Ni(II), Pd(II), and Pt(II) Complexes of the Hedgehog Pathway Inhibitor GANT61‑D

• Published in: Inorganic chemistry 2019-12, Vol.58 (23), p.16075-16086
• Main Authors: Ryan, Aisling L, Fitzgerald, Marie-Claire, Ozsváth, András, Twamley, Brendan, Buglyó, Péter, Murphy, Brona M, Griffith, Darren M
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Nickel - chemistry; Nickel - pharmacology; Palladium - chemistry; Palladium - pharmacology; Platinum - chemistry; Platinum - pharmacology
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.9b02632

GANT61-D is an important hedgehog pathway inhibitor and an interesting ligand candidate for metal coordination. The first examples of metal complexes of the potent hedgehog pathway inhibitor GANT61-D are described. The reaction of Ni­(II), Pd­(II), and Pt­(II) precursors with the hedgehog pathway inhibitor GANT61-D gave [NiII(GANT61-D)­(OH2)3(μ2-SO4)­(μ3-SO4)] (1), [PdII(Cl)­(GANT61-D)]Cl (2), [PtII(Cl)­(GANT61-D)]­Cl, and [PtII(CBDCA–2H)­(GANT61-D)]. X-ray crystal structure analysis revealed that GANT61-D is a versatile N-donor ligand that can act as a bidentate ligand via the diaminopropane (DAP) N atoms or a tridentate ligand via the DAP N atoms and one dimethylaniline N atom. Protonation constants of the GANT61-D ligand in water and in a 60:40 (w/w) dimethyl sulfoxide–water solvent mixture were determined. Potentiometric and spectroscopic data on the NiII(GANT61-D) system indicate the formation of octahedral 1:1 species with medium stability in solution. 1 and 2 exhibited noteworthy in vitro cytotoxicity against medulloblastoma cancer cells.