Publications by authors named "René Csuk"

153 Publications

Type and position of linkage govern the cytotoxicity of oleanolic acid rhodamine B hybrids.

Steroids 2021 Jun 12;172:108876. Epub 2021 Jun 12.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle, Saale, Germany. Electronic address:

Oleanolic acid/rhodamine B hybrids exhibit different cytotoxicity depending on the way these two structural elements are linked. While a hybrid holding a piperazinyl spacer at C-28 proved to be cytotoxic in the nano-molar concentration range, hybrids with a direct linkage of the Rho B residue to C-3 of the triterpenoid skeleton are cytotoxic only in the low micro-molar concentration range without any selectivity. This once again underlines the importance of selecting the right spacer and the most appropriate position on the skeleton of the triterpene to achieve the most cytotoxic hybrids possible.
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http://dx.doi.org/10.1016/j.steroids.2021.108876DOI Listing
June 2021

Synthesis of messagenin and platanic acid chalcone derivatives and their biological potential.

Nat Prod Res 2021 May 10:1-10. Epub 2021 May 10.

Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.

The chalcone derivatives of 20-oxo-lupanes have been synthesised and screened for some types of biological activity. Ozonolysis of lupanes afforded 20-oxo-derivatives with the following condensation using different aromatic aldehydes by Claisen‒Schmidt reaction to the target compounds. The configuration of 19-[3-(pyridin-3-yl)-prop-2-en-1-one]-fragment was established by X-ray analysis. Screening of cytotoxic activity against NCI-60 cancer cell line panel revealed, that messagenin derivative has the highest activity with GI value ranged from 0.304 to 0.804 μM. A colorimetric SRB assay revealed for the 2,30-bis-furfurylidene derivative and 30-bromo-20-oxo-29-nor-3,28-diacetoxy-betulin cytotoxic activity against breast carcinoma MCF-7 and ovarian carcinoma A2780 cell lines. Compounds and acted also as inhibitors of the enzyme -glucosidase (from ) with IC values of 1.76 μM and 3.3 μM thus being 97- and 52-fold more active than standard acarbose. Antiviral potency of compounds and against HCMV, HSV-1 and HPV is also discussed.
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http://dx.doi.org/10.1080/14786419.2021.1922904DOI Listing
May 2021

A simple but unusual rearrangement of an oleanane to a taraxerane-28,14 β -olide.

Steroids 2021 Apr 27;172:108853. Epub 2021 Apr 27.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany. Electronic address:

Reaction of 3-O-acetyl-oleanolic acid (3) with formic acid/hydrogen peroxide at 100 °C for several hours provides an extraordinary but simple pathway to a taraxeran-28,14 β -olide type triterpenoid while the same reaction at 0 °C occurred without re-arrangement of the carbon skeleton, and an oleanane-28,13 β -olide was obtained instead. The products from these reactions were subjected to a cytotoxicity screening employing several human tumor cell lines showing the latter compound not cytotoxic while the former was cytotoxic especially for MCF-7 (breast adenocarcinoma), and FaDu (hypopharyngeal carcinoma) cells. The highest cytotoxicity, however, was observed for 3 β, 12α, 13 β -trihydroxy-oleanan-28-oic acid (6) holding with EC = 4.2 μM for MCF-7 tumor cells.
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http://dx.doi.org/10.1016/j.steroids.2021.108853DOI Listing
April 2021

The Presence of a Cyclohexyldiamine Moiety Confers Cytotoxicity to Pentacyclic Triterpenoids.

Molecules 2021 Apr 6;26(7). Epub 2021 Apr 6.

Organic Chemistry, Martin-Luther University Halle-Wittenberg, Kurt-Mothes, Str. 2, D-06120 Halle (Saale), Germany.

Pentacyclic triterpenoids oleanolic acid, ursolic acid, betulinic acid, and platanic acid were acetylated and converted into several amides -; the cytotoxicity of which has been determined in sulforhodamine B assays employing seral human tumor cell lines and nonmalignant fibroblasts. Thereby, a betulinic acid/-1,4-cyclohexyldiamine amide showed excellent cytotoxicity (for example, EC = 0.6 μM for HT29 colon adenocarcinoma cells).
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http://dx.doi.org/10.3390/molecules26072102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038856PMC
April 2021

-Propyl 6-amino-2,6-dideoxy-2,2-difluoro-β-d-glucopyranoside is a good inhibitor for the β-galactosidase from .

