Anticancer (hexacarbonyldicobalt)propargyl aryl ethers: synthesis, antiproliferative activity, apoptosis induction, and effect on cellular oxidative stress.

While an increasing number of (hexacarbonyldicobalt)alkynes have been found to possess antiproliferative activity against a number of cancer cell lines, the role of the organometallic moiety in this bioactivity is not well understood. To gain a better understanding of cobalt's role in the medicinal chemistry of these compounds, several simplified analogs of a known organocobalt anticancer compound were synthesized and assessed for antiproliferative activity against MDA-MB-231 human breast cancer cells. These compounds, mostly (hexacarbonyldicobalt)propargyl aryl ethers, caused 45-93% growth inhibition of that cell line at 40μM in a 72h crystal violet staining assay. The most active analog was the organocobalt nitroaromatic ether 3a, with an IC(50) of 3.3±0.9μM. Flow cytometric assays on the same cell line demonstrated that 3a strongly induces apoptosis, arrests the cell cycle at the S phase, increases cellular oxidative stress levels, and induces permeability of the mitochondrial membrane. While the non-cobalt-containing precursor to 3a also caused an increase in mitochondrial membrane permeability, it did not produce an increase in oxidative stress levels, nor did it have apoptosis-inducing or antiproliferative effects. The induction of oxidative stress in the cell may be responsible for some of the antiproliferative activity of compound 3a against this cell line.