Original Multivalent Copper(II)-Conjugated Phosphorus Dendrimers and Corresponding Mononuclear Copper(II) Complexes with Antitumoral Activities

Abstract

Novel multivalent copper(II)-conjugated phosphorus dendrimers and their corresponding mononuclear copper(II) complexes were synthesized, characterized, and screened for antiproliferative activity against human cancer cell lines. Selected copper ligands were grafted on the surface of phosphorus dendrimers of generation G(n) (n = 1 to 3): N-(pyridin-2-ylmethylene)ethanamine for dendrimers 1G(n), N-(di(pyridin-2-yl)methylene)ethanamine for dendrimers 2G(n), and 2-(2-methylenehydrazinyl)pyridine for dendrimers 3G(n). The results indicated that the most potent derivatives are 1G(n) and 1G(n)-Cu versus 2G(n), 2G(n)-Cu, and 3G(n), 3G(n)-Cu. A direct relationship between the growth inhibitory effect and the number of terminal moieties or the amount of copper complexed to the dendrimer was observed in copper-complexed 1 series and noncomplexed 1 series. These data clearly suggested that cytotoxicity increased with the number of terminal moieties available and was boosted by the presence of complexed Cu atoms. Importantly, no cytotoxic effect was observed with CuCl2 at the same concentrations. Finally, 1G3 and 1G3-Cu have been selected for antiproliferative studies against a panel of tumor cell lines: 1G3 and 1G3-Cu demonstrated potent antiproliferative activities with IC50 values ranging 0.3-1.6 μM. Interestingly, the complexation of the terminal ligands of 1G3 dendrimers by copper(II) metal strongly increased the IC50 values in noncancer cells lines referred to as "safety" cell lines.

Recent therapeutic applications of the theranostic principle with dendrimers in oncology

“…Recently Mignani, Cresteil and Majoral et al [86] de- scribed first-in-class phosphorhydrazone dendrimers which were capped with pyridine imine terminal functions (free or complexing Cu(II)) showing good anticancer properties against a number of cancerous cell lines. The third generation was shown the most potent derivatives, with IC 50s values ranging 0.3-1.6 μmol.…”

Nanoformulations of a Potent copper-based Aquaporin Inhibitor With Cytotoxic Effect Against Cancer Cells

“…This has led to the design and development of novel technologies based on nanostructured materials, acting mainly as vectors for metallodrug delivery or simply as protectors of active species of the complexes for amplifying their activities and reducing their degradation [25,26]. In the case of anticancer copper complexes, few reports in the literature describe their delivery via TiO 2 nanoparticles or via conjugation to phosphorus dendrimers [27].…”

First-in-Class Combination Therapy of a Copper(II) Metallo-Phosphorus Dendrimer with Cytotoxic Agents

“…1G3-Cu was synthesized as previously described [6]. DMSO kept in the darkness was from the highest purity grade available at Sigma.…”

“…Numerous biological studies have been carried out using dendrimers, and their potential in various domains has been highlighted in review articles [5]. Dendrimers display a highly branched, three-dimensional architecture with an exponential number of dendritic branches radiating out from a central core [6]. Recently, StarPharma developed DEP ® -docetaxel (polylysine dendrimer-docetaxel) with remarkable preclinical results including an extended drug halflife and a higher tumor delivery than the native docetaxel [7].…”

“…The most promising dendrimer is 1G3-Cu bearing 48 complexed Cu(II) moieties with N-(pyridin-2-ylmethylene) ethanamine motif on its surface ( Fig. 1; for more details see [6]). 1G3-Cu demonstrated good antiproliferative potency against a panel of tumor cell lines with IC 50 s values ranging from 0.3 to 0.8 μM.…”