Bioinorganic chemistry
Coordination compounds exhibit a broad range of biological activities and represent a rapidly evolving research area at the borderline between inorganic chemistry, biochemistry and pharmacology.
The bioinorganic research established at our Department comprises especially the following subjects:
- Research on metal complexes with antiradical activity, especially copper complexes acting as mimics of the enzyme superoxide dismutase (SOD).
Reactive oxygen species (e.g., superoxide radicals) are among the products of normal cell metabolism. Environmental influences or pathological changes in the cell can cause increased production of these highly reactive species, leading to damage to biomolecules present in the cell and impairment of normal cellular function. This is regarded as contributing to the development of numerous diseases, such as cancer, diabetes and cardiovascular diseases. In the living organism there are several regulatory mechanisms able to cope with the surplus of free radicals in the cell. One of them is the enzyme superoxide dismutase, catalyzing the transformation of superoxide radicals to hydrogen peroxide and molecular oxygen according to the reaction:
2O2-⋅ + 2H+ → H2O2 + O2
Antioxidants are chemical compounds reducing the concentration of free radicals in the organism. Some of them are used as antioxidants in pharmacy or food industry and as food additives. These substances have a protective effect on the cell and are expected to guard against various medical conditions caused by the excess of free radicals.
Besides antioxidants of natural origin (e.g., flavonoids, carotenoids, vitamin C) there are numerous synthetic substances exerting antiradical activity. Among the most effective antioxidants are metal complexes, especially with copper, but also with iron, manganese, vanadium, etc.
Synthesis of coordination compounds with antiradical activity has a long-standing tradition in our Department. These are mainly copper complexes, e.g., the copper(II) complex with a reduced Schiff base, depicted in Fig. 1. Antiradical activities of the prepared complexes are investigated by several methods, such as DPPH (reaction with 2,2-diphenyl-1-picrylhydrazyl radical) or INT (inhibition of the production of a formazan dye).
Fig. 1.Selected publications:
Lintnerová L, Valentová J, Herich P, Kožíšek J, Devínsky F: Synthesis and antiradical activity of novel copper(II) complexes of long chain reduced Schiff base ligands. Monatshefte für Chemie – Chemical Monthly 149 (2018) 901-911. doi:10.1007/s00706-017-2137-z
Lintnerová L, Valentová J, Devínsky F: Antiradical activity of L-glutamine, L-asparagine and L-aspartic acid derived reduced schiff base copper(II) complexes. Studia Universitatis Babes-Bolyai Chemia 61 (2016) 85-98.
Puterová Z, Valentová J, Bojková Z, Kožíšek J, Devínsky F: Synthesis, crystal structure and antiradical effect of copper(II) Schiff base complexes containing five-, six- and unusual seven-membered rings. Dalton Transactions 40 (2011) 1484-1490. doi:10.1039/C0DT00901F
Contact: doc. PharmDr. Jindra Valentová, PhD., Mgr. Lucia Lintnerová, PhD.
- Metal complexes as prospective drugs for antimicrobial and anticancer chemotherapy.
Starting with the discovery of the anticancer effects of cisplatin in the late 1960s rapid development in the field of metallodrugs took off. Since that time a great number of coordination compounds with various metals have been investigated for their activity against cancer and infectious diseases.
Cisplatin has established itself as one of the most efficient anticancer drugs and, to this day, the most successful metallodrug. Despite its high efficiency in certain cancers the clinical application is limited by the occurence of resistance, be it intrinsic or acquired in the course of therapy. A serious problem is also its considerable systemic toxicity. To address these drawbacks, new anticancer drugs based on platinum complexes have been developed and introduced into clinical practice, prominent among them being carboplatin and oxaliplatin. The research in this area is still going on, with the aim of preparing compounds with increased and broader activity along with diminished toxicity.
At present, the attention of the researchers concentrates besides platinum also on other metals. In this regard, one of the most interesting metals is vanadium. Coordination compounds of vanadium show a wide range of bioactivities - anticancer, antimicrobial and antidiabetic, among others. An example from our research is vanadium(IV) complex depicted in Fig. 2, exhibiting cytotoxic activity in a cell line resistant against oxaliplatin.
Fig. 2.
In addition to aforementioned complexes, we concentrate also on other metals. Another attractive research subject is the area of antimicrobial therapy, recently gaining attention due to increased occurence of microbial pathogens resistant against standard therapies, since metal complexes are often capable of retaining their activity even in resistant bacterial strains.
Complexes of palladium are among the most promising metallodrugs, partly also because of the structural analogy between palladium and platinum complexes. Some of these complexes were found to exhibit anticancer activity even in cell lines resistant against cisplatin.
In the course of our research work, palladium(II) complexes derived from curcumin have been prepared. Curcumin is a compound of natural (plant) origin with marked antiradical, antiinflammatory and anticancer properties. The complexes exhibited strong growth inhibition in several cancer cell lines. One of the prepared complexes is shown in Fig. 3.
Fig. 3.