Med Chem Res 2021 Mar 5:1-9. Epub 2021 Mar 5.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes_Str. 2, D-06120 Halle (Saale), Germany.

A convenient route has been developed for the synthesis of novel 6-amino-2,2-(or 3,3-difluoro)-2-(or 3),6-dideoxy-hexopyranoses. Biological screening showed these compounds as good inhibitors for several glycosidases. Especially -propyl 6-amino-2,6-dideoxy-2,2-difluoro-β-d-glucopyranoside () was an excellent competitive inhibitor for the β-galactosidase from holding a of 0.50 μM.
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http://dx.doi.org/10.1007/s00044-021-02715-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934981PMC
March 2021

Rational Drug Repurposing: Focus on Lysosomotropism, Targets in Disease Process, Drug Profile, and Pulmonary Tissue Accumulation in SARS-CoV-2 Infection/COVID-19.

Front Pharmacol 2020 20;11:584881. Epub 2020 Nov 20.

Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Villingen-Schwenningen, Germany.

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http://dx.doi.org/10.3389/fphar.2020.584881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938238PMC
November 2020

Structure-Based Virtual Screening of Tumor Necrosis Factor-α Inhibitors by Cheminformatics Approaches and Bio-Molecular Simulation.

Biomolecules 2021 02 22;11(2). Epub 2021 Feb 22.

Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al-Mouz, Nizwa 616, Sultanate of Oman.

Tumor necrosis factor-α (TNF-α) is a drug target in rheumatoid arthritis and several other auto-immune disorders. TNF-α binds with TNF receptors (TNFR), located on the surface of several immunological cells to exert its effect. Hence, the use of inhibitors that can hinder the complex formation of TNF-α/TNFR can be of medicinal significance. In this study, multiple chem-informatics approaches, including descriptor-based screening, 2D-similarity searching, and pharmacophore modelling were applied to screen new TNF-α inhibitors. Subsequently, multiple-docking protocols were used, and four-fold post-docking results were analyzed by consensus approach. After structure-based virtual screening, seventeen compounds were mutually ranked in top-ranked position by all the docking programs. Those identified hits target TNF-α dimer and effectively block TNF-α/TNFR interface. The predicted pharmacokinetics and physiological properties of the selected hits revealed that, out of seventeen, seven compounds () possessed excellent ADMET profile. These seven compounds plus three more molecules () were chosen for molecular dynamics simulation studies to probe into ligand-induced structural and dynamic behavior of TNF-α, followed by ligand-TNF-α binding free energy calculation using MM-PBSA. The MM-PBSA calculations revealed that compounds and possess highest affinity for TNF-α; 8, 11, 13-15 exhibited moderate affinities, while compound showed weaker binding affinity with TNF-α. This study provides valuable insights to design more potent and selective inhibitors of TNF-α, that will help to treat inflammatory disorders.
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http://dx.doi.org/10.3390/biom11020329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926523PMC
February 2021

Drugs, Metabolites, and Lung Accumulating Small Lysosomotropic Molecules: Multiple Targeting Impedes SARS-CoV-2 Infection and Progress to COVID-19.

Int J Mol Sci 2021 Feb 11;22(4). Epub 2021 Feb 11.

Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany.

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.
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http://dx.doi.org/10.3390/ijms22041797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918659PMC
February 2021

Therapeutic potential of N-substituted thiosemicarbazones as new urease inhibitors: Biochemical and in silico approach.

Bioorg Chem 2021 Apr 2;109:104691. Epub 2021 Feb 2.

Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address:

Urease enzyme plays a key role in pathogenesis of gastritis and peptic ulcers. Its inhibition averts our bodies from many disorders including formation of urinary calculi. In agriculture, the high urease content causes severe environmental and hence economic problems. Due to deficiency of effective and safer drugs to tackle the aforementioned disorders, the quest for new scaffolds becomes mandatory in the field of medicinal chemistry. In this regard, we herein report a new series of N-substituted thiosemicarbazones 3a-v as potential candidates for urease inhibition. These new N-substituted thiosemicarbazones 3a-v of distant chemical scaffolds were characterized by advanced spectroscopic techniques, such as FTIR, HNMR, CNMR, ESI-MS and in the case of compound 3g by single crystal X-ray analysis. The compounds were evaluated for their urease inhibitory potential. All newly synthesized compounds showed significant urease inhibitions with IC values in range of 2.7 ± 0.320-109.2 ± 3.217 μM. Molecular docking studies were used for interactions pattern and structure-activity relationship for all compounds, which demonstrated excellent binding interactions with the active site residues, such as hydrogen bonding, π-π interactions, π-H and nickel atom coordination.
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http://dx.doi.org/10.1016/j.bioorg.2021.104691DOI Listing
April 2021

Cytotoxic Potential of a-Azepano- and 3-Amino-3,4-SeCo-Triterpenoids.

