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Small Molecule Catalysts with Therapeutic Potential

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (4 December 2017) | Viewed by 74041

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Prof. Dr. Claus Jacob

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Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany
Interests: bioorganic chemistry; catalytic sensor/effector agents; epistemology; intracellular diagnostics; nanotechnology; natural products; reactive sulfur and selenium species; redox regulation via the cellular thiolstat
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Dear Colleagues,

Most diseases, from trivial infections to serious inflammation and proliferative disorders, exhibit characteristic intracellular disturbances that are notably absent under normal, healthy conditions. These small but significant biochemical differences in metabolites, such as Reactive Oxygen Species (ROS), pH, or other biomolecules, may enable us to selectively target such disorders. Here, catalysts provide an interesting lead, as they combine high efficiency with considerable selectivity, i.e., are able to “sense” the presence of particular metabolites, such as increased concentrations of ROS in the cell, and selectively develop their activity in the presence, but not in the absence, of such substrates. Placed in a living system, catalysts therefore may well metamorphose into intelligent “sensor/effector” agents, which (a) on their own are virtually inactive, (b) are able to recognize the presence of suitable biochemical substrates and hence distinguish between different cells, (c) act in low to sub-micromolar concentrations, and (d) affect the target cell in a highly-efficient manner.

Indeed, during the last decade, various small molecule catalysts with impressive biological activities and considerable pharmaceutical promise have been reported in the literature. It is now time to take stock of these developments and to consider the chemistry, biochemical action and overall activity of various types of small molecule catalysts, and the kind of disorders they may be employed against. This Special Issue will, therefore, bring together researchers and research from different disciplines focussing on such catalytic agents, and their ability to selectively target certain diseases.

Prof. Dr. Claus Jacob
Guest Editor

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Keywords

catalyst
redox modulation
sensor/effector agent
selectivity
therapeutic activity

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Published Papers (9 papers)

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Research

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13 pages, 10518 KiB

Open AccessArticle

Resveratrol-Inspired Benzo[b]selenophenes Act as Anti-Oxidants in Yeast

by Dominika Mániková, Zuzana Šestáková, Jana Rendeková, Danuša Vlasáková, Patrícia Lukáčová, Edgars Paegle, Pavel Arsenyan and Miroslav Chovanec

Molecules 2018, 23(2), 507; https://doi.org/10.3390/molecules23020507 - 24 Feb 2018

Cited by 19 | Viewed by 5783

Abstract

Resveratrol is a natural (poly)phenol primarily found in plants protecting them against pathogens, as well as harmful effects of physical and chemical agents. In higher eukaryotic cells and organisms, this compound displays a remarkable range of biological activities, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-aging, cardio- and neuro-protective properties. Here, biological activities of synthetic selenium-containing derivatives of resveratrol—benzo[b]selenophenes—have been studied in lower eukaryotes Saccharomyces cerevisiae. Their toxicity, as well as DNA damaging and reactive oxygen species (ROS) inducing potencies, manifested through their ability to act as redox active anti-microbial agents, have been examined. We show that some benzo[b]selenophenes can kill yeast cells and that the killing effects are not mediated by DNA damage types that can be detected as DNA double-strand breaks. These benzo[b]selenophenes could potentially be used as anti-fungal agents, although their concentrations relevant to application in humans need to be further evaluated. In addition, most of the studied benzo[b]selenophenes display redox-modulating/anti-oxidant activity (comparable or even higher than that of resveratrol or Trolox) causing a decrease in the intracellular ROS levels in yeast cells. Therefore, after careful re-evaluation in other biological systems these observations might be transferred to humans, where resveratrol-inspired benzo[b]selenophenes could be used as supra-anti-oxidant supplements. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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2800 KiB

