Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects

Abstract

One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.

An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

“…After overnight incubation (16 h) at 37 °C in a 5 % CO 2 humidified atmosphere, the cells were treated with the tested compounds in the range 0 to 50 μ m in a final volume of 200 μL/well. After an additional 72 h, 20 μL of a freshly diluted MTT solution (1.25 mg mL −1 in PBS) was added to each well, and the plates were incubated at 37 °C in a humidified 5 % CO 2 atmosphere for 4 h. Other details can be found in previously published articles ,. Compound concentrations that induce 50 % cell death (IC 50 ) were calculated from curves constructed by plotting cell survival (%) versus drug concentration (μ m ).…”

Ruthenium–arene complexes with NSAIDs: synthesis, characterization and bioactivity

“…The potential of different metal ions conjugated to NSAIDs to damage DNA and alter the cell cycle was previously demonstrated. [58][59][60] Recent investigation by Kasparkova and colleagues 58 of new Pt(II) conjugates carrying the NSAID diclofenac demonstrated their potential to act as a so-called ''combi-molecule'' which combines the DNA-binding properties of the metal center and antitumor properties of NSAID ligands for cytotoxic activity.…”

Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG)

“…Coordination of bioactive ligands to platinum drugs is an established strategy, which can improve solubility, also having the potential to result in a synergistic anti-cancer effect, since the platinum fragment and bioactive ligand typically exert anticancer activity through different mechanisms. [11][12][13][14] Several types of therapeutics have been coordinated to platinum complexes, including kinase inhibitors 15 anti-inflammatories, 16 and HDAC inhibitors (see Fig. 2).…”