Int J Mol Sci 2021 Feb 8;22(4). Epub 2021 Feb 8.

Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.

Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial, alpha-glucosidase, and butyrylcholinesterase inhibitory activities. In this study, in an attempt to develop new antitumor candidates, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives of betulin, oleanolic, ursolic, and glycyrrhetinic acids were evaluated for their cytotoxic activity against five human cancer cell lines and non-malignant mouse fibroblasts by means of a colorimetric sulforhodamine assay. Azepanoallobetulinic acid amide derivative was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound to act mainly by apoptosis (44.3%) and late apoptosis (21.4%). The compounds were further screened at the National Cancer Institute towards a panel of 60 cancer cell lines. It was found that compounds , , , , , , , , , and showed growth inhibitory (GI) against the most sensitive cell lines at submicromolar concentrations (0.20-0.94 μM), and their cytotoxic activity (LC) was also high (1-6 μM). Derivatives , , , , and demonstrated a certain selectivity profile at GI level from 5.16 to 9.56 towards K-562, CCRF-CEM, HL-60(TB), and RPMI-8226 (Leukemia), HT29 (Colon cancer), and OVCAR-4 (Ovarian cancer) cell lines. Selectivity indexes of azepanoerythrodiol at TGI level ranged from 5.93 (CNS cancer cell lines SF-539, SNB-19 and SNB-75) to 14.89 for HCT-116 (colon cancer) with SI 9.56 at GI level for the leukemia cell line K-562. The present study highlighted the importance of A-azepano-ring in the triterpenic core for the development of novel antitumor agents, and a future aim to increase the selectivity profile will thus lie in the area of modifications of azepano-triterpenic acids at their carboxyl group.
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http://dx.doi.org/10.3390/ijms22041714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914897PMC
February 2021

Biosynthetic diversity in triterpene cyclization within the Boswellia genus.

Phytochemistry 2021 Apr 29;184:112660. Epub 2021 Jan 29.

Department of Organic Chemistry, Martin-Luther University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.

This review is not intended to describe the triterpenes isolated from the Boswellia genus, since this information has been covered elsewhere. Instead, the aim is to provide insights into the biosynthesis of triterpenes in Boswellia. This genus, which has 24 species, displays fascinating structural diversity and produces a number of medicinally important triterpenes, particularly boswellic acids. Over 300 volatile components have been reported in the essential oil of Boswellia, and more than 100 diterpenes and triterpenes have been isolated from this genus. Given that no triterpene biosynthetic enzymes have yet been isolated from any members of the Boswellia genus, this review will cover the likely biosynthetic pathways as inferred from structures in nature and the probable types of biosynthetic enzymes based on knowledge of triterpene biosynthesis in other plant species. It highlights the importance of frankincense and the factors and threats affecting its production. It covers triterpene biosynthesis in the genus Boswellia, including dammaranes, tirucallic acids, lupanes, oleananes, ursanes and boswellic acids. Strategies for elucidating triterpene biosynthetic pathways in Boswellia are considered. Furthermore, the possible mechanisms behind wound-induced resin synthesis by the tree and related gene expression profiling are covered. In addition, the influence of the environment and the genotype on the biosynthesis of resin and on variations in the compositions and types of resins will also be reviewed.
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http://dx.doi.org/10.1016/j.phytochem.2021.112660DOI Listing
April 2021

Challenges in Bone Tissue Regeneration: Stem Cell Therapy, Biofunctionality and Antimicrobial Properties of Novel Materials and Its Evolution.

Int J Mol Sci 2020 Dec 27;22(1). Epub 2020 Dec 27.

Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Strasse 17, 78054 Villingen-Schwenningen, Germany.

