TY - JOUR
T1 - Anticancer (hexacarbonyldicobalt)propargyl aryl ethers
T2 - Synthesis, antiproliferative activity, apoptosis induction, and effect on cellular oxidative stress
AU - Schimler, Sydonie D.
AU - Hall, David J.
AU - Debbert, Stefan L.
PY - 2013/2
Y1 - 2013/2
N2 - 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 40 μM in a 72 h crystal violet staining assay. The most active analog was the organocobalt nitroaromatic ether 3a, with an IC 50 of 3.3 ± 0.9 μM. 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.
AB - 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 40 μM in a 72 h crystal violet staining assay. The most active analog was the organocobalt nitroaromatic ether 3a, with an IC 50 of 3.3 ± 0.9 μM. 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.
KW - Organometallic medicinal chemistry
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=84869222731&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869222731&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2012.10.014
DO - 10.1016/j.jinorgbio.2012.10.014
M3 - Article
C2 - 23178649
AN - SCOPUS:84869222731
SN - 0162-0134
VL - 119
SP - 28
EP - 37
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
ER -