Abstract. Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro-and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimers disease.

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Iron chelators have traditionally been used in the treatment of iron overload. Recently, chelators have also been explored for their ability to limit oxidant damage in cardiovascular, neurologic, and inflammatory disease as well as to serve as anti-cancer agents. To determine the mechanism of cell death induced by iron chelators, we assessed the time course and pathways of caspase activation during apoptosis induced by iron chelators. We report that the chelator tachpyridine sequentially activates caspases 9, 3, and 8. These caspases were also activated by the structurally unrelated chelators dipyridyl and desferrioxamine. The critical role of caspase activation in cell death was supported by microinjection experiments demonstrating that p35, a broad spectrum caspase inhibitor, protected HeLa cells from chelator-induced cell death. Apoptosis mediated by tachpyridine was not prevented by blocking the CD95 death receptor pathway with a Fas-associated death domain protein (FADD) dominant-negative mutant. In contrast, chelator-mediated cell death was blocked in cells microinjected with Bcl-XL and completely inhibited in cells microinjected with a dominant-negative caspase 9 expression vector. Caspase activation was not observed in cells treated with N-methyl tachpyridine, an N-alkylated derivative of tachpyridine which lacks an ability to react with iron. These results suggest that activation of a mitochondrial caspase pathway is an important mechanism by which iron chelators induce cell death.

To illustrate the usefulness of conformational preorganization in amine carboxylate ligands, synthesis of the trans-cyclohexylene backbone analogue of diethylenetriaminepentaacetic acid (H5DTPA), N-(2-aminoethyl)-trans-1,2-diaminocyclohexane-N,N,N‘,N‘‘,N‘‘-pentaacetic acid (H5CyDTPA), was effected. Synthesis of [guanidinium]2[Bi(CyDTPA)2-] (complex anion on left) and the uncharged complex of diprotonated DTPA5-, Bi(H2DTPA)·2H2O, were prepared and structurally characterized. Conformational preorganization is responsible for the shorter Bi−O and Bi−N bond lengths of Bi(CyDTPA)2- compared to Bi(DTPA)2-. The shorter bond lengths of Bi(CyDTPA)2- are in accord with a greater stability of an antibody-labeled derivative of Bi(CyDTPA)2- over antibody-labeled Bi(DTPA)2- in vivo. Competition of protons for ligand donor atoms leads to bond length irregularities in the structure of Bi(H2DTPA) when compared to the known structure Bi(DTPA)2-.