2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2

Baiceanu, Elisabeta; Nguyen, Kim‐Anh; González-Lobato, Lucía; Nasr, Rachad; Baubichon‐Cortay, Hélène; Loghin, Felicia; Borgne, Marc Le; Chow, Larry M.C.; Boumendjel, Ahcène; Peuchmaur, Marine; Falson, Pierre

doi:10.1016/j.ejmech.2016.06.039

Cited by 21 publications

(20 citation statements)

References 43 publications

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“…This transporter has broad‐spectrum anticancer‐resistance activity, and for this reason, it belongs to the three main MDR proteins. Overexpression of this efflux pump was shown to be associated with resistance to many anticancer drugs, such as cisplatin, etoposide, doxorubicin, vincristine, methotrexate, and purine analogues …”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

et al. 2017

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A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P‐glycoprotein (P‐gp) modulators elacridar and tariquidar. Then, different aryl‐substituted amides were inserted, and to explore the effects of varying the amide function, the corresponding isosteric ester derivatives and some alkylamine analogues were synthesized. The new compounds were studied to evaluate their P‐gp interaction profile and selectivity toward the two other ABC transporters, multidrug‐resistance‐associated protein‐1 (MRP‐1) and breast cancer resistance protein (BCRP). Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate‐buffered saline and human plasma. This study allowed us to evaluate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P‐gp interaction profile. We identified two P‐gp substrates, a P‐gp inhibitor, and three ester derivatives that were active on BCRP, which opens a new scenario in the development of ligands active toward this pump.

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Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

et al. 2017

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“…This modification proved to be crucial in the design of leishmanicidal and antibacterial agents [23][24][25]. Moreover, the presence of an indolinone in the core structure of azaaurones makes them closely related to natural alkaloids and pharmaceuticals exhibiting significant biological activities [26].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance

et al. 2020

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The resistance of tumors against anticancer drugs is a major impediment for chemotherapy. Tumors often develop multidrug resistance as a result of the cellular efflux of chemotherapeutic agents by ABC transporters such as P-glycoprotein (ABCB1/P-gp), Multidrug Resistance Protein 1 (ABCC1/MRP1), or Breast Cancer Resistance Protein (ABCG2/BCRP). By screening a chemolibrary comprising 140 compounds, we identified a set of naturally occurring aurones inducing higher cytotoxicity against P-gp-overexpressing multidrug-resistant (MDR) cells versus sensitive (parental, non-P-gp-overexpressing) cells. Follow-up studies conducted with the P-gp inhibitor tariquidar indicated that the MDR-selective toxicity of azaaurones is not mediated by P-gp. Azaaurone analogs possessing pronounced effects were then designed and synthesized. The knowledge gained from structure-activity relationships will pave the way for the design of a new class of anticancer drugs selectively targeting multidrug-resistant cancer cells.

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“…Other members of the ABCC family include ABCC2, ABCC3, ABCC4, ABCC5, ABCC6 and 12 (Ween et al, 2015). Overexpression of these efflux pumps was shown to be associated with resistance to many anticancer drugs such as cisplatin, etoposide, doxorubicin, vincristine, MTX and purine analogs (Baiceanu et al, 2016). Protein expression of ABCC10 and ABCC11transporters was shown recently to be associated with survival of colorectal cancer patients (Krizkova et al, 2016).…”

Section: The Atp-binding Cassette (Abc)mentioning

confidence: 99%

The Role of Eukaryotic and Prokaryotic ABC Transporter Family in Failure of Chemotherapy

Saleh²,

et al. 2017

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Over the years chemotherapy failure has been a vital research topic as researchers have been striving to discover reasons behind it. The extensive studies carried out on chemotherapeutic agents confirm that resistance to chemotherapy is a major reason for treatment failure. “Resistance to chemotherapy,” however, is a comprehensive phrase that refers to a variety of different mechanisms in which ATP-binding cassette (ABC) mediated efflux dominates. The ABC is one of the largest gene superfamily of transporters among both eukaryotes and prokaryotes; it represents a variety of genes that code for proteins, which perform countless functions, including drug efflux – a natural process that protects cells from foreign chemicals. Up to date, chemotherapy failure due to ABC drug efflux is an active research topic that continuously provides further evidence on multiple drug resistance (MDR), aiding scientists in tackling and overcoming this issue. This review focuses on drug resistance by ABC efflux transporters in human, viral, parasitic, fungal and bacterial cells and highlights the importance of the MDR permeability glycoprotein being the mutual ABC transporter among all studied organisms. Current developments and future directions to overcome this problem are also discussed.

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2-Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2

Cited by 21 publications

References 43 publications

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance

The Role of Eukaryotic and Prokaryotic ABC Transporter Family in Failure of Chemotherapy

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