Optimization of Acryloylphenylcarboxamides as Inhibitors of ABCG2 and Comparison with Acryloylphenylcarboxylates

Kraege, Stefanie; Stefan, Katja; Köhler, Sebastian C.; Wiese, Michael

doi:10.1002/cmdc.201600455

Cited by 13 publications

(19 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the replacement of the phenyl ring of compound 52 by heterocyclic moieties, gave rise to the most active BCRP inhibitor of this series: the 2-thienyl derivative 54 (IC 50 = 0.60 µM) [ 101 ]. Further modifications showed that the introduction of the 4′-methoxy group at A-ring further increased of the BCRP inhibitory activity, as observed by comparing 55 (IC 50 = 0.22 µM, Hoechst 33342 assay) [ 102 ] with its analogous compound 52 (IC 50 = 0.50 µM) [ 101 ].…”

Section: Flavonoidsmentioning

confidence: 99%

“…These overall results depicted four key structural features that favors the BCRP inhibition, namely: the ortho -position of the amide linker; 3,4-dimethoxy substitution on ring B; and the presence of a phenyl or 2-thienyl substitution at the amide linker. The selectivity of all derivatives was assessed by evaluating their effects on P-gp-overexpressing A2780 adr and the MRP1-overexpressing H69 AR cell lines [ 101 , 102 ]. The majority of derivatives displayed no MRP1 inhibition and only a reduced affinity toward P-gp was observed.…”

Section: Flavonoidsmentioning

confidence: 99%

“…Differently, compound 53 displayed relevant BCRP and P-gp inhibition with IC 50 values of 0.57 and 0.49 µM, respectively, thus, this compound could act as dual BCRP/P-gp inhibitor. The reduced toxicity exhibited by the promising derivatives 53 , 54 , 55 (GI 50 = 65.90 µM, 93.20 µM, 78.00 µM respectively) toward MDCK II BCRP cells, renders these derivatives a high therapeutic ratio [ 101 , 102 ].…”

Section: Flavonoidsmentioning

confidence: 99%

See 2 more Smart Citations

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

2020

View full text Add to dashboard Cite

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.

show abstract

Section: Flavonoidsmentioning

confidence: 99%

Section: Flavonoidsmentioning

confidence: 99%

Section: Flavonoidsmentioning

confidence: 99%

See 1 more Smart Citation

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

2020

View full text Add to dashboard Cite

show abstract

“…The quinoxaline contributes the electrostatic interactions between the two nitrogen atoms and the ABCG2 protein (Kraege et al, 2016b). There are four key structural features that improve the ABCG2 inhibition: the orthoposition of the amide linker; the presence of a phenyl or 2-thienyl substitution at the amide linker; 3,4-dimethoxy substitution on ring B (Kraege et al, 2016a;Kraege et al, 2016c;Silbermann et al, 2019;Yin et al, 2019).…”

Section: Flavonoidsmentioning

confidence: 99%

Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance

et al. 2021

View full text Add to dashboard Cite

Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.

show abstract

“…In the same year, the same research group, reported another series of acryloylphenylcarboxamides [Figure 6] and of acryloylphenylcarboxylates with a 4’-methoxy group on ring A of the chalcone [ 133 ] . These compounds were investigated for their inhibitory activity on the BCRP overexpressing MDCK II BCRP cell line by using the pheophorbide A and Hoechst 33342 assays.…”

Section: Chalcone Derivativesmentioning

confidence: 99%

Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

Dei¹,

Braconi²,

Romanelli³

et al. 2019

CDR

View full text Add to dashboard Cite

The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette (ABC) transporters P-gp (P-glycoprotein, ABCB1), multidrug resistance-associated protein 1, ABCC1 and breast cancer resistance protein, ABCG2 (BCRP). These transporters are constitutively expressed in many tissues playing relevant protective roles by the regulation of the permeability of biological membranes, but they are also overexpressed in malignant tissues. P-gp is the first efflux transporter discovered to be involved in cancer drug resistance, and over the years, inhibitors of this pump have been disclosed to administer them in combination with chemotherapeutic agents. Three generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate that coadministration of pump inhibitors elicits an improvement in therapeutic efficacy of antitumor agents, although some of the latest compounds show better results. Therefore, new and innovative strategies, such as the fallback to natural products and the discover of dual activity ligands emerged as new perspectives. BCRP is the most recently ABC protein identified to be involved in multidrug resistance. It is overexpressed in several haematological and solid tumours together with P-gp, threatening the therapeutic effectiveness of different chemotherapeutic drugs. The chemistry of recently described BCRP inhibitors and dual P-gp/BCRP inhibitors, as well as their preliminary pharmacological evaluation are discussed, and the most recent advances concerning these kinds of MDR modulators are reviewed.

show abstract

Optimization of Acryloylphenylcarboxamides as Inhibitors of ABCG2 and Comparison with Acryloylphenylcarboxylates

Cited by 13 publications

References 40 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

Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance

Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

Contact Info

Product

Resources

About