Insertion Reactions in Ta–H and Ta–Me Bonds in Complexes Containing Tridentate κ³O,S,O-Type Ligands

A series of new tantalum complexes containing the κ³O,S,O-type alkoxide ligand from 2,2′-thiodiethanol (tdgolH₂) have been synthesized and characterized. The complexes [TaCp*Cl₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>1</b>) and [TaCp*Me₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>2</b>) were prepared by reaction of 2,2′-thiodiethanol with [TaCp*X₄] (X = Cl, Me). The tantalum dihydride complex [TaCp*H₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>3</b>) and its analogue containing the 2,2′-thiobis­(6-<i>tert</i>-octylphenolate) ligand (<b>4</b>) were synthesized by reaction of the respective dichlorides with 2 equiv of NaBHEt₃. In addition, [TaCp*Me­(TfO)­{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>5</b>) and [TaCp*­(TfO)₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>6</b>; TfO = F₃COSO₂^–) were synthesized by reaction of <b>2</b> with 1 and 2 equiv of triflic acid, respectively. The reactivity of this family of complexes with nucleophiles was also studied and, as a result, three azatantalacyclopropane complexes (<b>7</b>–<b>9</b>) and the carbene [TaCp*­{C­(Me)­N­(H)­xylyl-κ¹C}­(OH)­{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>10</b>) were characterized. The single-crystal structures of <b>1</b> and <b>6</b> were determined by X-ray diffraction methods

Insertion Reactions in Ta–H and Ta–Me Bonds in Complexes Containing Tridentate κ³O,S,O-Type Ligands

A series of new tantalum complexes containing the κ³O,S,O-type alkoxide ligand from 2,2′-thiodiethanol (tdgolH₂) have been synthesized and characterized. The complexes [TaCp*Cl₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>1</b>) and [TaCp*Me₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>2</b>) were prepared by reaction of 2,2′-thiodiethanol with [TaCp*X₄] (X = Cl, Me). The tantalum dihydride complex [TaCp*H₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>3</b>) and its analogue containing the 2,2′-thiobis­(6-<i>tert</i>-octylphenolate) ligand (<b>4</b>) were synthesized by reaction of the respective dichlorides with 2 equiv of NaBHEt₃. In addition, [TaCp*Me­(TfO)­{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>5</b>) and [TaCp*­(TfO)₂{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>6</b>; TfO = F₃COSO₂^–) were synthesized by reaction of <b>2</b> with 1 and 2 equiv of triflic acid, respectively. The reactivity of this family of complexes with nucleophiles was also studied and, as a result, three azatantalacyclopropane complexes (<b>7</b>–<b>9</b>) and the carbene [TaCp*­{C­(Me)­N­(H)­xylyl-κ¹C}­(OH)­{[O­(CH₂)₂]₂S-κ³<i>O</i>,<i>S</i>,<i>O</i>}] (<b>10</b>) were characterized. The single-crystal structures of <b>1</b> and <b>6</b> were determined by X-ray diffraction methods

Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

Early–late transition metal TiAu₂ compounds [(η-C₅H₅)₂Ti­{OC­(O)­CH₂PPh₂AuCl}₂] (<b>3</b>) and new [(η-C₅H₅)₂Ti­{OC­(O)-4-C₆H₄­PPh₂AuCl}₂] (<b>5</b>) were evaluated as potential anticancer agents <i>in vitro</i> against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold­(I) [{HOC­(O)­RPPh₂}­AuCl] (R = −CH₂– <b>6</b>, −4-C₆H₄– <b>7</b>) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for <b>5</b> in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells <i>in vitro</i> coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC₅₀ <b>3</b> = 91 nM, IC₅₀ <b>5</b> = 117 nM). The selectivity of the compounds <i>in vitro</i> against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially <b>5</b>) are excellent candidates for further development as potential renal cancer chemotherapeutics

Rearrangement of Tridentate [OSO]-Type Ligands and Migratory Insertion Reaction Mechanisms in Cyclopentadienyl Tantalum Complexes

The mechanism of the isocyanide migratory insertion into the metal–carbon bond of monocylopentadienyltantalum dimethyl derivatives with [OSO]^2– tridentate phenolate ligands has been investigated with DFT calculations. The presence of both a cyclopentadienyl and a tridentate ligand complicates a usually simple reaction, the migratory insertion reaction being coupled with a <i>fac</i> → <i>mer</i> rearrangement of the tridentate ligand. Two routes have been explored for the overall migratory insertion process, depending on the order of the <i>fac</i> → <i>mer</i> and insertion steps. Calculations show that the dissociative (first <i>fac</i> → <i>mer</i> rearrangement, then migratory insertion) and the associative (first migratory insertion, then <i>fac</i> → <i>mer</i> rearrangement) pathways are in principle competitive. However, electronic effects of the phenyl substituents can favor one of the pathways. The study also points out the influence of the donor atom, due to the inversion at the donor atom required in order to achieve the <i>fac</i> → <i>mer</i> interconversion

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