Selected publications:
Habala L, Pašková Ľ, Bilková A, Bilka F, Oboňová B, Valentová J: Antimicrobial activity and cytotoxicity of transition metal carboxylates derived from agaric acid. European Pharmaceutical Journal 68 (2021) 46-53. doi:10.2478/afpuc-2020-0018
Miklášová N, Herich P, Dávila-Becerril JC, Barroso-Flores J, Fischer-Fodor E, Valentová J, Leskovská J, Kožíšek J, Takáč P, Mojžiš J: Evaluation of antiproliferative palladium(II) complexes of synthetic bisdemethoxycurcumin towards in vitro cytotoxicity and molecular docking on DNA sequence. Molecules 26 (2021) 4369. doi:10.3390/molecules26144369
Valentová J, Varényi S, Herich P, Baran P, Bilková A, Kožíšek J, Habala L: Synthesis, structures and biological activity of copper(II) and zinc(II) Schiff base complexes derived from aminocyclohexane-1-carboxylic acid. New type of geometrical isomerism in polynuclear complexes. Inorganica Chimica Acta 480 (2018) 16-26. doi:10.1016/j.ica.2018.04.058
Fischer-Fodor E, Mikláš R, Rišiaňová L, Cenariu M, Grosu IG, Virag P, Perde-Schrepler M, Tomuleasa C, Berindan-Neagoe I, Devínsky F, Miklášová N: Novel palladium(II) complexes that influence prominin-1/CD133 expression and stem cell factor release in tumor cells. Molecules 22 (2017) 561. doi:10.3390/molecules22040561
Habala L, Bartel C, Giester G, Jakupec MA, Keppler BK, Rompel A: Complexes of N-hydroxyethyl-N-benzimidazolylmethylethylenediaminediaceticacid with group 12 metals and vanadium—Synthesis, structure and bioactivity of the vanadium complex. Journal of Inorganic Biochemistry 147 (2015) 147–152. doi:10.1016/j.jinorgbio.2015.04.004
Habala L, Valentová J: Metal complexes in medicine and pharmacy – the past and the present I. Česká a Slovenská Farmacie [Czech and Slovak Pharmacy] 67 (2018) 182-191 (download - Slovak version).Contact: Ing. Ladislav Habala, PhD., Mgr. Natalia Lucia Miklášová, PhD.
- Interactions between metal complexes and biomolecules (e.g., enzymes).
Numerous metal complexes exert marked inhibition activity towards certain enzymes. The mechanism of this inhibition is often different from purely organic inhibitors and is not yet sufficiently investigated. Inhibition of enzymes implied in the pathogenesis of various diseases is among the most important directions in the development of new medical drugs. One such enzyme is urease, a metalloenzyme containing nickel in the active center and catalyzing the decomposition of urea into ammonia and carbon dioxide. Urease is involved in the pathogenesis of several diseases, especially those connected with the bacterial pathogens Helicobacter pylori, Yersinia enterocolitica, Proteus mirabilis and Mycobacterium tuberculosis.
The bacterium Helicobacter pylori colonizes the upper gastrointestinal tract (stomach) and is implied in the development of diseases such as gastric ulcer and gastric cancer. For its survival the bacterium needs to adapt to a highly acidic environment in stomach. To achieve this, it activates the enzyme urease and starts the production of ammonia from urea, leading to an increase in pH.
Transition metal complexes are among the strongest known inhibitors of urease. The majority of cations of the metallic elements, to a greater or lesser degree, inhibit urease. It is possible to establish an order of inhibitory activity according to the particular metals. The strongest inhibition is observed in ions (and complexes) of copper, silver, nickel and vanadium. The activity is influenced (beside the metal atom itself) also by the type of the ligands and the overall structure of the complex (oxidation state, coordination number and geometry).
The aim of our research is to develop new metal complexes with marked urease inhibitory activity, as well as the investigation of the mechanism of inhibition (differences between various metals, impact of the coordination sphere and geometry of the complex, etc.). We are also interested in the establishment of the relationship between the urease inhibition of the complexes and their biological activities (e.g., antibacterial activity).
Selected publications:
Habala L, Devínsky F, Egger AE: Metal complexes as urease inhibitors. Journal of Coordination Chemistry 71 (2018) 907-940. doi:10.1080/00958972.2018.1458228
Habala L, Varényi S, Bilková A, Herich P, Valentová J, Kožíšek J, Devínsky F: Antimicrobial activity and urease inhibition of Schiff bases derived from isoniazid and fluorinated benzaldehydes and of their copper(II) complexes. Molecules 21 (2016) 1742. doi:10.3390/molecules21121742
Habala L, Bartel C, Giester G, Jakupec MA, Keppler BK, Rompel A: Complexes of N-hydroxyethyl-N-benzimidazolylmethylethylenediaminediaceticacid with group 12 metals and vanadium—Synthesis, structure and bioactivity of the vanadium complex. Journal of Inorganic Biochemistry 147 (2015) 147–152. doi:10.1016/j.jinorgbio.2015.04.004
Habala L, Roller A, Matuška M, Valentová J, Rompel A, Devínsky F: Complexes of N-hydroxyethyl-N-benzimidazolylmethylethyl-enediaminediacetic acid with copper(II) and cobalt(II):Preparation, crystal structure and urease inhibitory activity. Inorganica Chimica Acta 421 (2014) 423–426. doi:10.1016/j.ica.2014.06.035
Contact: Ing. Ladislav Habala, PhD.