Design and Synthesis of New Templates Derived from Pyrrolopyrimidine as Selective Multidrug-Resistance-Associated Protein Inhibitors in Multidrug Resistance

Wang, Shouming; Wan, Nan Chi; Harrison, John; Miller, Warren; Chuckowree, Irina; Sohal, Sukhjit; Hancox, Timothy; Baker, Stewart; Folkes, Adrian; Wilson, Francis X.; Thompson, Deanne; Cocks, Simon; Farmer, Hayley; Boyce, Anthony S.; Freathy, Caroline; Broadbridge, Jan; Scott, John; Depledge, Paul; Faint, Richard; Mistry, Prakash; Charlton, Peter

doi:10.1021/jm0310129

Cited by 39 publications

(46 citation statements)

References 14 publications

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“…Interestingly, some of them were rather specific for MRP1 over P-glycoprotein, and displayed limited interactions with enzymes involved in drug metabolism such as cytochrome P450s. A few compounds exhibited acceptable pharmacokinetics, and appeared indeed active in vivo as shown by trials on xenografted mice models where they potentiated the cytotoxic effects of vincristine 81,82 In an independent and unrelated study, Benyahia et al reported the ability of the antiinflammatory drug, indomethacin (Fig. 7), to chemosensitize MRP1-overexpressing cells to vincristine and etoposide.…”

Section: Raloxifene-based Inhibitorsmentioning

confidence: 99%

“…6). [81][82][83][84] The best derivatives exhibited high efficiency to inhibit MRP1, with half-maximal values in the range 0.02-0.2 mM towards daunomycin cellular efflux and cell growth sensitization to doxorubicin. Interestingly, some of them were rather specific for MRP1 over P-glycoprotein, and displayed limited interactions with enzymes involved in drug metabolism such as cytochrome P450s.…”

Section: Raloxifene-based Inhibitorsmentioning

confidence: 99%

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Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents

Boumendjel

Baubichon‐Cortay

Trompier

et al. 2005

Medicinal Research Reviews

132

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Multidrug resistance protein 1 (MRP1) belongs to the ATP-binding cassette (ABC) transporter family. It is able to transport a broad range of anticancer drugs through cellular membranes, thus limiting their antiproliferative action. Since its discovery in 1992, MRP1 has been the most studied among MRP proteins, which now count nine members. Besides the biological work, which targets structure elucidation, binding sites location, and mode of action, most efforts have been focused on finding molecules which act as MRP1 inhibitors. In this review, we attempt to summarize and highlight studies dealing with modulators of MRP1-mediated multidrug resistance (MDR), which have been accomplished in the last 5 years. The reported MRP1 inhibitors are discussed according to their chemical class. Finally, we try to bring information on structure-activity relationship (SAR) aspects and how modulators might interact with MRP1. This study may facilitate the rational design of future modulators of MDR.

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Section: Raloxifene-based Inhibitorsmentioning

confidence: 99%

Section: Raloxifene-based Inhibitorsmentioning

confidence: 99%

Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents

Boumendjel

Baubichon‐Cortay

Trompier

et al. 2005

Medicinal Research Reviews

132

View full text Add to dashboard Cite

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“…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%

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

et al. 2013

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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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“…[2][3][4][5][6] Much interest in this heterocyclic moiety has arisen in recent pharmacological programs as it serves as a bioisoster of indole or purine. [7][8][9][10][11][12][13][14][15][16] Applications in the preparation of bioactive molecules and in the syntheses of dopamine D-4 receptor ligands [17] as well as of potent GnRH antagonists [18] have been cited. The increased interest in this heterocyclic system has motivated considerable synthetic efforts towards functionalized azaindole derivatives.…”

Section: Introductionmentioning

confidence: 99%

Gold‐Catalyzed C‐3‐Alkylation of 7‐Azaindoles Through Michael‐Type Addition to α,β‐Enones

et al. 2006

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The AuIII‐catalyzed reactions of 7‐azaindole derivatives with α,β‐enones are described. Factors that can direct the C‐3‐ versus N‐1‐alkylation reaction on the 7‐azaindole nucleus are explored. The AuIII‐catalyzed reaction of 7‐azaindole with β‐unsubstituted α,β‐enones afforded 1‐substituted7‐azaindoles through an aza‐Michael‐type reaction. Incontrast, 6‐substituted 7‐azaindoles underwent regioselective C‐3‐alkylation through a Na[AuCl4]·2H2O‐catalyzed conjugate addition‐type reaction. Analogously, the Na[AuCl4]·2H2O‐catalyzed reaction of 7‐azaindole derivatives with β‐aryl‐substituted α,β‐enones gave 3‐substituted 7‐azaindoles in moderate‐to‐satisfactory yields. Moreover, the Na[AuCl4]·2H2O‐catalyzed reaction of 1‐substituted 7‐azaindoles with α,β‐enones allowed an easy entry to 1,3‐disubstituted 7‐azaindoles in moderate‐to‐high yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Design and Synthesis of New Templates Derived from Pyrrolopyrimidine as Selective Multidrug-Resistance-Associated Protein Inhibitors in Multidrug Resistance

Cited by 39 publications

References 14 publications

Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents

Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents

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

Gold‐Catalyzed C‐3‐Alkylation of 7‐Azaindoles Through Michael‐Type Addition to α,β‐Enones

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