Design, Synthesis, and Preclinical Activity in Ovarian Cancer Models of New Phosphanegold(I)-N-heterocyclic Carbene Complexes
Adam A. A. Sulaiman, Naike Casagrande, Cinzia Borghese, Giuseppe Corona, Anvarhusein A. Isab, Saeed Ahmad, Donatella Aldinucci, Muhammad Altaf
Abstract
A new series of seven gold(I) complexes ( 1 – 7 ) containing 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and phosphane ligands (L1–L7) were synthesized and evaluated for antitumor activity in ovarian cancer (OvCa) models. The synthesized complexes were characterized by IR, mass spectrometry and NMR spectroscopy, and complex 6 was characterized by XRD crystallography. The antiproliferative effect of the new complexes ( 1 – 7 ) was found to be higher than cisplatin and auranofin in OvCa cells sensitive and resistant to cisplatin. The anticancer activity of the most active complex 6 was investigated using OvCa in vitro models, including three-dimensional (3D) multicellular tumor spheroids and in vivo tumor xenografts. Both cisplatin and auranofin were used for comparative purposes. Complex 6 induced apoptosis, mitochondrial reactive oxygen species, and DNA damage; caused a G1 phase cell cycle arrest, inhibited proteasome activity, and cell migration; modified actin polymerization; and significantly inhibited OvCa murine xenografts. These promising results suggest further preclinical testing of these complexes for future applications.