Rational Design of Metal-Based Pharmacologically Active Compounds

Metal-based pharmacologically active compounds have been associated with many processes in vivo, acting as active sites of metalloproteins [1], natural and artificial metalloenzymes [2], and a variety of metal-based therapeutic and diagnostic complexes; in addition, they have been used in medicine as drugs and imaging agents and have been shown to have potential pharmacological activity [3]. Analyzing the specific properties and modes of action of newly reported metal-based agents could enable a more rational development of novel bioactive drugs in order to improve their pharmacological potential and range of activity.

Encompassing a carefully curated selection of research articles and review papers, this Special Issue, entitled “Rational design of metal-based pharmacologically active compounds”, focuses on the structure, properties, and modes of action of metal-based compounds and the most recent advances in research on their pharmacological effects and relevant applications. Metal-based agents represent various classes of promising candidates in anticancer therapy. In spite of the great interest they attract, their mechanisms and targets remain to be clarified. The nature of the metal cations and ligands, oxidation states, ligand exchange chemistry, and physicochemical properties, etc., of these compounds are of great importance for their reactivity on the cellular level, given that they modify their activity and affinity for the respective intracellular targets. Currently, research in the area of metal-based bioactive agents is directed at the rational design of chemotherapeutic candidates with specific biotargets. Thus, at the core of this Special Issue are the theoretical, analytical, and physicochemical approaches to the drug design of biologically active metal-containing compounds. We aim to provide the reader with up-to-date information on various aspects of this attractive interdisciplinary research field.

Metal-based complexes are mostly known as potent cytotoxic candidates applied in cancer therapy and diagnostics. The hard work of numerous scientific teams has given rise to the development of many metal-based drugs, which contain various bioactive organic ligands modulating their activity. The reported metal-based agents operate via different modes of action, which are still poorly characterized due to their various intracellular biomolecular targets. A significant number of studies have demonstrated that Cu(II)-based complexes with low toxicity and side effects can effectively act as potential antitumor and antibacterial agents [4]. Maity et al. [5] provide a comprehensive experimental and theoretical investigation of the biological effects of a new copper(II) complex of an aryl-derivative of the well-known pharmacophore semicarbazone [6]. Cu(II) complexes of semicarbazones have been found to display promising anticancer activity via an apoptotic mechanism and DNA intercalation [7]. Using various spectroscopic methods, Maity et al. [5] evaluated the cytotoxic activity of newly synthesized Cu(II) complex of aryl-semicarbazone against human cervix uteri carcinoma (SiHa cell line), as well as its potential binding interaction efficiency with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA). They proved that the compound bonded with CT-DNA through partial intercalation and hydrophobic interaction. The interaction with BSA protein was characterized as hydrogen bonding or a van der Waals interaction, instead of a hydrophobic one. The in vitro cytotoxicity results revealed strong anti-proliferative effects, with a substantial decrease in tumor cell viability.

Photodynamic therapy (PDT) has attracted extensive consideration for the treatment of different conditions, including cancer [8]. PDT utilizes photosensitizers (PSs), which can be photoactivated to produce reactive oxygen species (ROS) such as ¹O₂, O₂⁻, HO^⋅, or H₂O₂, mainly involved in cell death. At present, the most broadly used PSs are porphyrins, chlorins, bacteriochlorins, and phthalocyanines. Among metal-based anticancer chemotherapeutic agents, ruthenium complexes have received great attention because of their specific properties [9,10,11]. The combination of PDT with Ru-based chemotherapy has recently been introduced. Massoud et al. [12] studied the association of Ru-based agents and photosensitizers in a single molecule for the chemo- and photodynamic treatment of tumor growth. The authors synthesized arene–Ru tetrapyridylporphyrin compounds and assessed their cytotoxicity and phototoxic effects against colorectal cancer (CRC) cell lines such as HCT116 and HT-29. The compounds’ possible mechanism of action and process of cell death were also studied. CRC is the third most prevalent cancer worldwide, and substantial progress has recently been attained in its treatment, although an increased resistance and the constant toxic side effects on healthy cells still remain major problems. The results of the study [12] showed that the obtained arene–Ru photosensitizer-based compounds had good phototoxic effects, inducing apoptotic processes in human HCT116 and HT-29 CRC cells. Cell cycle distribution, phosphatidylserine externalization, caspase-3 activation, poly-ADP ribose polymerase (PARP) cleavage, and DNA fragmentation were also examined. In addition, the Ru-based assemblies generated cellular ROS production and exerted their anticancer activity through apoptosis, which characterizes them as good candidates for a PDT and chemotherapy combination approach. The presence of ruthenium ions was found to be crucial for the studied compounds, clearly demonstrating that the combination of metal ions and PS in Ru-based assemblies is an important strategy in PDT for the treatment of CRC.