Open AccessArticle

Synthesis of Selenium-Quinone Hybrid Compounds with Potential Antitumor Activity via Rh-Catalyzed C-H Bond Activation and Click Reactions

by Guilherme A. M. Jardim, Daisy J. B. Lima, Wagner O. Valença, Daisy J. B. Lima, Bruno C. Cavalcanti, Claudia Pessoa, Jamal Rafique, Antonio L. Braga, Claus Jacob, Eufrânio N. Da Silva Júnior and Eduardo H. G. Da Cruz

Molecules 2018, 23(1), 83; https://doi.org/10.3390/molecules23010083 - 30 Dec 2017

Cited by 50 | Viewed by 7537

Abstract

In continuation of our quest for new redox-modulating catalytic antitumor molecules, selenium-containing quinone-based 1,2,3-triazoles were synthesized using rhodium-catalyzed C-H bond activation and click reactions. All compounds were evaluated against five types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), SF295 (human glioblastoma cells), NCIH-460 (human lung cells) and PC3 (human prostate cancer cells). Some compounds showed good activity with IC₅₀ values below 1 µM. The cytotoxic potential of the naphthoquinoidal derivatives was also evaluated in non-tumor cells, exemplified by L929 cells. Overall, these compounds represent promising new lead derivatives and stand for a new class of chalcogenium-containing derivatives with potential antitumor activity. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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747 KiB

Open AccessFeature PaperArticle

Selenazolinium Salts as “Small Molecule Catalysts” with High Potency against ESKAPE Bacterial Pathogens

by Karolina Witek, Muhammad Jawad Nasim, Markus Bischoff, Rosmarie Gaupp, Pavel Arsenyan, Jelena Vasiljeva, Małgorzata Anna Marć, Agnieszka Olejarz, Gniewomir Latacz, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik and Claus Jacob

Molecules 2017, 22(12), 2174; https://doi.org/10.3390/molecules22122174 - 8 Dec 2017

Cited by 25 | Viewed by 5091

Abstract

In view of the pressing need to identify new antibacterial agents able to combat multidrug-resistant bacteria, we investigated a series of fused selenazolinium derivatives (1–8) regarding their in vitro antimicrobial activities against 25 ESKAPE-pathogen strains. Ebselen was used as reference compound. Most of the selenocompounds demonstrated an excellent in vitro activity against all S. aureus strains, with activities comparable to or even exceeding the one of ebselen. In contrast to ebselen, some selenazolinium derivatives (1, 3, and 7) even displayed significant actions against all Gram-negative pathogens tested. The 3-bromo-2-(1-hydroxy-1-methylethyl)[1,2]selenazolo[2,3-a]pyridinium chloride (1) was particularly active (minimum inhibitory concentrations, MICs: 0.31–1.24 µg/mL for MRSA, and 0.31–2.48 µg/mL for Gram-negative bacteria) and devoid of any significant mutagenicity in the Ames assay. Our preliminary mechanistic studies in cell culture indicated that their mode of action is likely to be associated with an alteration of intracellular levels of glutathione and cysteine thiols of different proteins in the bacterial cells, hence supporting the idea that such compounds interact with the intracellular thiolstat. This alteration of pivotal cysteine residues is most likely the result of a direct or catalytic oxidative modification of such residues by the highly reactive selenium species (RSeS) employed. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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1556 KiB

Open AccessCommunication

Cinnamic Acid Analogs as Intervention Catalysts for Overcoming Antifungal Tolerance

by Jong H. Kim, Kathleen L. Chan and Luisa W. Cheng

Molecules 2017, 22(10), 1783; https://doi.org/10.3390/molecules22101783 - 21 Oct 2017

