Triterpenoid pyrazines and pyridines – Synthesis, cytotoxicity, mechanism of action, preparation of prodrugs

Hodoň, Jiří; Frydrych, Ivo; Trhlíková, Zdeňka; Pokorný, Jan; Borkova, Lucie; Benická, Sandra; Vlk, Martin; Lišková, Barbora; Kubíčková, Agáta; Medvedíková, Martina; Pisár, Martin; Šarek, Jan; Das, Viswanath; Ligasová, Anna; Koberna, Karel; Džubák, Petr; Hajdúch, Marián; Urban, Milan

doi:10.1016/j.ejmech.2022.114777

Cited by 11 publications

(16 citation statements)

References 52 publications

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“…Oleanolic, betulinic and ursolic acids are good examples of well-studied pentacyclic triterpenes that have cytotoxic activities and selectivity against multiple cancer cell lines, such as breast, cervical, and colorectal cancer, sarcomas and in vivo models (Aswathy et al, 2022 ; Chan et al, 2019 ). Although not yet fully understood, several studies have demonstrated that pentacyclic triterpenes can induce cell death by apoptosis (Chudzik et al, 2015 ; Coricovac et al, 2021 ; Hodoň et al, 2022 ; Mioc et al, 2022 ; Oprean et al, 2018 ; Ren & Kinghorn, 2019 ) or autophagy (El-Baba et al, 2021 ; Fogde et al, 2022 ; Wang et al, 2022b ). Also, moronic acid was shown to have cytotoxic properties (Rios et al, 2001 ) as well as other beneficial effects such as anti-viral (Chang et al, 2010 ; Yu et al, 2006 ), anti-inflammatory (Ruan & Zha, 2022 ) and anti-diabetic activity (Cerón-Romero et al, 2016 ; Estrada-Soto et al, 2022 ; Ramírez-Espinosa et al, 2013 ), indicating the potential of triterpenoic acids and the necessity of further studies for the investigation of their biological properties.…”

Section: Resultsmentioning

confidence: 99%

Chemical and cytotoxicity profiles of 11 pink pepper (Schinus spp.) samples via non-targeted hyphenated high-performance thin-layer chromatography

Mügge

Morlock

2023

Metabolomics

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Introduction Pink pepper is a worldwide used spice that corresponds to the berries of two species, Schinus terebinthifolia Raddi or S. molle L. (Anacardiaceae). Toxic and allergic reactions by ingestion or contact with these plants were reported, and classical in vitro studies have highlighted the cytotoxic properties of apolar extracts from the fruits. Objectives Perform a non-targeted screening of 11 pink pepper samples for the detection and identification of individual cytotoxic substances. Methods After reversed-phase high-performance thin-layer chromatography (RP-HPTLC) separation of the extracts and multi-imaging (UV/Vis/FLD), cytotoxic compounds were detected by bioluminescence reduction from luciferase reporter cells (HEK 293 T-CMV-ELuc) applied directly on the adsorbent surface, followed by elution of detected cytotoxic substance into atmospheric-pressure chemical ionization high-resolution mass spectrometry (APCI-HRMS). Results Separations for mid-polar and non-polar fruit extracts demonstrated the selectivity of the method to different substance classes. One cytotoxic substance zone was tentatively assigned as moronic acid, a pentacyclic triterpenoid acid. Conclusion The developed non-targeted hyphenated RP-HPTLC–UV/Vis/FLD–bioluminescent cytotoxicity bioassay–FIA–APCI-HRMS method was successfully demonstrated for cytotoxicity screening (bioprofiling) and respective cytotoxin assignment.

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Section: Resultsmentioning

confidence: 99%

Chemical and cytotoxicity profiles of 11 pink pepper (Schinus spp.) samples via non-targeted hyphenated high-performance thin-layer chromatography

Mügge

Morlock

2023

Metabolomics

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“…Inhibition of BTK is a pivotal strategy in the field of molecular medicine, with compounds like ibrutinib and selective kinase inhibitor CHMFLÀ BTK-11 demonstrating their effectiveness in blocking the activation of downstream MAPK family proteins, such as p38, ERK1/2 and JNK. [31,33] This inhibition is particularly significant in THP-1 differentiated macrophages and RAMOS cells, where BTK is critical in orchestrating cellular responses. [26,29] Building upon this knowledge, we assessed the effect of the three most potent cytotoxic compounds -PID-4, PID-6, and PID-19 -on the inhibition of BTK and the ensuing downstream activation of ERK1/2, JNK, and p38 in RAMOS cells.…”

Section: Pid-4 Effect On Btk Signallingmentioning

confidence: 99%

“…The molecular docking method was applied to the selected ligands with the help of AutoDock Vina. [33] A grid box for BTK with the dimensions X:30, Y:30, Z:30 Å and a grid spacing of 1.0 Å focused on X: 18.309, Y:9.2081, Z: 7.9357 was identified as the protein target docking site, and best molecular interacting compounds were observed. The interactions between the active sites in the target and ligand conformation, along with the type of interaction and bond distances, were identified using Discovery Studio Visualizer.…”