An aging population leads to increasing demand for sustained quality of life with the aid of novel implants. Patients expect fast healing and few complications after surgery. Increased biofunctionality and antimicrobial behavior of implants, in combination with supportive stem cell therapy, can meet these expectations. Recent research in the field of bone implants and the implementation of autologous mesenchymal stem cells in the treatment of bone defects is outlined and evaluated in this review. The article highlights several advantages, limitations and advances for metal-, ceramic- and polymer-based implants and discusses the future need for high-throughput screening systems used in the evaluation of novel developed materials and stem cell therapies. Automated cell culture systems, microarray assays or microfluidic devices are required to efficiently analyze the increasing number of new materials and stem cell-assisted therapies. Approaches described in the literature to improve biocompatibility, biofunctionality and stem cell differentiation efficiencies of implants range from the design of drug-laden nanoparticles to chemical modification and the selection of materials that mimic the natural tissue. Combining suitable implants with mesenchymal stem cell treatment promises to shorten healing time and increase treatment success. Most research studies focus on creating antibacterial materials or modifying implants with antibacterial coatings in order to address the increasing number of complications after surgeries that are mostly caused by bacterial infections. Moreover, treatment of multiresistant pathogens will pose even bigger challenges in hospitals in the future, according to the World Health Organization (WHO). These antibacterial materials will help to reduce infections after surgery and the number of antibiotic treatments that contribute to the emergence of new multiresistant pathogens, whilst the antibacterial implants will help reduce the amount of antibiotics used in clinical treatment.
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http://dx.doi.org/10.3390/ijms22010192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794985PMC
December 2020

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates.

Molecules 2020 Nov 20;25(22). Epub 2020 Nov 20.

Organic Chemistry, Martin-Luther University Halle-Wittenberg, Kurt-Mothes Street 2, D-06120 Halle, Germany.

The combination of the "correct" triterpenoid, the "correct" spacer and rhodamine B () seems to be decisive for the ability of the conjugate to accumulate in mitochondria. So far, several triterpenoid rhodamine B conjugates have been prepared and screened for their cytotoxic activity. To obtain cytotoxic compounds with EC values in a low nano-molar range combined with good tumor/non-tumor selectivity, the Rho B unit has to be attached via an amine spacer to the terpenoid skeleton. To avoid spirolactamization, secondary amines have to be used. First results indicate that a homopiperazinyl spacer is superior to a piperazinyl spacer. Hybrids derived from maslinic acid or tormentic acid are superior to those from oleanolic, ursolic, glycyrrhetinic or euscaphic acid. Thus, a tormentic acid-derived conjugate , holding a homopiperazinyl spacer can be regarded, at present, as the most promising candidate for further biological studies.
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http://dx.doi.org/10.3390/molecules25225443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699795PMC
November 2020

4-Benzyloxylonchocarpin and Muracatanes A-C from L. and Their Biological Effects.

Biomolecules 2020 11 17;10(11). Epub 2020 Nov 17.

Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland, Stellenbosch 7600, South Africa.

L. is a spiny fruit buttercup that is used in various traditional medicinal systems. In the current investigation of , the new chalcone 4-benzyloxylonchocarpin (), the new anthraquinone muracatanes A (), the new-to-nature anthraquinone muracatanes B (), and the new naphthalene analog muracatanes C () were isolated, in addition to the three previously reported compounds, 4-methoxylonchocarpin (), β-sitosterol (), and β-sitosterol β-D-glucopyranoside (). Their structures were elucidated using 1D (H and C) and 2D (COSY, HSQC, and HMBC) NMR spectroscopy and HR-ESI-MS. Chalcone showed potent acetylcholinesterase inhibitory effects with of 5.39 µM and of 3.54 µM, but none of the isolated compounds showed inhibitory activity towards butyrylcholinesterase. Anthraquinone illustrated α-glucosidase inhibitory effects with IC-values of 164.46 ± 83.04 µM. Compound displayed moderate cytotoxic activity towards ovarian carcinoma (A2780, IC = 25.4 µM), colorectal adenocarcinoma (HT29, IC = 20.2 µM), breast cancer (MCF7, IC = 23.7 µM), and thyroid carcinoma (SW1736, IC = 26.2 µM) while it was inactive towards pharynx carcinoma (FaDu: IC > 30 µM).
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http://dx.doi.org/10.3390/biom10111562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698453PMC
November 2020

Cytotoxic triterpenoid-safirinium conjugates target the endoplasmic reticulum.

