Mercury Can Bond to α-Carbon of Curcumin Increasing Stability in Aqueous Medium and Demonstrated Selective Cytotoxicity against Acute Leukemia.

Natural products ranging from phytochemicals to metals are well-known for their therapeutic benefits on different cancer types, including acute leukemia. However, bioavailability significantly limited the applications of various polyphenolic molecules, such as curcumin, while toxicity challenged the medicinal applications of heavy metals, such as mercury (Hg). Specifically, in case of curcumin derivatives, simultaneous solubility, stability, and bioactivity in the aqueous medium remain unachieved, leading to poor clinical translation. We demonstrate for the first time that the above-mentioned challenges could be resolved by covalently bonding mercury to the α-carbon of curcumin. The resultant organomercury compound ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-4-yl)mercury or α-Mercurin is soluble in alkaline conditions and remains stable for at least 24 h. Cell viability assays demonstrated selective cytotoxicity of α-Mercurin against acute leukemia cells, compared to healthy human peripheral blood mononuclear cells, in vitro. Experimental IC(50) on MOLT-4 and HL-60 cells remained in the lower micromolar range, and potential mode of action includes apoptosis. Ex vivo analysis also demonstrated that α-Mercurin can eliminate immature blasts from acute lymphoblastic leukemia patients' blood samples and also enhance expression of immune markers, with no notable toxicity on red blood cells as well as lymphocytes. Finally, intravenous administration of α-Mercurin showed no subacute toxicity, in vivo.