Synthesis and biological evaluation of chalcogen containing redox modulators, and an analytical investigation of potential mechanisms responsible for some biological effects of chalcogen containing organic compounds

Redox active modulators have gained the attention of various sectors of the research field. The continuous progress in fields such as synthetic chemistry, medicinal chemistry, and biochemistry have made the redox modulators a topic of interest for the medical and pharmaceutical domains due to the increasing number of advantages obtained from including redox modulators in diets and medications. In this study, many naphthoquinones-based chalcogen containing compounds were prepared, and their biological activities were evaluated against several cancer cell lines and the parasite Trypanosoma cruzi. In general, the compounds demonstrated good biological activities towards the selected targets. The electrochemical synthetic technique was employed as a means to conduct fast and simple reactions performed in mild conditions. Also, as a part of this study, the sulfur and selenium analogues of phthalic acid anhydride were employed in an analytical study aiming to clarify the mechanisms responsible for the documented biological activities these compounds possess. Additionally, the redox potentials of a set of compounds synthesized in the study were observed by employing cyclic voltammetry (CV) as a technique. The results showed the changes in the redox potentials that accompanied the structures' chemical transformations after each synthetic step. The results obtained were used to correlate the biological activity and the redox potentials of these compounds.Redoxaktive Modulatoren haben die Aufmerksamkeit in verschiedenen Bereichen der Forschung gewonnen. Die kontinuierlichen Fortschritte in Bereichen wie der synthetischen Chemie, der medizinischen Chemie und der Biochemie haben die Redoxmodulatoren zu einem Thema für den medizinischen und pharmazeutischen Bereich gemacht. Aufgrund der zunehmenden Anzahl von Vorteilen können diese Verbindungen relevant für Diäten und Medikamente sein. In dieser Studie wurden eine Reihe von Naphtoquinon-basierten Chalkogen-haltigen Verbindungen hergestellt und ihre biologische Aktivität wurde durch Tests gegen mehrere Krebszelllinien und gegen den Parasiten Trypanosoma cruzi bewertet. Im Allgemeinen zeigten die synthetisierten Verbindungen eine gute biologische Aktivität gegenüber den ausgewählten Targets. Die elektrochemische Synthesetechnik wurde eingesetzt, um schnelle und einfache Reaktionen unter milden Bedingungen durchführen zu können. Im Rahmen dieser Studie wurden auch die Schwefel- und Selenanaloga von Phthalsäureanhydrid in einer analytischen Studie eingesetzt, mit dem Ziel die Mechanismen zu entschlüsseln, die die dokumentierten biologischen Aktivitäten dieser Verbindungen erklären. Darüber hinaus wurden die Redoxpotentiale einer Reihe von Verbindungen, die während dieser Studie synthetisiert wurden, unter Verwendung der Methode der zyklischen Voltammetrie (CV) verfolgt. Die Ergebnisse zeigten die Änderungen der Redoxpotentiale, die mit der chemischen Veränderung der Strukturen nach jedem Syntheseschritt einhergingen. Sie wurden genutzt, um die biologische Aktivität und die Redoxpotentiale dieser Verbindungen zu korrelieren

Small Molecule Catalysts with Therapeutic Potential

Catalysts are employed in many areas of research and development where they combine high efficiency with often astonishing selectivity for their respective substrates. In biology, biocatalysts are omnipresent. Enzymes facilitate highly controlled, sophisticated cellular processes, such as metabolic conversions, sensing and signalling, and are prominent targets in drug development. In contrast, the therapeutic use of catalysts per se is still rather limited. Recent research has shown that small molecule catalytic agents able to modulate the redox state of the target cell bear considerable promise, particularly in the context of inflammatory and infectious diseases, stroke, ageing and even cancer. Rather than being “active” on their own in a more traditional sense, such agents develop their activity by initiating, promoting, enhancing or redirecting reactions between biomolecules already present in the cell, and their activity therefore depends critically on the predisposition of the target cell itself. Redox catalysts, for instance, preferably target cells with a distinct sensitivity towards changes in an already disturbed redox balance and/or increased levels of reactive oxygen species. Indeed, certain transition metal, chalcogen and quinone agents may activate an antioxidant response in normal cells whilst at the same time triggering apoptosis in cancer cells with a different pre-existing “biochemical redox signature” and closer to the internal redox threshold. In pharmacy, catalysts therefore stand out as promising lead structures, as sensor/effector agents which are highly effective, fairly selective, active in catalytic, i.e., often nanomolar concentrations and also very flexible in their structural design

Inorganic Polysulfides and Related Reactive Sulfur–Selenium Species from the Perspective of Chemistry

Polysulfides (H2Sx) represent a class of reactive sulfur species (RSS) which includes molecules such as H2S2, H2S3, H2S4, and H2S5, and whose presence and impact in biological systems, when compared to other sulfur compounds, has only recently attracted the wider attention of researchers. Studies in this field have revealed a facet-rich chemistry and biological activity associated with such chemically simple, still unusual inorganic molecules. Despite their chemical simplicity, these inorganic species, as reductants and oxidants, metal binders, surfactant-like “cork screws” for membranes, components of perthiol signalling and reservoirs for inorganic hydrogen sulfide (H2S), are at the centre of complicated formation and transformation pathways which affect numerous cellular processes. Starting from their chemistry, the hidden presence and various roles of polysulfides in biology may become more apparent, despite their lack of clear analytical fingerprints and often murky biochemical footprints. Indeed, the biological chemistry of H2Sx follows many unexplored paths and today, the relationship between H2S and its oxidized H2Sx species needs to be clarified as a matter of “unmistaken identity”. Simultaneously, emerging species, such as HSSeSH and SenS8−n, also need to be considered in earnest

