Document Type

Honors Project

Publication Date

Spring 2012

Abstract

Inorganic medicinal chemistry is a current area of important research. While platinum containing compounds like cisplatin have wide use in cancer chemotherapy, organometallic compounds are an underscreened population which may have useful medicinal properties. Novel organometallic anticancer compounds are being designed such that they exhibit a different mode of action from cisplatin, as many of the side effects associated with this compound are a result of its interaction with DNA. Recently, a class of compounds consisting of hexacarbonyl dicobalt bound to an alkyne has been found to exhibit notable anticancer activity.

In order to evaluate the role of the hexacarbonyl dicobalt and the ligand in the bioactivity, a series of novel cobalt-alkyne complexes have been synthesized from propargyl aryl ethers and dicobalt octacarbonyl, and the cytotoxic properties of these compounds were assayed. Studies on the mode of action of these compounds were performed using flow cytometry, including the ability of the compounds to induce apoptosis, the effect of these compounds on the production of reactive oxygen species (ROS), the effect on the mitochondria, and the effect on the cell cycle. The most active of these compounds, (propargyl p-nitrophenyl ether) hexacarbonyldicobalt (Co-NO2), showed strong antiproliferative activity against the MDA-MB-231 breast cancer cell line. Further synthetic studies showed that this ligand and the cobalt-alkyne complex were essential for the antiproliferative activity. This compound has been shown to initiate apoptosis in this cell line as observed by the loss of plasma membrane asymmetry. Furthermore, Co-NO2 increases intracellular levels of ROS and disrupts the mitochondrial transmembrane potential. Co-NO2 affects the cell cycle in such a way that fewer cells are undergoing mitosis, indicating that this compound is having an effect on the ability of these compounds to proliferate. Co-NO2 represents a novel compound to the field of organometallic anticancer compounds.

Level of Honors

cum laude

Department

Chemistry

Advisor

Stefan Debbert

Comments

Advisor: Stefan Debbert

Level of Honors: cum laude

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