Cytotoxic gold compounds: synthesis, biological characterization and investigation of their inhibition properties of the zinc finger protein PARP-1

Serratrice, Maria; Edafe, Fabio; Mendes, Filipa; Scopelliti, Rosario; Zakeeruddin, Shaik M.; Gräetzel, Michael; Santos, Isabel; Cinellu, Maria Agostina; Casini, Angela

doi:10.1039/c2dt11913g

Cited by 63 publications

(44 citation statements)

References 49 publications

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“…18,19 Information on the reactivity of the gold complexes with the PARP-1 zinc-finger domain was also obtained by high-resolution mass spectrometry, and an excellent correlation between PARP-1 inhibition in protein extracts and the ability of the complexes to bind to the zinc finger motif (in competition with zinc) was established. 18 Thus, in order to further investigate the mechanisms of action of the new heteronuclear complexes, we tested the mononuclear compounds 5 and 6 for their PARP-1 inhibition properties in vitro as reported in the Experimental section. The obtained preliminary results showed that the trinuclear Au-Fe compound 5 is a potent PARP-1 inhibitor with an IC 50 = 1± 0.5 μM, while the trinuclear Pd-Fe analogue 6 is much less effective with an IC 50 = 17± 0.8 μM.…”

Section: Resultsmentioning

confidence: 99%

Potential Anticancer Heterometallic Fe–Au and Fe–Pd Agents: Initial Mechanistic Insights

et al. 2013

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A series of gold(III) and palladium(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenyl-phosphanes [{Cp-P(Ph2)=N-Ph}2Fe] (1), [{Cp-P(Ph2)=N-CH2-2-NC5H4}2Fe] (2) and [{Cp-P(Ph2)=N-CH2-2-NC5H4}Fe(Cp)] (3) have been synthesized and structurally characterized. Ligands 2 and 3 afford stable coordination complexes [AuCl2(3)]ClO4, [{AuCl2}2(2)](ClO4)2, [PdCl2(3)] and [{PdCl2}2(2)]. The complexes have been evaluated for their antripoliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). The highly cytotoxic trimetallic derivatives M2Fe (M = Au, Pd) are more cytotoxic to cancer cells than their corresponding monometallic fragments. Moreover, these complexes were significantly more cytotoxic than cisplatin in the resistant A2780R and the MCF7 cell lines. Studies of the interactions of the trimetallic compounds with DNA and the zinc-finger protein PARP-1 indicate that they exert anticancer effects in vitro based on different mechanisms of actions with respect to cisplatin.

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Section: Resultsmentioning

confidence: 99%

Potential Anticancer Heterometallic Fe–Au and Fe–Pd Agents: Initial Mechanistic Insights

et al. 2013

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“…Indeed, in recent years several gold(III) compounds have shown promising anticancer effects related to the inhibition of different protein targets, such as the proteasome and specific zinc finger proteins [57], [58], [59], [60]. In this context, we cannot exclude that inhibition of AQP3 might influence the biological effects of the compounds towards cancer cells, although other studies need to be performed to validate such a hypothesis.…”

Section: Discussionmentioning

confidence: 97%

Targeting Aquaporin Function: Potent Inhibition of Aquaglyceroporin-3 by a Gold-Based Compound

et al. 2012

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Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC50 = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development.

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“…Since the beginning of 21th century, a series of new gold(III) complexes turned out to be stable under physiological conditions and also exhibited appreciable in vitro and in vivo anticancer activity [12, 13, 15–18]. Parish et al [19] described the synthesis of stable gold(III) complex using damp (2-(Dimethylamino)methyl)phenyl) as uni-negative bidentate ligand as an analogy in the structural features of cisplatin as neutral coordination complex in the mid of 1990s.…”

Section: Introductionmentioning

confidence: 99%

New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status

et al. 2016

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We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.

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Cytotoxic gold compounds: synthesis, biological characterization and investigation of their inhibition properties of the zinc finger protein PARP-1

Cited by 63 publications

References 49 publications

Potential Anticancer Heterometallic Fe–Au and Fe–Pd Agents: Initial Mechanistic Insights

Potential Anticancer Heterometallic Fe–Au and Fe–Pd Agents: Initial Mechanistic Insights

Targeting Aquaporin Function: Potent Inhibition of Aquaglyceroporin-3 by a Gold-Based Compound

New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status

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