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

A series of gold­(III) and palladium­(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenylphosphanes [{Cp-P­(Ph₂)N-Ph}₂Fe] (<b>1</b>), [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}₂Fe] (<b>2</b>), and [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}­Fe­(Cp)] (<b>3</b>) have been synthesized and structurally characterized. Ligands <b>2</b> and <b>3</b> afford stable coordination complexes [AuCl₂(<b>3</b>)]­ClO₄, [{AuCl₂}₂(<b>2</b>)]­(ClO₄)₂, [PdCl₂(<b>3</b>)], and [{PdCl₂}₂(<b>2</b>)]. The complexes have been evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a nontumorigenic 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

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

A series of gold­(III) and palladium­(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenylphosphanes [{Cp-P­(Ph₂)N-Ph}₂Fe] (<b>1</b>), [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}₂Fe] (<b>2</b>), and [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}­Fe­(Cp)] (<b>3</b>) have been synthesized and structurally characterized. Ligands <b>2</b> and <b>3</b> afford stable coordination complexes [AuCl₂(<b>3</b>)]­ClO₄, [{AuCl₂}₂(<b>2</b>)]­(ClO₄)₂, [PdCl₂(<b>3</b>)], and [{PdCl₂}₂(<b>2</b>)]. The complexes have been evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a nontumorigenic 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

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

A series of gold­(III) and palladium­(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenylphosphanes [{Cp-P­(Ph₂)N-Ph}₂Fe] (<b>1</b>), [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}₂Fe] (<b>2</b>), and [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}­Fe­(Cp)] (<b>3</b>) have been synthesized and structurally characterized. Ligands <b>2</b> and <b>3</b> afford stable coordination complexes [AuCl₂(<b>3</b>)]­ClO₄, [{AuCl₂}₂(<b>2</b>)]­(ClO₄)₂, [PdCl₂(<b>3</b>)], and [{PdCl₂}₂(<b>2</b>)]. The complexes have been evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a nontumorigenic 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

Gold(I) Carbene Complexes Causing Thioredoxin <b>1</b> and Thioredoxin <b>2</b> Oxidation as Potential Anticancer Agents

Gold­(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = <i>N</i>-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au­(I)-phosphine compound auranofin

Docking of Auphen and Audien on AQP1 and AQP3.

<p>Top ranked poses of Auphen (top) and Audien (bottom) at periplasmic pocket of AQP1 (left) and AQP3 (right). Positions of metal centre for the other calculated poses are also displayed in golden yellow. SF domain residues are labelled in blue. Au–S and Au–N distances are reported in Å.</p

Conjugation of Organoruthenium(II) 3-(1<i>H</i>-Benzimidazol-2-yl)­pyrazolo[3,4-<i>b</i>]pyridines and Indolo[3,2-<i>d</i>]benzazepines to Recombinant Human Serum Albumin: a Strategy To Enhance Cytotoxicity in Cancer Cells

Following our strategy of coupling cyclin-dependent kinase (Cdk) inhibitors with organometallic moieties to improve their physicochemical properties and bioavailability, five organoruthenium complexes (<b>1c</b>–<b>5c</b>) of the general formula [RuCl­(η⁶-arene)­(L)]Cl have been synthesized in which the arene is 4-formylphenoxyacetyl-η⁶-benzylamide and L is a Cdk inhibitor [3-(1<i>H</i>-benzimidazol-2-yl)-1<i>H</i>-pyrazolo­[3,4-<i>b</i>]­pyridines (<b>L1</b>–<b>L3</b>) and indolo­[3,2-<i>d</i>]­benzazepines (<b>L4</b> and <b>L5</b>)]. All of the compounds were characterized by spectroscopic and analytical methods. Upon prolonged standing (2–3 months) at room temperature, the dimethyl sulfoxide (DMSO) solutions of <b>1c</b> and <b>2c</b>_{<b>–HCl</b>} afforded residues, which after recrystallization from EtOH and EtOH/H₂O, respectively, were shown by X-ray diffraction to be <i>cis</i>,<i>cis</i>-[Ru^IICl₂(DMSO)₂(<b>L1</b>)]·H₂O and <i>mer</i>-[Ru^IICl­(DMSO)₃(<b>L2</b>–H)]·H₂O. Compound <b>5c</b>, with a coordinated amidine unit, undergoes <i>E</i>/<i>Z</i> isomerization in solution. The antiproliferative activities and effects on the cell cycle of the new compounds were evaluated. Complexes <b>1c</b>–<b>5c</b> are moderately cytotoxic to cancer cells (CH1, SW480, A549, A2780, and A2780cisR cell lines). Therefore, in order to improve their antiproliferative effects, as well as their drug targeting and delivery to cancer cells, <b>1c</b>–<b>5c</b> were conjugated to recombinant human serum albumin, potentially exploiting the so-called “enhanced permeability and retention” effect that results in the accumulation of macromolecules in tumors. Notably, a marked increase in cytotoxicity of the albumin conjugates was observed in all cases

Identification of protein binding pockets.

<p>Ribbon view of the whole protein channel (left) and periplasmic pocket (right) with molecular surfaces displayed for AQP1 (top) and AQP3 (bottom). Hydrophilic and hydrophobic isosurfaces are also shown in light green and yellow, respectively.</p

Folds of expression and permeabilities of PC12 cells.

<p>Folds of mRNA expression were determined by Northern blot analysis and are normalized relative to the clone PC12wt.</p

Effect of Auphen on hRBC glycerol permeability.

<p>(A) Time dependent inhibition of glycerol permeability by 5 µM Auphen. The inset shows the progressive decrease of glycerol permeability observed in the assays where the increase in cell volume due to glycerol entrance decreases drastically with the incubation time. (B) Concentration dependent inhibition of glycerol permeability in hRBC by Auphen (compound concentrations in the range 0.1–10 µM; IC₅₀ = 0.8±0.08 µM). (C) Inhibition of glycerol permeability (% of control) of hRBCs after Auphen treatment (2 µM, 30 min at r.t.), and reversibility by washing with PBS or incubation with 2-mercaptoethanol (1 mM for 30 min) (***P<0.001).</p

Effect of compounds on hRBC permeability.

<p>(A) Water and glycerol permeabilities (% of control) after treatment with the compounds under study and with HgCl₂ (10 min at r.t.) A marked effect of Auphen (100 µM) is depicted (***P<0.001). (B) Stopped flow representative traces of water and (C) of glycerol permeability (control and after incubation with 5 µM Auphen, 30 min at r.t.). (D) Urea permeability showing no significant effect of Auphen treatment (5 and 100 µM, 30 min at r.t.; P>0.05).</p