title: Anticancer (hexacarbonyldicobalt)propargyl aryl ethers: synthesis, antiproliferative activity, apoptosis induction, and effect on cellular oxidative stress.
abstract: 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.
authors.affiliation: Department of Chemistry, Lawrence University, Appleton, WI 54911, United States.
authors.forename: Sydonie D
authors.initials: SD
authors.lastname: Schimler
authors.forename: David J
authors.initials: DJ
authors.lastname: Hall
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Debbert
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003035:Cobalt / Q000737:chemistry*; D004987:Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005840:Gentian Violet; D006801:Humans; D020128:Inhibitory Concentration 50; D018384:Oxidative Stress / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D004987:Ethers; D003035:Cobalt; D005840:Gentian Violet