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. 2009 Nov;44(11):4353-61.
doi: 10.1016/j.ejmech.2009.05.019. Epub 2009 May 24.

Metals in anticancer therapy: copper(II) complexes as inhibitors of the 20S proteasome

Sarmad Sahiel Hindo  1 , Michael Frezza, Dajena Tomco, Mary Jane Heeg, Lew Hryhorczuk, Bruce R McGarvey, Q Ping Dou, Cláudio N Verani
Affiliations

Metals in anticancer therapy: copper(II) complexes as inhibitors of the 20S proteasome

Sarmad Sahiel Hindo et al. Eur J Med Chem. 2009 Nov.

Abstract

Selective 20S proteasomal inhibition and apoptosis induction were observed when several lines of cancer cells were treated with a series of copper complexes described as [Cu(L(I))Cl] (1), [Cu(L(I))OAc] (2), and [Cu(HL(I))(L(I))]OAc (3), where HL(I) is the ligand 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol. These complexes were synthesized, characterized by means of ESI spectrometry, infrared, UV-visible and EPR spectroscopies, and X-ray diffraction when possible. After full characterization species 1-3 were evaluated for their ability to function as proteasome inhibitors and apoptosis inducers in C4-2B and PC-3 human prostate cancer cells and MCF-10A normal cells. With distinct stoichiometries and protonation states, this series suggests the assignment of species [CuL(I)](+) as the minimal pharmacophore needed for proteasomal chymotryspin-like activity inhibition and permits some initial inference of mechanistic information.

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Figures

Scheme 1
Scheme 1
Copper(II) complexes.
Figure 1
Figure 1
Experimental (bars) and simulated (continuum) ESIMS m/z data for monomeric [CuLI]+.
Figure 2
Figure 2
ORTEP diagram at 50% probability level for [Cu(LI)Cl] (1) with selected bond lengths (Å) and angles (°). Cu(1)-O(1) = 1.929(3), Cu(1)-N(2) = 1.990(4), Cu(1)-N(1) = 2.018(4), Cu(1)-Cl(1) = 2.2488(14), N(2)-Cu(1)-Cl(1) = 162.63(14), O(1)-Cu(1)-N(1) = 66.40(17).
Figure 3
Figure 3
IC50 values for cell death induction by 1 - 3. (a) Human leukemia Jurkat Tcells were treated with copper compounds 1-3 for 18 h, followed by measurement of cell death in a trypan blue exclusion assay. HLI, CuCl2, and DMSO are used as controls. Standard deviations are shown as error bars.
Figure 4
Figure 4
In vitro proteasome-inhibitory activity of 1-3 in C4-2B cell extracts: (a) Proteasomal chymotrypsin-like activity (%CT) of the ligand HLI, the salt CuCl2, and an 1:1 HLI:CuCl2 mixture in DMSO at 25 mmol/L stock solution. (b) Concentration dependent inhibition by 1-3 at 0.1, 1, 5, 10, and 25 μM.
Figure 5
Figure 5
Dose-dependent effects of 1-3 in C4-2B cells. The results were also compared to three negative controls (DMSO, HLI, and CuCl2·2H2O) for 18 h followed by measuring inhibition of proteasomal chymotrypsin-like activity.
Figure 6
Figure 6
Dose-dependent effects of 1-3 in C4-2B cells. Accumulation of ubiquitinated proteins (Ub-Prs), and cleavage of PARP.
Figure 7
Figure 7
Dose-dependent effects of 1-3 in C4-2B cells. Micrographs of apoptotic morphologic changes in HLI, CuCl2, 1, 2, and 3. (low definition PNG file)
Figure 8
Figure 8
Kinetic effect of proteasome inhibition and apoptosis induction by 2 in C4-2B cells. (a) measurement of proteasomal chymotrypsin-like activity over time, (b) accumulated ubiquitinated proteins (UB-Prs) and PARP cleavage with Actin as a loading control, and (c) apoptotic cellular morphological changes.
Scheme 2
Scheme 2
Suggested conversion of 3 into a [CuLI(H2O)n]+ species.
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