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  • 1
    Language: English
    In: ChemMedChem, 05 July 2010, Vol.5(7), pp.1153-1153
    Description: Wiley, Hoboken 2009. 459 pp., hardcover $ 125.00.—ISBN 978‐0‐470‐22734‐3
    ISSN: 1860-7179
    ISSN: ChemMedChem
    E-ISSN: 1860-7187
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  • 2
    Language: English
    In: ChemMedChem, April 2012, Vol.7(4), pp.650-662
    Description: Multidrug resistance observed in cancer chemotherapy is commonly attributed to overexpression of efflux transporter proteins. These proteins act as ATP‐dependent drug efflux pumps, actively extruding chemotherapeutic agents from cells and causing a decrease in intracellular drug accumulation. Besides the well‐recognized role of P‐glycoprotein (P‐gp, ABCB1), the breast cancer resistance protein (BCRP, ABCG2) is becoming increasingly accepted as playing an important role in multidrug resistance. In contrast to P‐glycoprotein, only a few inhibitors of ABCG2 are known. According to the literature, tyrosine kinase inhibitors (TKIs) can be considered to be broad‐spectrum inhibitors, interacting with ABCB1, ABCC1 and ABCG2. Here, we investigated seven different TKIs, gefitinib, erlotinib, AG1478, PD158780, PD153035, nilotinib and imatinib, for their potential to restore ABCG2 sensitivity to cells. Furthermore, we analyzed the alteration of ABCG2 expression caused by TKIs and demonstrated that EGFR inhibitors such as gefitinib and PD158780 reduced both total and surface expression of ABCG2 in EGRF‐positive MDCK BCRP cells by interaction with the PI3K/Akt signaling pathway. The reduced ABCG2 content led to an increased effect of XR9577, a well‐known ABCG2 modulator, lowering the concentration required for half maximal inhibition. On the other hand, BCR‐ABL inhibitors had no influence on ABCG2 expression and modulator activity. Interestingly, a combination of an EGFR inhibitor with the PI3K/Akt inhibitor LY294002 led to a significant reduction of ABCG2 expression at low concentrations of the drugs. Based on our results, we assume that EGFR exerts a post‐transcriptional enhancing effect on ABCG2 expression via the PI3K/Akt signaling pathway, which can be attenuated by EGFR inhibitors. Blocking the key signaling pathway regulating ABCG2 expression with EGFR inhibitors, combined with the inhibition of ABCG2 with potent modulators might be a promising approach to circumvent MDR in cancer cells. The interaction of known tyrosine kinase inhibitors (TKIs) with ABC transporter ABCG2 was investigated in detail. Insight was gained into the signal transduction cascade that regulates ABCG2. And the results suggest that combining a modulator of drug resistance with an EGFR inhibitor might be an ideal way to combat multidrug resistance in cancer cells in the future.
    Keywords: Abcg2 ; Cancer ; Egfr ; Inhibitors ; Pi3k/Akt Signaling Pathway
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 3
    Language: English
    In: ChemMedChem, April 2015, Vol.10(4), pp.742-751
    Description: We recently reported the synthesis and quantitative structure–activity relationships of a new breast cancer resistance protein (BCRP) inhibitor class. In the study presented herein, we investigated the possibility to better define the scaffold of this compound class by removing or modifying the aromatic ring A with various substituents selected on the basis of their electronic and lipophilic properties. The results show that this aromatic ring is important, but not essential, for activity. Many of the selected substituents led to compounds with low activity, but in some cases activity was retained. Among these, a phenolic hydroxy group proved to impart as much potency to the molecule as a hydroxyethyl side chain, initially considered necessary for activity. This derivative is one of the most active compounds in this class, maintaining an inhibitory activity similar to that of the reference compound; it is also selective for BCRP. In this study, we set out to better define the scaffold of a new class of compounds we recently reported as breast cancer resistance protein (BCRP) inhibitors. We removed or modified one aromatic ring (ring A) with various substituents that were chosen on the basis of their electronic and lipophilic properties. Intriguingly, this aromatic ring is important, yet not essential, for activity.