Eur J Med Chem 2021 Jan 8;209:112920. Epub 2020 Oct 8.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120, Halle, Saale, Germany. Electronic address:

Safirinium P and Q fluorescence labels were synthesized and conjugated with spacered triterpenoic acids to access hybrid structures. While the parent safirinium compounds were not cytotoxic at all, many triterpenoid safirinium P and Q conjugates showed moderate cytotoxicity. An exception, however, was safirinium P derived compound 30 holding low EC = 5.4 μM (for A375 cells) to EC = 7.5 μM (for FaDu cells) as well as EC = 6.6 μM for non-malignant fibroblasts NIH 3T3. Fluorescence imaging showed that the safirinium core structures cannot enter the cells (not even after a prolonged incubation time of 24 h), while the conjugates (as exemplified for 30) are accumulating in the endoplasmic reticulum but not in the mitochondria. The development of safirinium-hybrids targeting the endoplasmic reticulum can be regarded as a promising strategy in the development of cytotoxic agents.
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http://dx.doi.org/10.1016/j.ejmech.2020.112920DOI Listing
January 2021

Betulinic acid derived amides are highly cytotoxic, apoptotic and selective.

Eur J Med Chem 2020 Dec 9;207:112815. Epub 2020 Sep 9.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120, Halle (Saale), Germany. Electronic address:

Betulinic and platanic acid derived amides were prepared and screened for their cytotoxic activity. All of the compounds were shown to be cytotoxic for a panel of human tumor cell lines, and especially apoptotic betulinic acid derived compounds 6, 8 and 19 showed low EC values. Of special interest was a 4-isoquinolinyl amide of 3-O-acetyl-betulinic acid (compound 19), being the most cytotoxic compound of this series and holding EC values as low as EC = 1.48 μM (A375 melanoma cells) while being significantly less cytotoxic for non-malignant fibroblasts NIH 3T3 with a selectivity index of >91.2. This finding parallels previous results obtained for SAA21, a augustic acid derived compound thus making the 4-isoquinolinyl moiety to a privileged scaffold.
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http://dx.doi.org/10.1016/j.ejmech.2020.112815DOI Listing
December 2020

Antiproliferative and Pro-Apoptotic Effect of Uvaol in Human Hepatocarcinoma HepG2 Cells by Affecting G0/G1 Cell Cycle Arrest, ROS Production and AKT/PI3K Signaling Pathway.

Molecules 2020 Sep 16;25(18). Epub 2020 Sep 16.

Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Avenida Fuentenueva, 1, 18071 Granada, Spain.

Natural products have a significant role in the development of new drugs, being relevant the pentacyclic triterpenes extracted from . Anticancer effect of uvaol, a natural triterpene, has been scarcely studied. The aim of this study was to understand the anticancer mechanism of uvaol in the HepG2 cell line. Cytotoxicity results showed a selectivity effect of uvaol with higher influence in HepG2 than WRL68 cells used as control. Our results show that uvaol has a clear and selective anticancer activity in HepG2 cells supported by a significant anti-migratory capacity and a significant increase in the expression of HSP-60. Furthermore, the administration of this triterpene induces cell arrest in the G/G phase, as well as an increase in the rate of cell apoptosis. These results are supported by a decrease in the expression of the anti-apoptotic protein Bcl2, an increase in the expression of the pro-apoptotic protein Bax, together with a down-regulation of the AKT/PI3K signaling pathway. A reduction in reactive oxygen species (ROS) levels in HepG2 cells was also observed. Altogether, results showed anti-proliferative and pro-apoptotic effect of uvaol on hepatocellular carcinoma, constituting an interesting challenge in the development of new treatments against this type of cancer.
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http://dx.doi.org/10.3390/molecules25184254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571068PMC
September 2020

Metabolite Patterns in Human Myeloid Hematopoiesis Result from Lineage-Dependent Active Metabolic Pathways.

Int J Mol Sci 2020 Aug 24;21(17). Epub 2020 Aug 24.

Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Straße 17, 78054 Villingen-Schwenningen, Germany.

Assessment of hematotoxicity from environmental or xenobiotic compounds is of notable interest and is frequently assessed via the colony forming unit (CFU) assay. Identification of the mode of action of single compounds is of further interest, as this often enables transfer of results across different tissues and compounds. Metabolomics displays one promising approach for such identification, nevertheless, suitability with current protocols is restricted. Here, we combined a hematopoietic stem and progenitor cell (HSPC) expansion approach with distinct lineage differentiations, resulting in formation of erythrocytes, dendritic cells and neutrophils. We examined the unique combination of pathway activity in glycolysis, glutaminolysis, polyamine synthesis, fatty acid oxidation and synthesis, as well as glycerophospholipid and sphingolipid metabolism. We further assessed their interconnections and essentialness for each lineage formation. By this, we provide further insights into active metabolic pathways during the differentiation of HSPC into different lineages, enabling profound understanding of possible metabolic changes in each lineage caused by exogenous compounds.
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http://dx.doi.org/10.3390/ijms21176092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504406PMC
August 2020

The presence of a cationic center is not alone decisive for the cytotoxicity of triterpene carboxylic acid amides.