The study of the modes of action of metal-based drugs is essential for the advancement of more efficient treatment approaches. Metabolomics, focused on the examination of metabolites (organic acids, amino acids, nucleotides, sugars, etc.), determines the variations in metabolites induced by drugs on the intracellular and extracellular levels. The respective discrepancies could be directly associated with the up- or down-regulation of precise pathways of mechanisms of action. This method offers the opportunity to recognize the specific markers of tumor sensitivity or resistance to metal-based antitumor agents. In this regard, NMR metabolomics is widely used to estimate the metabolic responses of tumor cells to diverse metal-based compounds. A review by Ghini [13] displays how ¹H NMR metabolomics offers an excellent, powerful tool to examine the metabolic alterations induced by metallodrugs at the cellular level. This relatively fast approach is particularly suitable for the study of the modes of action of metallodrugs, which have various unrecognized intracellular targets. With the use of NMR, the chemical character of metal-based drugs, as well as the concentration of metabolites and their growth, can be observed as a global fingerprint which defines the drug treatment responses. In this context, the application of NMR-based metabolomics to investigate the cellular properties caused by treatment with antineoplastic metallodrugs is described in depth [13]. The author reviews Pt(II)- and Pd(II)-based, Ru(III)-, and Au(I)-based classes of classical potent antineoplastic compounds reported in the literature, including the well-known cisplatin, oxaliplatin, carboplatin, Pd(II)–spermine, NAMI-A, NKP1339, GA113, and auranofin, along with their detected metabolites. Additionally, the application of NMR metabolomics in the investigation of drug resistance, particularly cisplatin resistance, is also described.

The ions of transition metals (Fe, Cu, Zn, etc.) have been shown to play a vital role in many bioprocesses, including brain functions and the respective neurodegenerative disorders, such as Alzheimer’s disease [14]. Numerous Alzheimer’s disease treatments have recently been tried, but none of them are definitive or conclusive as of yet. One of the most promising methods for Alzheimer’s disease therapy is to reduce the toxicity of the neurotoxic amyloid-β protein, accumulated in the brain under pathological conditions. One option is to decrease its toxicity by altering the secondary protein structure. One of the methods is infrared free-electron laser (IR-FEL) irradiation, which changes the protein structure. In addition, it has been found that the binding of amyloid-β to metals such as Al, Fe, Cu, and Zn is synaptotoxic and causes neuronal cell death during IR-FEL irradiation [15]. In a study by Takashima et al. [16], changes in the secondary structure of the protein are investigated by binding salen-type Schiff base Zn(II) complexes to human serum albumin (HSA) and irradiating them with IR-FEL. Thanks to the introduction of Zn(II) complexes, structural changes are observed in the ratio of the α-helix and β-sheet of the secondary structure of HAS. Thus, this approach is expected to become an effective method for the preventive treatment of Alzheimer’s disease [17].

Along with the recognized d-block Pt(II)/Pt(IV), Pd(II), Ru(II)/Ru(III), Au(I)/Au(III), Ag(I), Ti(IV), and p-block Ga(III) therapeutic complexes, many other metal complexes with antiproliferative activity have been extensively studied and reported in recent years [18]. Kostova reviewed the potential activity of metals and metalloids from the main groups in the periodic table and their complexes with antineoplastic activity, described as potent chemopharmaceutics [19]. Some of these complexes and organometallic compounds exhibit entirely different and specific mechanisms of action, as well as different biotargets. Many metals and metalloids from the s- and p-blocks of elements are not vital for the organism, but they have been shown to hinder carcinogenesis anyway. The systematic study of the main group of metals and their coordination compounds could reveal new classes of cytotoxic drugs with better pharmacological profiles and selectivity, low toxicity, and specific mechanisms of action and spectra of activity different from those of classical metallodrugs, thus providing new alternative strategies and novel guidelines for upcoming research. The s- and p-block elements (Ga, In, Tl, Ge, Sn, Pb, As, Sb, Bi, Se, Te, At) and their compounds reviewed by the author have been shown to offer new design opportunities based on their multifaceted coordination chemistry. These elements differ from each other in terms of their chemical interactions, oxidation states, and chemical bonding—all this connected with their specific biological activity and modes of action. It has been demonstrated that the metal- and metalloid-based compounds of these elements possess interesting biological functions and are viable therapeutic or diagnostic candidates in both chemotherapy and radiotherapy. Further investigations are required to provide more information in this interesting field of research.

As the Guest Editor of the Special Issue “Rational design of metal-based pharmacologically active compounds”, I sincerely hope that readers of Inorganics will find information of interest for future studies that address the critical challenges in the field of chemical, biological, and medical scientific investigations into the design of metal-based bioactive compounds.