Synthesis and cytotoxic activities of goniothalamins and derivatives

Weber, Anja; Döhl, Katja; Sachs, Julia; Nordschild, Anja C.M.; Schröder, Dennis; Kulik, Andrea; Fischer, Thomas; Schmitt, Lutz; Teusch, Nicole; Pietruszka, Jörg

doi:10.1016/j.bmc.2017.02.004

Cited by 18 publications

(10 citation statements)

References 63 publications

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“…Cytotoxic activity of test compounds was analyzed after 48 h using the CellTiter-Glo Luminescent Cell Viability Assay published previously (Weber et al, 2017) in 384-well plates with the following cell densities: A549, MCF-7/MX: 2 × 10 3 cells/well; HCT-15: 3 × 10 3 cells/well; H69AR: 5 × 10 3 cells/well. Pipetting was conducted with the CyBi-Well 96-channel simultaneous pipettor (Analytik Jena AG, Jena, Germany).…”

Section: Methodsmentioning

confidence: 99%

Novel 3,4-Dihydroisocoumarins Inhibit Human P-gp and BCRP in Multidrug Resistant Tumors and Demonstrate Substrate Inhibition of Yeast Pdr5

et al. 2019

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Multidrug resistance (MDR) in tumors and pathogens remains a major problem in the efficacious treatment of patients by reduction of therapy options and subsequent treatment failure. Various mechanisms are described to be involved in the development of MDR with overexpression of ATP-binding cassette (ABC) transporters reflecting the most extensively studied. These membrane transporters translocate a wide variety of substrates utilizing energy from ATP hydrolysis leading to decreased intracellular drug accumulation and impaired drug efficacy. One treatment strategy might be inhibition of transporter-mediated efflux by small molecules. Isocoumarins and 3,4-dihydroisocoumarins are a large group of natural products derived from various sources with great structural and functional variety, but have so far not been in the focus as potential MDR reversing agents. Thus, three natural products and nine novel 3,4-dihydroisocoumarins were designed and analyzed regarding cytotoxicity induction and inhibition of human ABC transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) in a variety of human cancer cell lines as well as the yeast ABC transporter Pdr5 in Saccharomyces cerevisiae . Dual inhibitors of P-gp and BCRP and inhibitors of Pdr5 were identified, and distinct structure-activity relationships for transporter inhibition were revealed. The strongest inhibitor of P-gp and BCRP, which inhibited the transporters up to 80 to 90% compared to the respective positive controls, demonstrated the ability to reverse chemotherapy resistance in resistant cancer cell lines up to 5.6-fold. In the case of Pdr5, inhibitors were identified that prevented substrate transport and/or ATPase activity with IC 50 values in the low micromolar range. However, cell toxicity was not observed. Molecular docking of the test compounds to P-gp revealed that differences in inhibition capacity were based on different binding affinities to the transporter. Thus, these small molecules provide novel lead structures for further optimization.

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Section: Methodsmentioning

confidence: 99%

Novel 3,4-Dihydroisocoumarins Inhibit Human P-gp and BCRP in Multidrug Resistant Tumors and Demonstrate Substrate Inhibition of Yeast Pdr5

et al. 2019

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“…4 (R)-Goniothalamin (2) presents remarkable antiproliferative activities in cell lines including MCF-7 (breast carcinoma) and HeLa cells (human cervical carcinoma 5,6 ), amongst others; these interesting anticancer activities have unchained a number of recent studies on (R)-goniothalamin derivative syntheses and pharmacologic activities. [7][8][9] Both 1 10,11 and 2 11,12 have been the subject of a number of total syntheses. ,-Unsaturated -lactones are structural motifs widely found in many natural products with diverse activities, often attributed to their capability to act as Michael acceptors with some protein functional groups.…”

Section: Corresponding Authormentioning

confidence: 99%

Total Synthesis of (R)-Argentilactone and (R)-Goniothalamin Using a Free-Radical Photoredox Approach to α,β-Unsaturated δ-Lactones

Fuentes-Pantoja¹,

Cordero‐Vargas²

2021

Synthesis

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α,β-Unsaturated δ-lactones are structural motifs found in diverse pharmacologically active natural products. In fact, the unsaturated lactone is often responsible for the biological activity. Herein, we report a new approach for the syntheses of (R)-argentilactone and (R)-goniothalamin based on a photoredox intermolecular iodolactonization mediated by a photoredox process. This new approach, already employed in our research group, stands as a new methodology to achieve several natural products containing α,β-unsaturated δ-lactones.

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“…Previous works have demonstrated that both endo and exo double bonds in the dihydropyranone ring are important for its cytotoxic activity (Figure ). The α,β‐unsaturated lactone acts as a Michael acceptor, and its absence results in the complete loss of cytotoxic activity against cancer cells, while the exo double bond provides the required rigidity for higher activity . Thus, the benzene ring remains the most evident site for structural modifications, and a great amount of effort has been made in this direction .…”

Section: Introductionmentioning

confidence: 99%

“…The a,b-unsaturated lactone acts as aM ichael acceptor, and its absence results in the complete loss of cytotoxic activity againstc ancerc ells, while the exo double bond provides the required rigidity for highera ctivity. [20,21] Thus, the benzene ring remains the most evident site for structuralm odifications, and ag reat amount of effort has been made in this direction. [14,[20][21][22][23] Our research group previously found that (R)-, (S)-, and rac-goniothalamin show no Twos eries of racemic goniothalamin analogues displaying nitrogen-containing groups were designed and synthesized.…”

Section: Introductionmentioning

confidence: 99%

“…[20,21] Thus, the benzene ring remains the most evident site for structuralm odifications, and ag reat amount of effort has been made in this direction. [14,[20][21][22][23] Our research group previously found that (R)-, (S)-, and rac-goniothalamin show no Twos eries of racemic goniothalamin analogues displaying nitrogen-containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against ap anel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity.A mong them, goniothalamin chloroacrylamide 13 e displayed the lowest IC 50 values for both MCF-7 (0.5 mm)a nd PC3 (0.3 mm)c ells, about 26-fold more potent than goniothalamin (1).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Nitrogen‐Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells

et al. 2019

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Two series of racemic goniothalamin analogues displaying nitrogen‐containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against a panel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity. Among them, goniothalamin chloroacrylamide 13 e displayed the lowest IC50 values for both MCF‐7 (0.5 μm) and PC3 (0.3 μm) cells, about 26‐fold more potent than goniothalamin (1). Besides its higher potency, compound 13 e also displayed much higher selectivity than goniothalamin. In contrast, goniothalamin isobutyramide 13 c was the most potent analogue against Caco‐2 cells (IC50=0.8 μm), about 10‐fold more potent and 17‐fold more selective than 1. These results reveal the potential of compounds 13 c and 13 e for further in vivo studies, representing the first goniothalamin analogues with IC50 values in the low micromolar range and high selectivity against MCF‐7, Caco‐2, and PC3 cancer cell lines.

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Synthesis and cytotoxic activities of goniothalamins and derivatives

Cited by 18 publications

References 63 publications

Novel 3,4-Dihydroisocoumarins Inhibit Human P-gp and BCRP in Multidrug Resistant Tumors and Demonstrate Substrate Inhibition of Yeast Pdr5

Novel 3,4-Dihydroisocoumarins Inhibit Human P-gp and BCRP in Multidrug Resistant Tumors and Demonstrate Substrate Inhibition of Yeast Pdr5

Total Synthesis of (R)-Argentilactone and (R)-Goniothalamin Using a Free-Radical Photoredox Approach to α,β-Unsaturated δ-Lactones

Synthesis of Nitrogen‐Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells

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