Steroids 2020 11 12;163:108713. Epub 2020 Aug 12.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.

3-O-Acetyl-ursolic acid (2) and 3-O-acetyl oleanolic acid (8) were converted into piperazinylamides holding a distal NH, NMe or a NMe group. These compounds as well as the corresponding N-methyl-N-oxides were accessed. Their cytotoxicity was assessed in SRB assays employing a panel of human tumor cell lines and non-malignant fibroblasts (NIH 3T3). As a result, compounds holding a quaternary distal N-substituent were less cytotoxic that those holding a NH-moiety. Hence, the presence of a distal cationic center seems not to be a sufficient criterion for obtaining triterpenoids of high cytotoxicity and selectivity.
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http://dx.doi.org/10.1016/j.steroids.2020.108713DOI Listing
November 2020

Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids.

Bioorg Chem 2020 08 10;101:104001. Epub 2020 Jun 10.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.

In this study, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives were synthesized from betulin, oleanolic, ursolic and glycyrrhetinic acids aiming to develop new cholinesterase inhibitors. Azepanobetulin, azepanoerythrodiol and azepanouvaol were modified to give amide and tosyl derivatives, while azepano-anhydrobetulines and azepano-glycyrrhetols were obtained for the first time. Oleanane and ursane type 3-amino-3,4-seco-4(23)-en triterpenic alcohols were synthesized by reducing the corresponding 2-cyano-derivatives accessible from Beckmann type 2 rearrangements. The compounds were screened in colorimetric Ellman's assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). While most of these compounds were only moderate inhibitors for AChE, several of them were shown to be inhibitors for BChE acting as mixed-type inhibitors. Azepanobetulin 1, its C28-amide derivatives 7 and 8, azepano-11-deoxo-glycyrrhetol 12 and azepanouvaol 18 held inhibition constants K ranging between 0.21 ± 0.06 to 0.68 ± 0.19 μM. Thus, they were approximately 4 to 10 times more active than standard galantamine hydrobromide. For all of the compounds reasonably high docking scores for BChE were obtained being in good agreement with the experimental results from the enzymatic studies. As a result, A-ring azepano-triterpenoids were found to be new scaffolds for the development of BChE inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2020.104001DOI Listing
August 2020

Diterpenoids and Triterpenoids From Frankincense Are Excellent Anti-psoriatic Agents: An Approach.

Front Chem 2020 25;8:486. Epub 2020 Jun 25.

Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman.

Psoriasis is a chronic autoimmune disease that affects 2-3% of the global population and requires an effective treatment. Frankincense has been long known for its potent anti-inflammatory activities. In this study, a structural bioinformatics approach was used to evaluate the efficacy of individual active components of frankincense, macrocyclic diterpenoid derivatives (-), and boswellic acids (-) in the treatment of psoriasis. Initially, major druggable targets of psoriasis were identified. Subsequently, structure-based screening was employed by using three different docking algorithms and scoring functions (MOE, AutoDock Vina, and MVD) for the target fishing of compounds against 18 possible targets of psoriasis. Janus Kinase 1, 2, 3 (JAK 1/2/3), eNOS, iNOS, interleukin-17 (IL-17), and Tumor necrosis factor-α (TNF-α) were identified as the preferred molecular targets for these compounds. This computational analysis reflects that frankincense diterpenoids and triterpenoids can serve as excellent anti-psoriatic agents by targeting major cytokines (TNF-α, IL-17, IL-13, IL-23, and IL-36γ,) exacerbated in psoriasis, and inflammatory pathways particularly JAK1/2/3, eNOS, iNOS, MAPK2, and IFNγ. The results were compared with the reported experimental findings which correlates well with our verdicts.
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http://dx.doi.org/10.3389/fchem.2020.00486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330179PMC
June 2020

COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks.

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany.

