Aurones as Modulators of ABCG2 and ABCB1: Synthesis and Structure–Activity Relationships

Sim, Hong May; Loh, Ker Yun; Yeo, Wee Kiang; Lee, Chong Yew; Go, Mei‐Lin

doi:10.1002/cmdc.201000520

Cited by 55 publications

(47 citation statements)

References 41 publications

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“…A more detailed structure-activity relationship study further confirmed the potential of the aurone template as a lead for developing potent non-toxic modulators of ABCG2 and ABCB1 [21]. Notably, we identified several methoxylated aurones and related analogs that were equipotent to FTC, an established ABCG2 inhibitor, in reducing the efflux of pheophorbide A (PhA, an ABCG2 substrate) in ABCG2 over-expressing human breast cancer cells (MDA-MB-231/R).…”

Section: Introductionsupporting

confidence: 60%

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In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs

Sim

Ambudkar

et al. 2011

Biochemical Pharmacology

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Over-expression of ABCG2 is linked to multidrug resistance in cancer chemotherapy. We have previously shown that functionalized aurones effectively reduced the efflux of pheophorbide A (an ABCG2 substrate) from ABCG2 over-expressing MDA-MB-231/R (“R”) cells. In the present report, we investigated the functional relevance of this observation and the mechanisms by which it occurs. Aurones and related analogs were investigated for re-sensitization of R cells to mitoxantrone (MX, a chemotherapeutic substrate of ABCG2) in cell-based assays, accumulation of intracellular MX by cell cytometry, interaction with ABCG2 by biochemical assays and in vivo efficacy in MX resistant nude mice xenografts. We found that methoxylated aurones interacted directly with ABCG2 to inhibit efflux activity, possibly by competing for occupancy of one of the substrate binding sites on ABCG2. The present evidence suggests that they are not transported by ABCG2 although they stimulate ABCG2-ATPase activity. Alteration of ABCG2 protein expression was also discounted. One member was found to re-sensitize R cells to MX in both in vitro and in vivo settings. Our study identified methoxylated aurones as promising compounds associated with low toxicities and potent modulatory effects on the ABCG2 efflux protein. Thus, they warrant further scrutiny as lead templates for development as reversal agents of multidrug resistance.

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Section: Introductionsupporting

confidence: 60%

“…Cells were sub-cultured when they reached 80-90% confluency and used within 10 passages for assays. The syntheses and purification (to at least 95% purity) of the compounds investigated in this study (Table 1) have been reported by the authors [21]. Their systematic nomenclatures are given in Supplementary Information.…”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs

Sim

Ambudkar

et al. 2011

Biochemical Pharmacology

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“…14 Probably due to their scarce occurrence in nature, aurones have not been extensively studied for their biological activities although this is rapidly changing. Natural and synthetic aurones have been shown so far to possess a broad spectrum of bioactivity including anticancer, 15 antiparasitic 18,19 and neuroprotective. 20 Some aurone analogues have been recently identified by Manjulatha et al as SIRT1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Aurones as histone deacetylase inhibitors: Identification of key features

Zwick

Chatzivasileiou

Deschamps

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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“…Because some of the aurone analogs have unique chemical reactivities 24) and show anticancer or neuroprotective activity in cells or in in vivo studies, [25][26][27] we were interested in the relationship between its HDAC inhibitory activity and its biological effects (Fig. 1D).…”

Section: )mentioning

confidence: 99%

“…[25][26][27] Although we think that HDAC is not the molecular target of compound 7, it has been reported that compound 7 inhibits aurora kinase.…”

Section: )mentioning

confidence: 99%

False HDAC Inhibition by Aurone Compound

Itoh

Suzuki

Matsui

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fluorescence assays are useful tools for estimating enzymatic activity. Their simplicity and manageability make them suitable for screening enzyme inhibitors in drug discovery studies. However, researchers need to pay attention to compounds that show auto-fluorescence and quench fluorescence, because such compounds lower the accuracy of the fluorescence assay systems by producing false-positive or negative results. In this study, we found that aurone compound 7, which has been reported as a histone deacetylase (HDAC) inhibitor, gave false-positive results. Although compound 7 was identified by an in vitro HDAC fluorescence assay, it did not show HDAC inhibitory activity in a cell-based assay, leading us to suspect its in vitro HDAC inhibitory activity. As a result of verification experiments, we found that compound 7 interferes with the HDAC fluorescence assay by quenching the HDAC fluorescence signal. Our findings underscore the faults of fluorescence assays and call attention to careless interpretation.Key words fluorescence assay; histone deacetylase (HDAC); drug discovery screening; enzymatic activityThe evaluation of enzymatic activity is essential for understanding the biology of an enzyme or identifying its inhibitors. At present, in vitro or cell-based fluorescence assays are often used for the estimation of enzymatic activity, or for high-throughput screening for drug candidates.1-4) For example, substrates bearing a fluorophore are available for estimating the activity of trypsin or caspase-3 or searching their inhibitors 5-7) (Figs. 1A-C). Trypsin or caspase-3 recognizes a particular amino acid or amino acid sequence in the fluorescent substrates and specifically cleaves the peptide bond of the C-terminus to release a fluorophore, such as 7-amino-4-methylcoumarin (AMC, 1) (Fig. 1A). Because N-acylated AMC (2) does not emit strong fluorescence, the detected fluorescence should correspond to the enzymatic activity (Figs. 1A-C); in this way, the enzymatic activity or inhibitory activity can be evaluated. Such assay systems based on fluorometric methods are frequently utilized in drug discovery studies.Assay systems based on fluorescent substrates are often used for evaluating the activity of histone deacetylases (HDACs).8-10) HDACs, which catalyze the deacetylation of acetyl lysine residues in histone or non-histone proteins, are an interesting molecular target of cancer therapeutic agents. 11)Many HDAC inhibitors have been identified 11,12) and some have been approved by the Food and Drug Administration (FDA). Examples include vorinostat (3) 13) and romidepsin (4) 14) for cutaneous T-cell lymphoma; belinostat (5) 15) for peripheral T-cell lymphoma; and panobinostat (6) 16) for use in the combination therapy for recurrent multiple myeloma with bortezomib and dexamethasone (Fig. 2). However, problems persist regarding the approved HDAC inhibitors, including adverse effects and limited additional indications. Therefore, explorative studies of novel HDAC inhibitors should be performed. To this end, fluoresc...

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Aurones as Modulators of ABCG2 and ABCB1: Synthesis and Structure–Activity Relationships

Cited by 55 publications

References 41 publications

In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs

In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs

Aurones as histone deacetylase inhibitors: Identification of key features

False HDAC Inhibition by Aurone Compound

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