Inorganic Polysulfides and Related Reactive Sulfur–Selenium Species from the Perspective of Chemistry

Polysulfides (H2Sx) represent a class of reactive sulfur species (RSS) which includes molecules such as H2S2, H2S3, H2S4, and H2S5, and whose presence and impact in biological systems, when compared to other sulfur compounds, has only recently attracted the wider attention of researchers. Studies in this field have revealed a facet-rich chemistry and biological activity associated with such chemically simple, still unusual inorganic molecules. Despite their chemical simplicity, these inorganic species, as reductants and oxidants, metal binders, surfactant-like “cork screws” for membranes, components of perthiol signalling and reservoirs for inorganic hydrogen sulfide (H2S), are at the centre of complicated formation and transformation pathways which affect numerous cellular processes. Starting from their chemistry, the hidden presence and various roles of polysulfides in biology may become more apparent, despite their lack of clear analytical fingerprints and often murky biochemical footprints. Indeed, the biological chemistry of H2Sx follows many unexplored paths and today, the relationship between H2S and its oxidized H2Sx species needs to be clarified as a matter of “unmistaken identity”. Simultaneously, emerging species, such as HSSeSH and SenS8−n, also need to be considered in earnest.This review is based upon work from University of Saarland, Saarbruecken, Germany, the INTERREG VA GR programme (BIOVAL, Grant No. 4-09-21), the COST Action NutRedOx-CA16112 supported by COST (European Cooperation in Science and Technology), the Landesforschungsfoerderungsprogramm” of the State of Saarland (Grant No. WT/2—LFFP16/01), the Slovak Research & Development Agency (grant numbers APVV-15-0371 to A.M., M.G., and K.O.; APVV-17-0384 to M.C. and APVV-15-0565 to A.M.); VEGA Grant Agency of the Slovak Republic (grant number 2/0079/19 to M.G.; 2/0053/19 to M.C. and 2/0014/17 to K.O.)We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI

Products of Sulfide/Selenite Interaction Possess Antioxidant Properties, Scavenge Superoxide-Derived Radicals, React with DNA, and Modulate Blood Pressure and Tension of Isolated Thoracic Aorta

Selenium (Se), an essential trace element, and hydrogen sulfide (H2S), an endogenously produced signalling molecule, affect many physiological and pathological processes. However, the biological effects of their mutual interaction have not yet been investigated. Herein, we have studied the biological and antioxidant effects of the products of the H2S (Na2S)/selenite (Na2SeO3) interaction. As detected by the UV-VIS and EPR spectroscopy, the product(s) of the H2S-Na2SeO3 and H2S-SeCl4 interaction scavenged superoxide-derived radicals and reduced ¿cPTIO radical depending on the molar ratio and the preincubation time of the applied interaction mixture. The results confirmed that the transient species are formed rapidly during the interaction and exhibit a noteworthy biological activity. In contrast to H2S or selenite acting on their own, the H2S/selenite mixture cleaved DNA in a bell-shaped manner. Interestingly, selenite protected DNA from the cleavage induced by the products of H2S/H2O2 interaction. The relaxation effect of H2S on isolated thoracic aorta was eliminated when the H2S/selenite mixture was applied. The mixture inhibited the H2S biphasic effect on rat systolic and pulse blood pressure. The results point to the antioxidant properties of products of the H2S/selenite interaction and their effect to react with DNA and influence cardiovascular homeostasis. The effects of the products may contribute to explain some of the biological effects of H2S and/or selenite, and they may imply that a suitable H2S/selenite supplement might have a beneficial effect in pathological conditions arisen, e.g., from oxidative stress.This research was funded by the Slovak Research and Development Agency (grant numbers APVV-15-0371 to A.M., M.G., and K.O.; APVV-17-0384 to M.C.; and APVV-15- 0565 to A.M, S.C., A.B., and P.B.), the VEGA Grant Agency of the Slovak Republic (grant numbers 2/0079/19 to M.G.; 1/0026/18 to V.B.; 2/0053/19 to M.C.; and 2/0014/17 to K.O.), and University Science Park for Biomedicine (ITMS 2624022008

Small Molecule Catalysts with Therapeutic Potential

Catalysts are employed in many areas of research and development where they combine high efficiency with often astonishing selectivity for their respective substrates. In biology, biocatalysts are omnipresent. Enzymes facilitate highly controlled, sophisticated cellular processes, such as metabolic conversions, sensing and signalling, and are prominent targets in drug development. In contrast, the therapeutic use of catalysts per se is still rather limited. Recent research has shown that small molecule catalytic agents able to modulate the redox state of the target cell bear considerable promise, particularly in the context of inflammatory and infectious diseases, stroke, ageing and even cancer. Rather than being “active” on their own in a more traditional sense, such agents develop their activity by initiating, promoting, enhancing or redirecting reactions between biomolecules already present in the cell, and their activity therefore depends critically on the predisposition of the target cell itself. Redox catalysts, for instance, preferably target cells with a distinct sensitivity towards changes in an already disturbed redox balance and/or increased levels of reactive oxygen species. Indeed, certain transition metal, chalcogen and quinone agents may activate an antioxidant response in normal cells whilst at the same time triggering apoptosis in cancer cells with a different pre-existing “biochemical redox signature” and closer to the internal redox threshold. In pharmacy, catalysts therefore stand out as promising lead structures, as sensor/effector agents which are highly effective, fairly selective, active in catalytic, i.e., often nanomolar concentrations and also very flexible in their structural design