In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide. SARS-CoV-2 infection/COVID-19 provides numerous therapeutic targets, each of them promising, but not leading to the success of therapy to date. Neither an antiviral nor an immunomodulatory therapy in patients with SARS-CoV-2 infection/COVID-19 or pre-exposure prophylaxis against SARS-CoV-2 has proved to be effective. In this review, we try to close the gap and point out the likely relationships among lysosomotropism, increasing lysosomal pH, SARS-CoV-2 infection, and disease process, and we deduce an approach for the treatment and prophylaxis of COVID-19, and cytokine release syndrome (CRS)/cytokine storm triggered by bacteria or viruses. Lysosomotropic compounds affect prominent inflammatory messengers (e.g., IL-1B, CCL4, CCL20, and IL-6), cathepsin-L-dependent viral entry of host cells, and products of lysosomal enzymes that promote endothelial stress response in systemic inflammation. As supported by recent clinical data, patients who have already taken lysosomotropic drugs for other pre-existing conditions likely benefit from this treatment in the COVID-19 pandemic. The early administration of a combination of antivirals such as remdesivir and lysosomotropic drugs, such as the antibiotics teicoplanin or dalbavancin, seems to be able to prevent SARS-CoV-2 infection and transition to COVID-19.
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http://dx.doi.org/10.3390/ijms21144953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404102PMC
July 2020

Heterogeneous Pd/C-catalyzed, ligand free Suzuki-Miyaura coupling reaction furnishes new -terphenyl derivatives.

Nat Prod Res 2020 Jul 13:1-5. Epub 2020 Jul 13.

Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman.

A series of new -terphenyls derivatives have been efficiently synthesized by a ligand-free heterogeneous Pd/C-catalyzed two-fold Suzuki-Miyaura coupling reaction. Methyl 5-bromo-2-iodobenzoate was selected to react with a variety of different aryl boronic acids (). Nine new -terphenyl derivatives (-) were prepared and the structures were confirmed by several analytical techniques including infrared, spectroscopy, H and C NMR spectroscopy, mass spectrometry, and in the case of compound by X-ray diffraction method. The new derivatives were obtained in very good yields (78-91%). This synthetic facile route is envisioned to improve the preparation of -terphenyl-based natural products.
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http://dx.doi.org/10.1080/14786419.2020.1791112DOI Listing
July 2020

Synthesis of some steroidal mitocans of nanomolar cytotoxicity acting by apoptosis.

Eur J Med Chem 2020 Aug 11;199:112425. Epub 2020 May 11.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120, Halle (Saale), Germany. Electronic address:

Several steroids (abiraterone, prednisone, testosterone, cholesterol) and the BCL-2 inhibitor bexarotene were used as starting materials to synthesize iperazinyl-spacered rhodamine B conjugates. The conjugates were screened for their cytotoxicity in SRB assays against several human tumor cell lines and found to be active in a low μM to nM range. The conjugate derived from testosterone held an EC = 59 nM against MCF-7 tumor cells and acted mainly by necrosis. The prednisone conjugate, however, was less cytotoxic but acted mainly by apoptosis and held a moderate selectivity against MCF-7 tumor cells.
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http://dx.doi.org/10.1016/j.ejmech.2020.112425DOI Listing
August 2020

Triterpenic Acids as Non-Competitive α-Glucosidase Inhibitors from with Structure-Activity Relationship: In Vitro and In Silico Studies.

Biomolecules 2020 05 12;10(5). Epub 2020 May 12.

Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, Birkat Al Mauz, Nizwa 616, Oman.

Fourteen triterpene acids, viz., three tirucallane-type (-), eight ursane-type (-), two oleanane-type (, ) and one lupane type (), along with boswellic aldehyde (), α-amyrine (), epi-amyrine (), straight chain acid (), sesquiterpene () and two cembrane-type diterpenes (, ) were isolated, first time, from the methanol extract of resin. Compound () was isolated for first time as a natural product, while the remaining compounds (‒) were reported for first time from The structures of all compounds were confirmed by advanced spectroscopic techniques including mass spectrometry and also by comparison with the reported literature. Eight compounds (- and ) were further screened for in vitro α-glucosidase inhibitory activity. Compounds - and showed significant activity against α-glucosidase with IC values ranging from 9.9-56.8 μM. Compound (IC = 9.9 ± 0.48 μM) demonstrated higher inhibition followed by (IC = 14.9 ± 1.31 μM), (IC = 20.9 ± 0.05 μM) and (IC = 56.8 ± 1.30 μM), indicating that carboxylic acid play a key role in α-glucosidase inhibition. Kinetics studies on the active compounds - and were carried out to investigate their mechanism (mode of inhibition and dissociation constants ). All compounds were found to be non-competitive inhibitors with values in the range of 7.05 ± 0.17-51.15 ± 0.25 µM. Moreover, in silico docking was performed to search the allosteric hotspot for ligand binding which is targeted by our active compounds investigates the binding mode of active compounds and it was identified that compounds preferentially bind in the allosteric binding sites of α-glucosidase. The results obtained from docking study suggested that the carboxylic group is responsible for their biologic activities. Furthermore, the α-glucosidase inhibitory potential of the active compounds is reported here for the first time.
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http://dx.doi.org/10.3390/biom10050751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278020PMC
May 2020

