Optimizing the Flavanone Core Toward New Selective Nitrogen-Containing Modulators of ABC Transporters

Ferreira, Ricardo B.; Baptista, Rafael; Moréno, Alexis; Madeira, Patricia G; Khonkarn, Ruttiros; Baubichon‐Cortay, Hélène; Santos, Daniel J. V. A. dos; Falson, Pierre; Ferreira, Maria‐José U.

doi:10.4155/fmc-2017-0228

Cited by 27 publications

(23 citation statements)

References 42 publications

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“…Recently, a study regarding derivatives of the flavanone naringenin ( 65 ) as inhibitors of P-gp, MRP1, and BCRP was performed by Ferreira et al [ 104 ]. The carbonyl group was modified into a series of derivatives containing nitrogen atoms and extra aromatic moieties such as hydrazones, azines and carbohydrazide derivatives aiming at increasing their inhibitory properties (e.g., 66 – 69 , Table 5 ).…”

Section: Flavonoidsmentioning

confidence: 99%

“…Additionally, the azine derivatives 68 and 69 were found to display an interesting inhibitory activity pattern towards both MRP1 (efflux inhibition of 56.3 and 45.1%, respectively) and BCRP (efflux inhibition of 53.5 and 71.1%, respectively) pumps, rendering these compounds the ability to act as dual MRP1/BCRP inhibitors. These inhibitory results for azine derivatives 68 and 69 prove that the introduction of the C=N-N=C chain could be important for the ability of these compounds to inhibit both BCRP and MRP1 pumps [ 104 ].…”

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%

Section: Flavonoidsmentioning

confidence: 99%

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

2020

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“…The B-ring is in another lipophilic bag made of Phe545, Pro574 and Val516. An improvement in the interaction between the transporter MRP1 and the carbohydrazide derivatives of flavonones due to the resulting flexibility was also observed (Ferreira et al, 2018).…”

Section: In Silico Analysis Of Phytochemicals As Mdr Reversing Agentsmentioning

confidence: 85%

“…Comparing flavonols to their corresponding flavones such as kaempferol to apigenin, better docking properties have been found in flavonols due to the number of hydrogen bonds (Badhan and Penny, 2006). A number of naringenin derivatives such as hydrazones and azines were produced by Ferreira et al (2018) to achieve an improved MDR reversal in P-gp and BCRP. There was a high selectivity for most members of these two groups.…”

Section: In Silico Analysis Of Phytochemicals As Mdr Reversing Agentsmentioning

confidence: 99%

Phytochemicals: Potential Lead Molecules for MDR Reversal

2020

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Multidrug resistance (MDR) is one of the main impediments in the treatment of cancers. MDR cancer cells are resistant to multiple anticancer drugs. One of the major mechanisms of MDR is the efflux of anticancer drugs by ABC transporters. Increased activity and overexpression of these transporters are important causes of drug efflux and, therefore, resistance to cancer chemotherapy. Overcoming MDR is a fundamental prerequisite for developing an efficient treatment of cancer. To date, various types of ABC transporter inhibitors have been employed but no effective anticancer drug is available at present, which can completely overcome MDR. Phytochemicals can reverse MDR in cancer cells via affecting the expression or activity of ABC transporters, and also through exerting synergistic interactions with anticancer drugs by addressing additional molecular targets. We have listed numerous phytochemicals which can affect the expression and activity of ABC transporters in MDR cancer cell lines. Phytochemicals in the groups of flavonoids, alkaloids, terpenes, carotenoids, stilbenoids, lignans, polyketides, and curcuminoids have been examined for MDR-reversing activity. The use of MDR-reversing phytochemicals with low toxicity to human in combination with effective anticancer agents may result in successful treatment of chemotherapy-resistant cancer. In this review, we summarize and discuss published evidence for natural products with MDR modulation abilities.

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“…Moreover, they suggested that the encapsulated naringenin showed higher cytotoxicity when compared with free naringenin due to a more controlled drug release [ 105 ]. Another option that could enhance the anticancer properties of naringenin involves the synthesis of naringenin derivatives [ 106 ].…”

Section: Polyphenolsmentioning

confidence: 99%

Current Perspectives of the Applications of Polyphenols and Flavonoids in Cancer Therapy

et al. 2020

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The development of anticancer therapies that involve natural drugs has undergone exponential growth in recent years. Among the natural compounds that produce beneficial effects on human health, polyphenols have shown potential therapeutic applications in cancer due to their protective functions in plants, their use as food additives, and their excellent antioxidant properties. The possibility of combining conventional drugs—which are usually more aggressive than natural compounds—with polyphenols offers very valuable advantages such as the building of more efficient anticancer therapies with less side effects on human health. This review shows a wide range of trials in which polyphenolic compounds play a crucial role as anticancer medicines alone or in combination with other drugs at different stages of cancer: cancer initiation, promotion, and growth or progression. Moreover, the future directions in applications of various polyphenols in cancer therapy are emphasized.

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Optimizing the Flavanone Core Toward New Selective Nitrogen-Containing Modulators of ABC Transporters

Abstract: The observed activities, together with pharmacophoric analysis and molecular docking studies, identified the spatial orientation of the substituents as a key structural feature toward a possible mechanism by which naringenin derivatives may reverse MDR in cancer.

Cited by 27 publications

References 42 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

Phytochemicals: Potential Lead Molecules for MDR Reversal

Current Perspectives of the Applications of Polyphenols and Flavonoids in Cancer Therapy

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