Section: Dockingmentioning

confidence: 99%

“…The cytotoxicity of compounds was tested using an MTS assay protocol developed for routine compound screening at our facility, and IC 50 values were calculated, as described previously. [33] Drug treatment and western blotting analysis RAMOS and JURKAT cells were plated at 0.5×10 6 /mL density in 6well cell culture plates in complete growth media and treated with PID-4, PID-6 and PID-19 at 1-50 μM concentrations for 24 hours. For LPS stimulation, RAMOS cells in a growth medium containing 1 % FCS were exposed to 1 μg/ml LPS for 10 minutes.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

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Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton's Tyrosine Kinase Inhibitors**

Koraboina,

Maddipati,

Annadurai

et al. 2023

ChemMedChem

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Bruton's tyrosine kinase (BTK) is a promising molecular target for several human B‐cell‐related autoimmune disorders, inflammation, and haematological malignancies. The pathogenic alterations in various cancer tissues depend on mutant BTK for cell proliferation and survival, and BTK is also overexpressed in a range of hematopoietic cells. Due to this, BTK is emerging as a potential drug target to treat various human diseases, and several reversible and irreversible inhibitors have been developed and are being developed. As a result, BTK inhibition, clinically validated as an anticancer treatment, is finding great interest in B‐cell malignancies and solid tumours. This study focuses on the design and synthesis of new oxindole sulfonamide derivatives as promising inhibitors of BTK with negligible off‐target effects. The most cytotoxic compounds with greater basicity were PID‐4 (2.29 ± 0.52 µM), PID‐6 (9.37 ± 2.47 µM), and PID‐19 (2.64 ± 0.88 µM). These compounds caused a selective inhibition of Burkitt's lymphoma RAMOS cells without significant cytotoxicity in non‐BTK cancerous and non‐cancerous cell lines. Further, PID‐4 showed promising activity in inhibiting BTK and downstream signalling cascades. As a potent inhibitor of Burkitt's lymphoma cells, PID‐4 is a promising lead for developing novel chemotherapeutics.

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“…Hodon and co-workers synthesized a series of glucose conjugates 500 – 503 , 508 – 511 by click cycloaddition of the corresponding terpenic propargyl esters ( 497 , 499 , 505 and 507 ) with 2,3,4,6-tetra-O-acetyl-β- d -glucopyranosyl azide 27h or β- d -glucopyranosyl azide 45 164 in the presence of CuI, and DMF at 40 °C (Scheme 49 ). 165…”

Section: Cuaac Click Chemistry Mediated Synthesis Of Triazole-based G...mentioning

confidence: 99%

Recent Advances in the Synthesis of Bioactive Glycohybrids via Click-Chemistry

Singh

Tyagi

Mishra

et al. 2023

SynOpen

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Carbohydrates, traditionally known for their energy-providing role, have gained significant attention in drug discovery due to their diverse bioactivities and stereodiversity. However, pure carbohydrate molecules often exhibit limited bioactivity and suboptimal chemical and physical characteristics. To address these challenges, functional groups with bioactive scaffolds have been incorporated into carbohydrate to enhance their bioactivity and improve their overall properties. Among the various synthetic methods available, click chemistry has emerged as a powerful tool for the synthesis of carbohydrate-containing bioactive scaffolds, known as glycohybrids. Click chemistry offers several advantages, including high chemo- and regioselectivity, mild reaction conditions, easy purification and compatibility with multiple functional groups. In the present review, we have emphasized the recent advances and most pertinent research on the development of 1,2,3-triazole-containing glycohybrids using click reaction, their biological evaluations and the structure-activity relationship during 2017-2023. These newly synthesised glycohybrids could potentially be developed as new chemical entities (NCE) in pharmaceutical chemistry and may encourage the use of carbohydrates in drug discovery processes. 1 Introduction 2 CuAAC click chemistry mediated synthesis of triazole based glycohybrids and their biological activities 3 Conclusions and perspective

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Triterpenoid pyrazines and pyridines – Synthesis, cytotoxicity, mechanism of action, preparation of prodrugs

Cited by 11 publications

References 52 publications

Chemical and cytotoxicity profiles of 11 pink pepper (Schinus spp.) samples via non-targeted hyphenated high-performance thin-layer chromatography

Chemical and cytotoxicity profiles of 11 pink pepper (Schinus spp.) samples via non-targeted hyphenated high-performance thin-layer chromatography

Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton's Tyrosine Kinase Inhibitors**

Recent Advances in the Synthesis of Bioactive Glycohybrids via Click-Chemistry

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