Cytotoxic Rhodium(III) and Iridium(III) Polypyridyl Complexes: Structure–Activity Relationships, Antileukemic Activity, and Apoptosis Induction

<jats:title>Abstract</jats:title><jats:p><jats:bold>Whereas the cytostatic agents</jats:bold> <jats:italic>mer</jats:italic>‐[RhX<jats:sub>3</jats:sub>(DMSO)(pp)] (X=Cl, Br; pp=phen, dpq) are considerably more potent than their facial isomers, this order is reversed for the analogous kinetically more inert Ir<jats:sup>III</jats:sup> polypyridyl complexes. The complexes induce specific apoptotic cell death in leukemia and lymphoma cells via the intrinsic mitochondrial pathway and cause negligible necrotic damage.<jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/gif" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/mcontent.gif"><jats:alt-text>magnified image</jats:alt-text></jats:graphic></jats:boxed-text></jats:p><jats:p>Meridional rhodium(III) polypyridyl complexes of the type <jats:italic>mer</jats:italic>‐[RhX<jats:sub>3</jats:sub>(DMSO)(pp)] (X=Cl, pp=phen <jats:bold>1</jats:bold>, dpq <jats:bold>2</jats:bold>, dppz <jats:bold>3</jats:bold>; X=Br, pp=phen <jats:bold>4</jats:bold>) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the <jats:italic>mer</jats:italic> and the generally less active <jats:italic>fac</jats:italic> isomers. As a result, the IC<jats:sub>50</jats:sub> values of <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> toward HT‐29 cells increase from 0.19 and 0.069 μ<jats:sc>M</jats:sc> on immediate use in the dark to 0.66 and 0.312 μ<jats:sc>M</jats:sc>, respectively, after exposure of their DMSO stock solutions to light for 7 days. In striking contrast, the complexes <jats:italic>mer</jats:italic>‐[IrX<jats:sub>3</jats:sub>(DMSO)(phen)] (X=Cl <jats:bold>7</jats:bold>, Br <jats:bold>8</jats:bold>) are significantly less cytotoxic than their facial Ir<jats:sup>III</jats:sup> polypyridyl counterparts: IC<jats:sub>50</jats:sub>=20.3 μ<jats:sc>M</jats:sc> for <jats:bold>7</jats:bold> and 4.6 μ<jats:sc>M</jats:sc> for <jats:italic>fac</jats:italic>‐[IrCl<jats:sub>3</jats:sub>(DMSO)(phen)] <jats:bold>5</jats:bold> toward MCF‐7 cells. The IC<jats:sub>50</jats:sub> values for the complexes <jats:italic>fac</jats:italic>‐[IrX<jats:sub>3</jats:sub>(L)(pp)] <jats:bold>9</jats:bold>–<jats:bold>13</jats:bold> decrease in the orders: a) Cl>Br for X and b) H<jats:sub>2</jats:sub>O>DMSO for L. Specific apoptotic cell death by DNA fragmentation was detected for leukemia (NALM‐6) and lymphoma (BJAB) cells after incubation with <jats:bold>2</jats:bold>, <jats:bold>3</jats:bold>, and <jats:bold>11</jats:bold> (X=Br, L=H<jats:sub>2</jats:sub>O, pp=phen) for 72 h. Loss of the mitochondrial membrane potential in lymphoma cells indicates that apoptosis is mediated via the intrinsic mitochondrial pathway. LDH release assays after 1 or 3 h demonstrate that necrotic damage is negligible.</jats:p>