A new family of drugs with antitumour properties based on organometallic compounds of palladium and platinum has been developed by a team of scientists from St Petersburg University, Belarusian State University, the Medicinal Chemistry Centre of Togliatti State University, and the Technische Universität Braunschweig.
The research results have been published in the in the New Journal of Chemistry of the Royal Society of Chemistry.
According to the World Health Organization, cancer is the second leading cause of death in the world. At present, a drug class based on platinum compounds is considered one of the most effective in combating cancerous tumours. The platinum compound most commonly used in clinical practice is cisplatin. However, its low water solubility and high general toxicity prompted research for new anticancer drugs based on platinum group metal compounds. To date, thousands of potentially active anticancer platinum complexes have been synthesised. Only five such compounds have been introduced into clinical practice so far. The main problem of the known platinum-based drugs is their high general toxicity. This is the rationale for searching for analogues based on other transition metals. The latter involves investigation of molecular mechanisms of drug action.
The scientists have synthesised and studied a new class of anticancer agents: palladium complexes with acyclic diaminocarbene (ADC) ligands and structurally identical platinum complexes. Palladium ADC complexes are often utilised in the catalysis of organic reactions, since they enable the synthesis of pharmaceutically important organic compounds in environmentally friendly conditions. However, no data on their biological activity had previously been reported.
We have tested the developed drugs on breast cancer cells and colon carcinoma cells. These are very dangerous types of oncological diseases, specific medications for which are being developed in the world. Both platinum and palladium complexes exhibit antiproliferative activity comparable to that of cisplatin, which has been the standard cancer treatment drug. Furthermore, palladium compounds exhibit lower levels of cytotoxicity in normal cells than platinum compounds.
Mikhail Kinzhalov, Candidate of Chemistry and Associate Professor of St Petersburg University
In the research conducted at the Medicinal Chemistry Centre of Togliatti State University, the scientists analysed cell death types caused by the developed drugs and identified the molecular mechanisms of cell death. The studied platinum and palladium compounds are capable of inducing apoptosis, or ‘cell suicide.’ Unlike necrosis, characterised by the premature death of cells in a living tissue, apoptosis is a programmed cell death involving cell fragmentation. In a few hours, the cell fragments are absorbed by phagocytes and neighbouring cells. As a result, the cancer cells are replaced by morphologically healthy tissue.
Visualisation of interaction of DNA with ADC compounds. The images obtained by atomic force microscopy (AFM) show the interaction of DNA with a palladium complex (A) and a platinum complex (B). For comparison purposes, AFM images of free DNA (C) and DNA-cisplatin adducts (D) are presented. The AFM images demonstrate conformational changes in DNA upon interaction with metal compounds. The interaction of DNA with new organometallic complexes is accompanied by the formation of intermolecular hydrogen bonds.
‘The study objectives were to find the compounds that exhibit the highest level of antiproliferative activity and to determine the mechanism of their action. The research findings show that several factors are responsible for the outcome. The primary selection criterion was high water solubility. The structure of the diaminocarbene fragments in the complexes proved to be of the utmost importance. The ADC binding to DNA occurs due to the formation of hydrogen bonds between the hydrogen atoms of the diaminocarbene fragments and the oxygen atoms of phosphate groups. In other words, the ability of ADC compounds to form hydrogen bonds correlates to their anticancer properties. The initial hypothesis has been supported in experiments with cells. Finally, the high trans influence of the carbene ligands facilitates the binding of the ADC complexes to the nitrogen-containing bases in DNA, with formation of multiple coordination bonds. This interferes with DNA synthesis in rapidly dividing tumour cells, causing their deaths, or impeding cell replication,’ explains Mikhail Kinzhalov, Associate Professor of St Petersburg University.
Thus, the scientists discovered the biological activity of palladium ADC complexes, which holds a promising opportunity for anticancer treatment. ‘According to popular belief, different strategies are required to develop efficient catalysts and effective therapeutic drugs. This discovery, conversely, indicates that the development of catalytic systems and drugs based on organometallic compounds share common principles,’ concludes Mikhail Kinzhalov. Currently, the research team is studying the biological activity of other compounds in this class.