Ether-Substituted Group 4 Metallocene Complexes: Cytostatic Effects and Applications in Ethylene Polymerization

The synthesis of the ether-substituted group 4 metallocene complexes [Ti­(η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)­(η<sup>5</sup>-C<sub>5</sub>H<sub>4</sub>{CMeRCH­(OMe)<sub>2</sub>})­Cl<sub>2</sub>] (R = Me (<b>4</b>), Ph (<b>5</b>)) and [M­(η<sup>5</sup>-C<sub>5</sub>H<sub>4</sub>{CMeRCH­(OMe)<sub>2</sub>})<sub>2</sub>Cl<sub>2</sub>] (M = Ti, R = Me (<b>6</b>), Ph (<b>7</b>); M = Zr, R = Me (<b>8</b>), Ph (<b>9</b>)) is reported. In addition, the titanocene derivatives <b>4</b>–<b>7</b> have been supported on the mesoporous silica-based material KIT-6, giving the functionalized materials <b>K4</b>–<b>K7</b>, respectively. All compounds and materials have been characterized by different analytical techniques such as solution NMR spectroscopy, mass spectrometry, elemental analysis, solid-state multinuclear NMR spectroscopy, IR spectroscopy, N<sub>2</sub> adsorption–desorption isotherms, X-ray fluorescence and diffraction, SEM, and TEM. Additionally, the molecular structures of the zirconocene derivative <b>8</b> and the hydrolysis product [Ti­(η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)­(η<sup>5</sup>-C<sub>5</sub>H<sub>4</sub>{CMe<sub>2</sub>COO})­Cl] (<b>4a</b>) of titanocene complex <b>4</b> have been determined by X-ray diffraction studies. The structure of <b>4a</b> reveals a five-membered metallacyclic arrangement. The ether-substituted titanocene compounds <b>4</b>–<b>6</b> and the functionalized material <b>K5</b> have been tested for their antiproliferative and cytotoxic effects in vitro in three human cancer cell lines (A549 lung adenocarcinoma, MCF-7 breast adenocarcinoma, and HCT-116 colorectal adenocarcinoma), as well as in normal human fibroblasts. Compounds <b>4</b>–<b>6</b> and <b>K5</b> showed moderate but specific cytostatic effects. Moreover, additional studies related to the hydrolytic stability (for <b>4</b>–<b>7</b>) and DNA interaction (for <b>6</b>) have been carried out. Finally, taking into account the feasible applicability of metallocene complexes, a preliminary ethylene polymerization study has been performed using the two synthesized zirconocene compounds (<b>8</b> and <b>9</b>).