Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1)

Norman, Bryan H.; Lander, Peter A.; Gruber, Joseph M.; Kroin, Julian S.; Cohen, Jeffrey; Jungheim, Louis N.; Starling, James J.; Law, Kenneth S.; Self, Tracy D.; Tabas, Linda B.; Williams, Daniel C.; Paul, Donald C.; Dantzig, Anne H.

doi:10.1016/j.bmcl.2005.08.075

Cited by 50 publications

(21 citation statements)

References 8 publications

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“…For example, MRP1 and MRP2 are good transporters of the proinflammatory cysteinyl leukotriene C 4 , whereas MRP3 and MRP4 are not. Further, the potent glutathione-dependent tricyclic isoxazole inhibitor of MRP1, LY475776, does not interact with MRP2, MRP3, 4 or 5 (Mao et al, 2002;Dantzig et al, 2004;Norman et al, 2005).…”

Section: Discussionmentioning

confidence: 95%

“…MRP1 was discovered more than 15 years after P-glycoprotein, and thus it is not surprising that fewer MRP1-specific modulators have been identified (Cole et al, 1992;Chen et al, 2001;Wang et al, 2004;Boumendjel et al, 2005;Norman et al, 2005). Similar to P-glycoprotein, MRP1 can confer resistance to natural product drugs in tumor cells (Cole et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

Myette

Conseil

Ebert

et al. 2013

Drug Metabolism and Disposition

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Multidrug resistance proteins (MRPs) mediate the ATP-dependent efflux of structurally diverse compounds, including anticancer drugs and physiologic organic anions. Five classes of chalcogenopyrylium dyes (CGPs) were examined for their ability to modulate transport of [ 3 H]estradiol glucuronide (E 2 17bG; a prototypical MRP substrate) into MRP-enriched inside-out membrane vesicles.Additionally, some CGPs were tested in intact transfected cells using a calcein efflux assay. Sixteen of 34 CGPs inhibited MRP1-mediated E 2 17bG uptake by >50% (IC 50 values: 0.7-7.6 mM). Of 9 CGPs with IC 50 values £2 mM, two belonged to class I, two to class III, and five to class V. When tested in the intact cells, only 4 of 16 CGPs (at 10 mM) inhibited MRP1-mediated calcein efflux by >50% (III-1, V-3, V-4, V-6), whereas a fifth (I-5) inhibited efflux by just 23%.These five CGPs also inhibited [ 3 H]E 2 17bG uptake by MRP4. In contrast, their effects on MRP2 varied, with two (V-4, V-6) inhibiting E 2 17bG transport (IC 50 values: 2.0 and 9.2 mM) and two (V-3, III-1) stimulating transport (>2-fold), whereas CGP I-5 had no effect. Strikingly, although V-3 and V-4 had opposite effects on MRP2 activity, they are structurally identical except for their chalcogen atom (Se versus Te). This study is the first to identify class V CGPs, with their distinctive methine or trimethine linkage between two disubstituted pyrylium moieties, as a particularly potent class of MRP modulators, and to show that, within this core structure, differences in the electronegativity associated with a chalcogen atom can be the sole determinant of whether a compound will stimulate or inhibit MRP2.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

Myette

Conseil

Ebert

et al. 2013

Drug Metabolism and Disposition

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“…LY475776 and LY402913 inhibit MRP1/ABCC1 with a high selectivity (e.g. 1115-fold against P-gp/MDR1) in intact cells at low micromolar concentration (0.06-0.09 μM) [250,251]. They are much less active against P-gp/MDR1, BCRP/ABCG2, MRP2/ABCC2, and MRP3/ABCC3.…”

Section: Inhibitors Of Mrp1/abcc1mentioning

confidence: 98%

“…These include tricyclic isoxazole derivatives such as LY475776 and LY402913 (Fig. (32)) [249][250][251][252][253]. They were initially identified by a highthroughput screening strategy.…”

Section: Inhibitors Of Mrp1/abcc1mentioning

confidence: 99%

Substrates and Inhibitors of Human Multidrug Resistance Associated Proteins and the Implications in Drug Development

Zhou¹,

Wang²,

Di³

et al. 2008

CMC

330

239

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Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.

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“…Isoxazoles were reported for their various biological activities[1–3]. The reactive intermediate chalcones involved in their synthesis also exhibit wide range of biological activities[4–6].…”

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confidence: 99%

Synthesis, antiinflammatory and antibacterial activity of novel indolyl-isoxazoles

Panda¹,

Chowdary²,

Jayashree³

2009

Indian J Pharm Sci

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Chalcones were synthesized by reacting indole-3-aldehyde, prepared by Vilsemeir Haack reaction with 4-substituted acetophenone in ethanolic KOH solution. These chalcones were immediately reacted with hydroxylamine hydrochloride in presence of glacial acetic acid as reagent to obtain the corresponding isoxazole derivatives. The synthesized heterocycles were characterized on the basis of physical, chemical tests and spectroscopic data. These compounds were tested for the acute antiinflammatory activity and antibacterial activity using carrageenan-induced rat paw edema method and cup-plate method, respectively.

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Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1)

Cited by 50 publications

References 8 publications

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

Substrates and Inhibitors of Human Multidrug Resistance Associated Proteins and the Implications in Drug Development

Synthesis, antiinflammatory and antibacterial activity of novel indolyl-isoxazoles

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