Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2

Silbermann, Katja; Shah, Chetan; Sahu, Niteshkumar U.; Juvale, Kapil; Stefan, Sven Marcel; Kharkar, Prashant S.; Wiese, Michael

doi:10.1016/j.ejmech.2018.12.019

Cited by 40 publications

(44 citation statements)

References 62 publications

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“…Recently, a panel of chalcone derivatives with varying substitutions on the A and B rings (e.g., derivatives 57 – 59, Figure 9 ) was prepared and evaluated for their inhibitory potential towards BCRP, P-gp and MRP1 in pheophorbide A (BCRP) and calcein AM (P-gp and MRP1) assays ( Table 3 ) [ 103 ]. Derivative 57 , which does not have any nitrogen in its structure, was the most active BCRP inhibitor (IC 50 = 1.97 µM).…”

Section: Flavonoidsmentioning

confidence: 99%

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Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

2020

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Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

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Section: Flavonoidsmentioning

confidence: 99%

“…Lower EC 50 values mean stronger MDR reversal properties values. Thus, the results of this study suggested that the para -substituted amide derivative 59 is a highly potent reverser of BCRP-mediated MDR and displays BCRP/MRP1 dual inhibition [ 103 ].…”

Section: Flavonoidsmentioning

confidence: 99%

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

2020

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“…In literature, other chalcones have been shown to inhibit ABCB1 activity more potently than verapamil (14,15). The precise mechanism by which chalcones inhibit ABCB1 is still not fully understood; however, according to several authors, chalcones can overlap two binding sites of the nucleotide-binding domain (NBD2) of ABCB1 (17,34). The key factors influencing ABCB1 inhibitory activity of chalcones are believed to be lipophilicity as well as the size and shape of molecules (17).…”

Section: Cell Linesmentioning

confidence: 99%

“…The precise mechanism by which chalcones inhibit ABCB1 is still not fully understood; however, according to several authors, chalcones can overlap two binding sites of the nucleotide-binding domain (NBD2) of ABCB1 (17,34). The key factors influencing ABCB1 inhibitory activity of chalcones are believed to be lipophilicity as well as the size and shape of molecules (17). Structure-activity relationship (SAR) studies have shown that the presence of methoxy groups (-OCH 3 ) on ring A or basic functional groups (i.e.…”

Section: Cell Linesmentioning

confidence: 99%

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New Chalcone Derivative Inhibits ABCB1 in Multidrug Resistant T-cell Lymphoma and Colon Adenocarcinoma Cells

et al. 2019

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Background/Aim: Development of new potential drugs to overcome multidrug resistance to chemotherapy is a big challenge for cancer treatment. Attention is also given to the natural compounds and their derivatives. The study aimed at evaluating the impact of a new chalcone derivative (1C) on multidrug resistant cell lines, focusing on P-glycoprotein (P-gp, ABCB1) inhibition, as well as 1C-doxorubicin interaction in vitro. Materials and Methods: Cytotoxic and antiproliferative effects of the 1C compound were assessed by thiazolyl blue tetrazolium bromide (MTT) method in mouse T-cell lymphoma and human colon adenocarcinoma cells expressing ABCB1. Alterations in ABCB1 activity were evaluated by rhodamine 123 accumulation assay using flow cytometry. Drug-drug interaction was studied using combination assay. Results: Our results confirmed antiproliferative, cytotoxic, as well as ABCB1 inhibitory potential of 1C in both tested ABCB1-expressing cancer cell lines. Furthermore, 1C displayed synergistic interaction with doxorubicin. Conclusion: Our results suggest the 1C chalcone derivative as a promising compound against resistant lymphoma and colon cancer, which could be used in monotherapy or in combination with other chemotherapeutics.

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Antiproliferative effects of chalcones on T cell acute lymphoblastic leukemia‐derived cells: Role of PKCβ

Corsini

Facchetti

Esposito

et al. 2020

Archiv der Pharmazie

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A series of twenty chalcone derivatives was synthetized and their anti-proliferative activity was tested against the human T-cell acute lymphoblastic leukemia-derived cell line (CCRF-CEM).Based on the structural features of the most active compounds a new library of chalcone derivatives, according to SAR design, was synthetized and their antiproliferative activity was tested on the same cancer cell line. Four of them (compounds 3, 4, 8, 28), based on lower IC50 values (between 6.1 and 8.9 M), were selected for further investigation regarding the modulation of the protein expression of receptor for activated C kinase (RACK1), PKCα and PKCβ, and their action at cell cycle level.Cell cycle analysis indicated a block in G0/G1 phase for all four compounds, with a statistically significant decrease in the percentage of cells in S phase, with no indication of apoptosis (subG0/G1 phase). Compounds 4 and 8 showed a statistical significant reduction in the expression of PKCα and an increase in PKCβ, which together with the demonstration of an antiproliferative role of PKCβ as assessed by treating cells with a selective PKCβ activator, indicated that the antiproliferative effect observed is likely to be mediated through PKCβ induction.

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Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2

Cited by 40 publications

References 62 publications

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

New Chalcone Derivative Inhibits ABCB1 in Multidrug Resistant T-cell Lymphoma and Colon Adenocarcinoma Cells

Antiproliferative effects of chalcones on T cell acute lymphoblastic leukemia‐derived cells: Role of PKCβ

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