Trackable Metallodrugs Combining Luminescent Re(I) and Bioactive Au(I) Fragments

Hetero-bimetallic and -trimetallic complexes were synthesized by the combination of different metallic fragments, a luminescent Re­(I) species, and a bioactive Au­(I) derivative. A ditopic P,N-donor ligand (L) was used as linker between both metals, affording six new bipyridine (bipy) Re­(I)/Au­(I) hetero-metallic complexes of the type <i>fac-</i>[Re­(bipy)­(CO)₃­(LAuCl)]⁺ (<b>4</b>–<b>6</b>) and [(<i>fac-</i>[Re­(bipy)­(CO)₃(L)])₂Au]³⁺ (<b>7</b>–<b>9</b>) after a thorough synthetic procedure. Their emission is associated with a triplet metal-to-ligand charge transfer (Re­(dπ) → bipy­(π*)) transition and red-shifted in polar solvents with lifetimes in the range of nanoseconds and quantum yield values up to 12.5%. Cytotoxicity values in A549 cells of hetero-trimetallic species are almost twice that for the hetero-bimetallic (ca. 37 vs 69 μM, respectively), being the L-Au fragment the source of the antiproliferative activity. Species <b>7</b> and <b>8</b> showed similar behavior by fluorescence microscopy, with a nonuniform cytoplasmatic distribution, a clear accumulation in single spots at the edge of the inner cell membrane as well as in areas within the nucleus. Preliminary studies suggest the DNA as one of the targets and passive diffusion as the entrance pathway

Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand As Potential Anticancer Agents

The synthesis and characterization of a new water-soluble iminophosphorane ligand TPAN-C­(O)-2BrC₆H₄ (<b>1</b>, C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) is reported. Oxidative addition of <b>1</b> to Pd₂(dba)₃ affords the orthopalladated dimer [Pd­(μ-Br)­{C₆H₄(C­(O)­NTPA-kC,N)-2}]₂ (<b>2</b>) as a mixture of <i>cis</i> and <i>trans</i> isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to <b>2</b>, the bridging chlorides can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium­(II) complexes of the type [Pd­{C₆H₄(C­(O)­NTPA-kC,N)-2}­(L-L)] (L-L = acac (<b>3</b>); S₂CNMe₂ (<b>4</b>); 4,7-diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C₁₂H₆N₂(C₆H₄SO₃Na)₂ (<b>5</b>)), [Pd­{C₆H₄(C­(O)­NTPA-kC,N)-2}­(L)­Br] (L = P­(mC₆H₄SO₃Na)₃ (<b>6</b>); P­(3-pyridyl)₃ (<b>7</b>)), and [Pd­(C₆H₄(C­(O)­NTPA)-2}­(TPA)₂Br] (<b>8</b>) are obtained as single isomers. All new complexes were tested as potential anticancer agents, and their cytotoxicity properties were evaluated <i>in vitro</i> against human Jurkat-T acute lymphoblastic leukemia cells, normal T-lymphocytes (PBMC), and DU-145 human prostate cancer cells. Compounds [Pd­(μ-Br)­{C₆H₄(C­(O)­NTPA-kC,N)-2}]₂ (<b>2</b>) and [Pd­{C₆H₄(C­(O)­NTPA-kC,N)-2}­(acac)] (<b>3</b>) (which has been crystallographically characterized) display higher cytotoxicity against the above-mentioned cancer cell lines while being less toxic to normal T-lymphocytes (peripheral blood mononuclear cells: PBMC). In addition, <b>3</b> is very toxic to cisplatin-resistant Jurkat shBak, indicating a cell death pathway that may be different from that of cisplatin. The interaction of <b>2</b> and <b>3</b> with plasmid (pBR322) DNA is much weaker than that of cisplatin, pointing to an alternative biomolecular target for these cytotoxic compounds. All the compounds show an interaction with human serum albumin faster than that of cisplatin

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold­(III) and platinum­(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt­(II) derivatives <b>4</b> and <b>5</b>, which differ only in the anion, Hg₂Cl₆^2– or PF₆^– respectively, display almost identical IC₅₀ values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds <b>3</b>, <b>4</b>, and <b>5</b> can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound <b>5</b> does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of <b>5</b> by two different assays, <i>in vitro</i> Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold­(III) and platinum­(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt­(II) derivatives <b>4</b> and <b>5</b>, which differ only in the anion, Hg₂Cl₆^2– or PF₆^– respectively, display almost identical IC₅₀ values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds <b>3</b>, <b>4</b>, and <b>5</b> can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound <b>5</b> does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of <b>5</b> by two different assays, <i>in vitro</i> Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration

In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer

A series of organometallic ruthenium­(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70–100 mg/mL). Most compounds (especially highly water-soluble <b>2</b>) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of <b>2</b> on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption of <b>2</b> in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo