Abstract
Overheating can affect solubility or lipophilicity, among other properties, of some anticancer drugs. These temperature-dependent changes can improve efficiency and selectivity of the drugs, since they may affect their bioavailability, diffusion through cell membrane or activity. One recent approach to create thermosensitive molecules is the incorporation of fluorine atoms in the chemical structure, since fluor can tune some chemical properties such as binding affinity. Herein we report the anticancer effect of gold derivatives with phosphanes derived from 1,3,5-triaza-7-phosphaadamantane (PTA) with long hydrocarbon chains and the homologous fluorinated chains. Besides, we analysed the influence of temperature in the cytotoxic effect. The studied gold(I) complexes with phosphanes derived from PTA showed antiproliferative effect on human colon carcinoma cells (Caco-2/TC7 cell line), probably by inhibiting cellular TrxR causing a dysfunction in the intracellular redox state. In addition, the cell cycle was altered by the activation of p53, and the complexes produce apoptosis through mitochondrial depolarization and the consequent activation of caspase-3. Furthermore, the results suggest that this cytotoxic effect is enhanced by hyperthermia and the presence of polyfluorinated chains.
Highlights
Mitochondria have emerged as important biological targets, since they are known as an essential biosynthetic, bioenergetic, and signalling organelles, playing a key role in cellular differentiation, proliferation, and death [1]
Previous studies with gold derivatives had shown disturbances in Reactive Oxygen Species (ROS) balance when cancerous cells were treated with metal complexes [16,55,56], commonly increasing intracellular ROS levels, since different gold(I) derivatives have been proved to interact with thioredoxin reductase (TrxR) inhibiting its antioxidant activity [14,56]
We have synthesized and fully characterized six new gold(I) derivatives and two new alkylated PTA (1,3,5-triaza-7-phosphaadamantane) ligands functionalised with long hydrocarbon chains and with the homologous fluorinated chains with the purpose of knowing the influence of the fluorine atoms and an increase of the temperature, hyperthermia, in the activity
Summary
Mitochondria have emerged as important biological targets, since they are known as an essential biosynthetic, bioenergetic, and signalling organelles, playing a key role in cellular differentiation, proliferation, and death [1]. Most of the anti-mitochondrial metal complexes are Au-, Ru-, Ir- and Pt-based compounds and exert their activity via mitochondrial damage and mitochondria-mediated apoptosis, thioredoxin reductase inhibition and/or interaction with protein translocators. Au(I)-N-heterocyclic carbene complexes constitute one of the most studied groups of mitochondria-targeting lipophilic cationic metal derivatives. Thermoresponsive small molecules [29], such as arene ruthenium complexes [30,31], platinum compounds [32] and chlorambucil derivatives [33], both with long polyfluorinated appendages, have shown an increased cytotoxic activity under hyperthermia conditions. With this idea we describe here the synthesis of gold derivatives with phosphanes derived from 1,3,5-triaza-7-phosphaadamantane (PTA) after introduction of perfluorinated chains in order to lead to thermoresponsive properties. The new complexes were tested against human colon carcinoma cells (Caco-2 cells) at 37 ◦ C and following a hyperthermia treatment at 40 ◦ C and their possible intracellular target was studied, including TrxR and possible mitochondrial disturbances and apoptotic implications
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