Cited by 8 | Viewed by 6130

Abstract

Disruption of fungal cell wall should be an effective intervention strategy. However, the cell wall-disrupting echinocandin drugs, such as caspofungin (CAS), cannot exterminate filamentous fungal pathogens during treatment. For potency improvement of cell wall-disrupting agents (CAS, octyl gallate (OG)), antifungal efficacy of thirty-three cinnamic acid derivatives was investigated against Saccharomyces cerevisiae slt2Δ, bck1Δ, mutants of the mitogen-activated protein kinase (MAPK), and MAPK kinase kinase, respectively, in cell wall integrity system, and glr1Δ, mutant of CAS-responsive glutathione reductase. Cell wall mutants were highly susceptible to four cinnamic acids (4-chloro-α-methyl-, 4-methoxy-, 4-methyl-, 3-methylcinnamic acids), where 4-chloro-α-methyl- and 4-methylcinnamic acids possessed the highest activity. Structure-activity relationship revealed that 4-methylcinnamic acid, the deoxygenated structure of 4-methoxycinnamic acid, overcame tolerance of glr1Δ to 4-methoxycinnamic acid, indicating the significance of para substitution of methyl moiety for effective fungal control. The potential of compounds as chemosensitizers (intervention catalysts) to cell wall disruptants (viz., 4-chloro-α-methyl- or 4-methylcinnamic acids + CAS or OG) was assessed according to Clinical Laboratory Standards Institute M38-A. Synergistic chemosensitization greatly lowers minimum inhibitory concentrations of the co-administered drug/agents. 4-Chloro-α-methylcinnamic acid further overcame fludioxonil tolerance of Aspergillus fumigatus antioxidant MAPK mutants (sakAΔ, mpkCΔ). Collectively, 4-chloro-α-methyl- and 4-methylcinnamic acids possess chemosensitizing capability to augment antifungal efficacy of conventional drug/agents, thus could be developed as target-based (i.e., cell wall disruption) intervention catalysts. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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3668 KiB

Open AccessFeature PaperArticle

Diallylthiosulfinate (Allicin), a Volatile Antimicrobial from Garlic (Allium sativum), Kills Human Lung Pathogenic Bacteria, Including MDR Strains, as a Vapor

by Jana Reiter, Natalja Levina, Mark Van der Linden, Martin Gruhlke, Christian Martin and Alan J. Slusarenko

Molecules 2017, 22(10), 1711; https://doi.org/10.3390/molecules22101711 - 12 Oct 2017

Cited by 119 | Viewed by 17052

Abstract

Garlic (Allium sativum) has potent antimicrobial activity due to allicin (diallylthiosulfinate) synthesized by enzyme catalysis in damaged garlic tissues. Allicin gives crushed garlic its characteristic odor and its volatility makes it potentially useful for combating lung infections. Allicin was synthesized (>98% pure) by oxidation of diallyl disulfide by H₂O₂ using formic acid as a catalyst and the growth inhibitory effect of allicin vapor and allicin in solution to clinical isolates of lung pathogenic bacteria from the genera Pseudomonas, Streptococcus, and Staphylococcus, including multi-drug resistant (MDR) strains, was demonstrated. Minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) were determined and compared to clinical antibiotics using standard European Committee on Antimicrobial Susceptibility Testing (EUCAST) procedures. The cytotoxicity of allicin to human lung and colon epithelial and murine fibroblast cells was tested in vitro and shown to be ameliorated by glutathione (GSH). Similarly, the sensitivity of rat precision-cut lung slices (PCLS) to allicin was decreased by raising the [GSH] to the approximate blood plasma level of 1 mM. Because allicin inhibited bacterial growth as a vapor, it could be used to combat bacterial lung infections via direct inhalation. Since there are no volatile antibiotics available to treat pulmonary infections, allicin, particularly at sublethal doses in combination with oral antibiotics, could make a valuable addition to currently available treatments. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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Review

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22 pages, 12189 KiB

Open AccessFeature PaperReview

Small Molecule Catalysts with Therapeutic Potential

by Yannick Ney, Muhammad Jawad Nasim, Ammar Kharma, Lama A. Youssef and Claus Jacob

Molecules 2018, 23(4), 765; https://doi.org/10.3390/molecules23040765 - 27 Mar 2018

Cited by 5 | Viewed by 6475

Abstract

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. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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19 pages, 1440 KiB

