forskolin analogues. Treatment of a forskolin-derived thionocarbonate with 1,3-dimethyl-2-phenyl-1,3-diaza-phospholidine resulted in an interesting rearrangement presumably via a carbene intermediate to yield a cyclic carbonate. Two new compounds were tested for their ability to activate adenylyl cyclase 1, 2 and 5 and found to be able to stimulate cAMP production at micromolar concentrations