Homoleptic phosphino copper(i) complexes with in vitro and in vivo dual cytotoxic and anti-angiogenic activity

Abstract

Homoleptic, tetrahedral Cu(i) complexes of the type [Cu(P)4]BF4 (1-3), where P are the phosphine ligands, 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) and 2-thia-1,3,5-triaza-phosphoaadamantane-2,2-dioxide (PTA-SO2), have been prepared. Novel complexes [Cu(DAPTA)4]BF42 and [Cu(PTA-SO2)4]BF43 have been fully characterized by means of spectroscopic methods, corroborated by XAS-EXAFS analysis of 2. In vitro cell culture experiments revealed a significant antiproliferative activity for Cu(i) compounds against several human cancer cell lines derived from solid tumors with preferential cell growth inhibition towards tumour compared to non-malignant cells. In vitro monitoring of migration and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) showed an anti-angiogenic effect of copper(i) complexes at sub-cytotoxic concentrations. In vivo studies on the antitumor efficacy and ability to inhibit angiogenesis confirmed the dual cytotoxic and anti-angiogenic properties of Cu(i) derivatives.

New Findings in Metal Complexes with Antiproliferative Activity Containing 1,3,5‐Triaza‐7‐phosphaadamantane (PTA) and Derivative Ligands

“…Complexes [Cu(PTA) 2 ] + , [Cu(PTA) 3 ] + and [Ag(PTA) 2 ] + are predicted to be the species involved in the cytotoxic mechanism of these compounds. [36] Furthermore, the complex [Cu(THP) 4 ]PF 6 displays efficacy in the treatment of Lewis pulmonary tumour in mice in both early and advanced stage treatment schedule. [35] Complex 39 is neurotoxic, and produces the inhibition of proteasome activity in DRG neurons even at lower concentrations than the IC 50 , while copper complex 37 does not induce neurotoxicity.…”

Heteroleptic Copper(I) Complexes of “Scorpionate” Bis-pyrazolyl Carboxylate Ligand with Auxiliary Phosphine as Potential Anticancer Agents: An Insight into Cytotoxic Mode

“…In this regard, copper has attracted significant interest, since it plays key roles in biochemical processes such as nitrite reductase22, amine oxidases23, superoxide dismutase24, catechol oxidase25 and tyrosinase26. Copper(II) complexes have been intensily studied1027 whereas the potential of Cu(I) complexes has been scarcely tested as antimicrobial28, antiviral29, antifungal30 and anticancer drugs1731323334. Mostly, coordination compounds having S-/N-donor and/or phosphine ligands are highly suitable candidates for clinical investigation, given their proven cytotoxicity on cancer cells and high stability in aqueous solution35.…”

Evaluation of the Modulatory Effects of Copper Salts on the Process of Angiogenesis (Neovascularization) with Therapeutic Perspectives

“…Cu in the form of salt (CuSO 4 ) or nanoparticles, when introduced into chicken embryos did not interfere with embryonic growth or development, but has been shown to increase angiogenesis via increasing the mRNA of activators like VEGF and FGF (Mroczek-Sosnowska et al, 2015). Recently, in few reports, contradictory to previous findings, Cu has been found to be anti-angiogenic too (Chang et al, 2015;Gandin et al, 2015 …”

“…Chang et al (2015) revealed that CuO nanoparticles down-regulated the expression of vascular endothelial growth factor (VEGF) and VEGF receptors in endothelial cells. Homoleptic phosphino copper (I) complexes also repressed angiogenesis by inhibiting the fundamental steps of blood vessel formation like endothelial cell adhesion, migration, alignment, protease secretion and tubule formation (Chang et al, 2015;Gandin et al, 2015). The reason behind the contradictory behaviour can be explained on the basis of nature of material used for study, like solubility, ionic strength, dissociation constant and pH change in microenvironment surrounding the affected area.…”