Multichiral Half-Sandwich Ru(II) and Os(II) Anticancer Complexes Containing a Glutathione Synthesis Inhibitor

Two novel half-sandwich organometallic complexes, [(<i>p</i>-cymene)-M-(XY)-Cl], XY = <i>L</i>-BSO, M = Ru^II (<b>Ru-LBSO</b>), Os^II (<b>Os-LBSO</b>), containing the amino acid <i>L</i>-buthionine sulfoximine (<i>L</i>-BSO), as well as their XY = glycine analogs (<b>Ru-Gly</b> and <b>Os-Gly</b>), have been synthesized, characterized and their solution chemistry investigated. <i>L</i>-BSO is an inhibitor of the enzyme γ-glutamyl cysteine synthetase and, hence, glutathione synthesis. The diastereomers of <b>Ru-LBSO</b> and <b>Os-LBSO</b> were also characterized by DFT calculations which suggested the higher stability of [S_M,r_S] and [S_M,s_S] compared to [R_M,r_S] and [R_M,s_S] configurations [chirality at M-(II), chirality at sulfur of <i>L</i>-BSO]. Interestingly, glycine complexes are non-toxic toward both cancer and normal cells, whereas <b>Os-LBSO</b> was cytotoxic toward human IGROV-1 ovarian cancer cells, but not toward lung and cervical cancer cells. <b>Os-LBSO</b>, but not <b>Ru-LBSO</b>, demonstrated glutathione inhibition. These studies on <b>Ru-LBSO</b> and <b>Os-LBSO</b> complexes demonstrate the challenges of making progress toward the development for clinical use of organometallic complexes that contain multiple chiral centers. However, they offer exciting possibilities for discovery of novel drugs with new mechanisms of action.