Flavonoid compounds as reversal agents of the P-glycoprotein-mediated multidrug resistance: biology, chemistry and pharmacology

Ferreira, Ana; Pousinho, Sarah; Fortuna, Ana; Falcão, Amílcar; Alves, Gilberto

doi:10.1007/s11101-014-9358-0

Cited by 41 publications

(51 citation statements)

References 189 publications

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“…The formation of a nonabsorbable morin–nimodipine complex in the gastrointestinal tract has been proposed as a possible explanation for the lack of influence of morin on nimodipine bioavailability. Surprisingly, the oral bioavailability of other P‐gp/CYP3A4 substrates (tamoxifen, cyclosporine) was reduced when coadministered with P‐gp/CYP3A4 inhibitors (biochanin A, quercetin) . As already mentioned, the unexpected decrease in cyclosporine bioavailability can be attributed, at least in part, to CYP3A4 activation by quercetin serum metabolites .…”

Section: Efflux Transportersmentioning

confidence: 79%

“…Although P‐gp–flavonoid interactions are very complex and have not been completely elucidated, several mechanisms have been proposed to explain, at least in part, the modulation of P‐gp activity by flavonoids. Flavonoids might interact with different sites on P‐gp (substrate‐binding site, other drug‐binding sites, ATP‐binding site, steroid‐interacting region, allosteric site) . However, the controversial findings on P‐gp modulation by flavonoids might be, in part, attributable to numerous drug‐binding sites expressed by P‐gp, both regulatory and transport sites that interact allosterically (i.e., drug binding to one site changes the conformation of other sites and, consequently, drug affinity) .…”

Section: Efflux Transportersmentioning

confidence: 99%

“…Besides, flavonoid metabolites (glucuronide and sulfate conjugates) present in the human plasma cannot interact with P‐gp owing to their hydrophilic properties. Thus, P‐gp–flavonoid interactions are unlikely to occur in other tissues …”

Section: Efflux Transportersmentioning

confidence: 99%

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Flavonoids as modulators of metabolic enzymes and drug transporters

Miron

Aprotosoaie

Trifan

et al. 2017

Annals of the New York Academy of Sciences

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Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR.

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Section: Efflux Transportersmentioning

confidence: 79%

Section: Efflux Transportersmentioning

confidence: 99%

See 1 more Smart Citation

Flavonoids as modulators of metabolic enzymes and drug transporters

Miron

Aprotosoaie

Trifan

et al. 2017

Annals of the New York Academy of Sciences

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“…Specifically, there are structural requirements necessary for the inhibitory effects of flavonoids on P-gp function. 30 The structure–activity relationships for flavonoid–P-gp interaction have been extensively studied. The presence of the 5-hydroxyl group, the 3-hydroxyl group, and the 2,3-double bond appears to be important for potent flavonoid-P-gp interaction and are required for the P-gp inhibitory activity 39,10 Isoflavonoids have lower P-gp interaction activity due to the different position where the ring B is branched.…”

Section: Resultsmentioning

confidence: 99%

“…30 The P-gp inhibitory potential of some of the natural flavonoids was found to be comparable with verapamil and cyclosporine A, the well-known P-gp inhibitors. 31,32 Flavonoids increase accumulation of various structurally and functionally diverse chemotherapeutic drugs in MDR cells.…”

Section: Introductionmentioning

confidence: 96%

Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer

et al. 2016

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P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various approaches of virtual screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P-gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P-gp. Dietary flavonoids exhibit better interactions with homology modeled human P-gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P-gp transport function and significantly reduced resistance in cytotoxicity assay to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer.

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Robust alkyl‐bridged bis(N‐heterocyclic carbene)palladium(II) complexes anchored on Merrifield's resin as active catalysts for the selective synthesis of flavones and alkynones

Mansour

Fettouhi

Saleem

et al. 2021

Applied Organom Chemis

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Highly active and efficient propylene‐bridged bis(N‐heterocyclic carbene)palladium(II) complexes covalently anchored on Merrifield's resin were synthesized and characterized using various physical and spectroscopic techniques. The two anchored Pd(II) complexes consist of the system: Merrifield's resin‐linker‐bis(NHC)Pd(II), the linkers being benzyl and benzyl‐O‐(CH2)3 for (Pd‐NHC1@M) and (Pd‐NHC2@M), respectively. The short linker anchored bis‐benzimidazolium ligand precursor (PBBI‐1@M) was synthesized via direct carbon–nitrogen alkylation of a propylene‐bridged bis(benzimidazole) (PBBI‐1) by Merrifield's resin chlorobenzyl group. The longer linker anchored bis‐benzimidazolium ligand precursor (PBBI‐2@M) was obtained in a two‐step reaction involving first alkylation of (PBBI‐1) with 3‐chloro‐1‐propanol followed by a nucleophilic substitution at Merrifield's resin chlorobenzyl group. Both supported ligand precursors (PBBI‐1@M and PBBI‐2@M) reacted with palladium acetate to produce the two heterogeneous catalysts (Pd‐NHC1@M) and (Pd‐NHC2@M). 13C NMR palladation shift of the benzimidazole N–C–N (C2) carbon was found very similar in both the liquid NMR spectra of the homogeneous complexes and the CP/MASS spectra of the corresponding covalently anchored complexes. The catalytic activity, stability, and the recycling ability of the supported catalysts have been investigated in the carbonylative Sonogashira coupling reactions of aryl iodides with aryl alkynes and alkyl alkynes and also in the cyclocarbonylative Sonogashira coupling reactions of aryl iodides with aryl alkynes via one pot reactions. The longer linker catalyst Pd‐NHC2@M demonstrated excellent catalytic activity, stability, and very high recycling ability in the two carbonylative coupling reactions. These systems exhibit the hypothesized thermodynamic stability offered by the chelate effect in addition to the strong sigma donor ability of a bis(NHC) ligand system generating electron‐rich palladium centers that favor the oxidative addition step of the aryl halide.

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Flavonoid compounds as reversal agents of the P-glycoprotein-mediated multidrug resistance: biology, chemistry and pharmacology

Cited by 41 publications

References 189 publications

Flavonoids as modulators of metabolic enzymes and drug transporters

Flavonoids as modulators of metabolic enzymes and drug transporters

Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer

Robust alkyl‐bridged bis(N‐heterocyclic carbene)palladium(II) complexes anchored on Merrifield's resin as active catalysts for the selective synthesis of flavones and alkynones

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