Complexes of N- and O-Donor Ligands as Potential Urease Inhibitors.

ACS Omega 2020 May 20;5(17):10200-10206. Epub 2020 Apr 20.

Natural and Medical Sciences Research Centre, University of Nizwa, Birkat Almouz, Nizwa 616, Oman.

We report five new transition-metal complexes that inhibit the urease enzyme. Barbituric acid (), thiobarbituric acid (), isoniazid (), and nicotinamide () ligands were employed in complexation reactions. The resulting complexes were characterized using a variety of analytical techniques including infra-red and UV-vis spectroscopy, H NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction analysis. We describe two mononuclear complexes with a general formula {[M()(HO)]()(HO)}, where M = Co () and Zn (), a mononuclear complex {[Ni()(HO)]()(HO)} (), and two polymeric chains of a general formula {[M() (HO)]()(HO)}, where M = Co () and Zn (). These complexes displayed significant urease enzyme inhibition with IC values in the range of 3.9-19.9 μM.
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http://dx.doi.org/10.1021/acsomega.0c01089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203987PMC
May 2020

In the Mists of a Fungal Metabolite: An Unexpected Reaction of 2,4,5-Trimethoxyphenylglyoxylic Acid.

Molecules 2020 Apr 23;25(8). Epub 2020 Apr 23.

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.

The reactions of phenylglyoxylic acids during the synthesis and biological evaluation of fungal metabolites led to the discovery of hitherto unknown compounds with a -quinone methide (-QM) structure. The formation of these -QMs using C-labelled starting materials revealed a key-step of this reaction being a retro-Friedel-Crafts alkylation.
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http://dx.doi.org/10.3390/molecules25081978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221594PMC
April 2020

Recent Advances in the Stereoselective Total Synthesis of Natural Pyranones Having Long Side Chains.

Molecules 2020 Apr 20;25(8). Epub 2020 Apr 20.

Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Birkat Al Mauz 616, Nizwa, Oman.

Pyranone natural products have attracted great attention in recent years from chemists and biologists due to their fascinating stereoisomeric structural features and impressive bioactivities. A large number of stereoselective total syntheses of these compounds have been described in the literature. The natural pyranones with long side chains have recently received significant importance in the synthetic field. In the present article, we aim to review the modern progress of the stereoselective total syntheses of these natural pyranones containing long-chain substituents.
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http://dx.doi.org/10.3390/molecules25081905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221952PMC
April 2020

Cytotoxic Dehydroabietylamine Derived Compounds.

Anticancer Agents Med Chem 2020 ;20(15):1756-1767

Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.

Background And Methods: Chemotherapy remains one of the most important methods for the treatment of cancer. More recently in this context, some products derived from natural products have raised scientific interest which especially include many terpenes. Thereby, diterpenoids represent a special class, and within this class of important secondary natural products, especially compounds derived from Dehydroabietylamine (DA), are of particular interest.

Results: This review not only gives a summary of the most important findings on the cytotoxic behavior of DAderived compounds but also shows some drawbacks of these compounds, such low bioavailability and/or poor solubility of several derivatives of DA. It focusses on the chemical aspects and summarizes the DA related biological effects without deep discussion of underlying biochemical pathways.

Conclusion: Dehydroabietylamine-derived cytotoxic compounds hold a high potential to be developed into efficient antitumor active drugs.
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http://dx.doi.org/10.2174/1871520620666200317110010DOI Listing
June 2021

Editorial for the special issue on frankincense.

Phytochemistry 2020 05 26;173:112299. Epub 2020 Feb 26.

Natural and Medical Sciences Research Center, University of Nizwa, Oman. Electronic address:

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http://dx.doi.org/10.1016/j.phytochem.2020.112299DOI Listing
May 2020