Open AccessFeature PaperReview

Selenides and Diselenides: A Review of Their Anticancer and Chemopreventive Activity

by Mónica Álvarez-Pérez, Wesam Ali, Małgorzata Anna Marć, Jadwiga Handzlik and Enrique Domínguez-Álvarez

Molecules 2018, 23(3), 628; https://doi.org/10.3390/molecules23030628 - 10 Mar 2018

Cited by 129 | Viewed by 8004

Abstract

Selenium and selenocompounds have attracted the attention and the efforts of scientists worldwide due to their promising potential applications in cancer prevention and/or treatment. Different organic selenocompounds, with diverse functional groups that contain selenium, have been reported to exhibit anticancer and/or chemopreventive activity. Among them, selenocyanates, selenoureas, selenoesters, selenium-containing heterocycles, selenium nanoparticles, selenides and diselenides have been considered in the search for efficiency in prevention and treatment of cancer and other related diseases. In this review, we focus our attention on the potential applications of selenides and diselenides in cancer prevention and treatment that have been reported so far. The around 80 selenides and diselenides selected herein as representative compounds include promising antioxidant, prooxidant, redox-modulating, chemopreventive, anticancer, cytotoxic and radioprotective compounds, among other activities. The aim of this work is to highlight the possibilities that these novel organic selenocompounds can offer in an effort to contribute to inspire medicinal chemists in their search of new promising derivatives. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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14 pages, 931 KiB

Open AccessFeature PaperReview

The Application of Embelin for Cancer Prevention and Therapy

by Jeong-Hyeon Ko, Seok-Geun Lee, Woong Mo Yang, Jae-Young Um, Gautam Sethi, Srishti Mishra, Muthu K. Shanmugam and Kwang Seok Ahn

Molecules 2018, 23(3), 621; https://doi.org/10.3390/molecules23030621 - 9 Mar 2018

Cited by 53 | Viewed by 8309

Abstract

Embelin is a naturally-occurring benzoquinone compound that has been shown to possess many biological properties relevant to human cancer prevention and treatment, and increasing evidence indicates that embelin may modulate various characteristic hallmarks of tumor cells. This review summarizes the information related to the various oncogenic pathways that mediate embelin-induced cell death in multiple cancer cells. The mechanisms of the action of embelin are numerous, and most of them induce apoptotic cell death that may be intrinsic or extrinsic, and modulate the NF-κB, p53, PI3K/AKT, and STAT3 signaling pathways. Embelin also induces autophagy in cancer cells; however, these autophagic cell-death mechanisms of embelin have been less reported than the apoptotic ones. Recently, several autophagy-inducing agents have been used in the treatment of different human cancers, although they require further exploration before being transferred from the bench to the clinic. Therefore, embelin could be used as a potential agent for cancer therapy. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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1971 KiB

Open AccessFeature PaperReview

ROS Modulator Molecules with Therapeutic Potential in Cancers Treatments

by Carole Nicco and Frédéric Batteux

Molecules 2018, 23(1), 84; https://doi.org/10.3390/molecules23010084 - 31 Dec 2017

Cited by 49 | Viewed by 8086

Abstract

Reactive Oxygen Species (ROS) are chemically reactive chemical species containing oxygen. The redox status of a cell is function of the relative concentrations of oxidized and reduced forms of proteins, enzymes, ROS, molecules containing thiol and other factors. In the organism, the redox balance is based on the generation and elimination of ROS produced by endogenous and exogenous sources. All living organisms must maintain their redox equilibrium to survive and proliferate. Enzymatic and molecular pathways control ROS levels tightly but differentially depending on the type of cell. This review is an overview of various molecules that modulate ROS production/detoxification and have a synergistic action with the chemotherapies to kill cancer cells while preserving normal cells to avoid anticancer drugs side effects, allowing a better therapeutic index of the anticancer treatments. Full article

(This article belongs to the Special Issue Small Molecule Catalysts with Therapeutic Potential)

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