Anticancer organometallic half-sandwich complexes of estrone-derived (N, N) donor ligands with enhanced aqueous solubility

Four steroidal derivatives (L1-4) bearing an (N,N) metal-chelating subunit on the D-ring, in addition to the organometallic [M(arene)(N,N)Cl]Cl complexes of L1,2 were synthesized and characterized, in which M(arene) is Rh(III)(eta 5-C5Me5) or Ir(III)(eta 5-C5Me5) or Ru(II)(eta 6-p-cymene). The solution chemical properties of both the estrone-based ligands and selected complexes were investigated by spectroscopic methods. At pH = 7.4, the ligands are predominantly positively charged, moderately lipophilic (logD7.4 = +0.6- +3.2), and exhibit low-to- medium micromolar solubility (S7.4 = 9-543 mu M) and are more hydrophilic than estrone; however, complexation improved the aqueous solubility of the obtained organometallics. The Rh(eta 5-C5Me5) and Ru(eta 6-p-cymene) complexes of L1 demonstrated high stability in solution (<1 % bidentate ligand dissociation at pH 7.4 for 48 h), forming a higher fraction of mixed hydroxido species [M(arene)(N,N)(OH)]+ in the case of the Ru complexes. Both coordination and intermolecular interactions of the organometallic complexes with human serum albumin were observed. The ligands and their complexes were tested in human cancer cell lines to investigate their in vitro anticancer activity. Studies in Colo-205 and MCF-7 cells revealed the moderate-to-strong cytotoxicity of the ligands (IC50 = 5-50 mu M) with limited selectivity toward cancer cells over the non-cancerous CCD-19Lu fibroblast cell line. Complexation increased the cytotoxicity, especially for Rh(III)(eta 5-C5Me5) and Ir(III)(eta 5-C5Me5) complexes in the MCF-7 cell line compared to the ligands.