    Keywords: Abcg2 ; Abc Transporter ; Bcrp ; Inhibitors ; Multidrug Resistance
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 4
    Language: English
    In: ChemMedChem, 03 September 2010, Vol.5(9), pp.1498-1505
    Description: A new class of specific breast cancer resistance protein (BCRP) inhibitors was identified, showing no inhibition of the ATP binding cassette (ABC) transporters P‐gp and MRP1. Some of these modulators inhibit BCRP with high potency; they are only slightly less potent than Ko143 and could serve as promising lead structures for the design of novel effective BCRP inhibitors. These inhibitors are structurally related to tariquidar (XR9576) and belong to a library of multidrug‐resistance modulators synthesized by our research group. The absence of the tetrahydroisoquinoline substructure appears to play a crucial role for specificity; we found that the presence of this substructure is not essential for interaction with BCRP. To determine the type of interaction between pheophorbide A and compounds with and without the tetrahydroisoquinoline substructure, various substrate pheophorbide A concentrations were used in enzyme kinetics assays. The resulting data show that these compounds share a noncompetitive‐type interaction with pheophorbide A. Experiments with imatinib and pheophorbide A revealed a mixed‐type interaction. The combination of imatinib and compounds with and without the tetrahydroisoquinoline substructure resulted in a positive cooperative effect, indicating that imatinib engages a binding site distinct from that of the new compounds on one side and distinct from that of pheophorbide A on the other side as well. The results of this study suggest that the category of BCRP‐specific inhibitors, which includes only fumitremorgin C, Ko143 and analogues, and novobiocin needs to be extended by this new class of inhibitors, which possess three key characteristics: specificity, potency, and low toxicity. Until now, BCRP‐specific inhibitors have included only fumitremorgin C, Ko143 and analogues, and novobiocin; extension into a new class of inhibitors was greatly needed. Our work has led to a new series of BCRP inhibitors that possess an outstanding potential owing to three important characteristics: specificity, potency, and low toxicity.
    Keywords: Abc Transporters ; Biological Activity ; Breast Cancer ; Inhibitors ; Multidrug Resistance
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 5
    Language: English
    In: ChemMedChem, January 2013, Vol.8(1), pp.125-135
    Description: The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross‐resistance against various drugs used in chemotherapeutic treatment. In a previous work we showed that a new class of compounds derived from XR9576 (tariquidar) selectively inhibits BCRP. In this work we synthesized more members of this class, with modification on the second and third aromatic rings. The inhibitory activities against BCRP and P‐gp were assayed using a Hoechst 33342 assay for BCRP and a calcein AM assay for P‐gp. Finally, quantitative structure–activity relationships for both aromatic rings were established. The results obtained show the importance of the electron density on the third aromatic ring, influenced by substituents, pointing to interactions with aromatic residues of the protein binding site. In the second aromatic ring the activity of compounds is influenced by the steric volume of the substituents. The breast cancer resistance protein (BCRP/ABCG2) plays a crucial role in protecting the body from xenobiotics, but its overexpression in certain tumors causes resistance against various chemotherapeutics. We synthesized 25 compounds of a new class of selective BCRP inhibitors. A QSAR model for the second and third aromatic ring was established. The results show the importance of the electron density on the third aromatic ring and of steric hindrance on the second aromatic ring.
    Keywords: Abc Transporter ; Antitumor Agents ; Bcrp ; Drug Design ; Inhibitors ; Qsar
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 6
    Language: English
    In: ChemMedChem, 07 November 2016, Vol.11(21), pp.2422-2435
    Description: Chalcones are easily synthesized natural precursors of secondary plant metabolites, and their derivatives show various biological activities including inhibition of ABC transporters. Especially, their role as inhibitors of ABCG2, the most recently discovered ABC transporter involved in multidrug resistance, inspired the synthesis of new structurally diverse derivatives. Therefore, we combined the typical chalcone moiety with several acid chlorides by using an amide linker at position 2′, 3′, or 4′ on ring A of the chalcone. The resulting 35 compounds covered a wide spectrum of substitution patterns, which allowed development of structure–activity relationships and to find the optimal structural features for further investigations. Synthesized acryloylphenylcarboxamides were investigated for their inhibitory activity against ABCG2 and their behavior toward ABCB1 and ABCC1. Furthermore, for the most promising compounds, their intrinsic cytotoxicity and their ability to reverse ABCG2‐mediated multidrug resistance were determined. ! Acryloylphenylcarboxamides represent a new class of ABCG2 inhibitors. We combined the chalcone moiety with an additional aromatic residue by an amide linker. The position of the aromatic residue as well as that of the dimethoxy substituent on ring B have a large impact on activity. The most promising compound shows high potency and no cytotoxicity.
    Keywords: Acryloylphenylcarboxamides ; Amides ; Chalcones ; Inhibitors ; Multidrug Resistance
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 7
    Language: English
    In: ChemMedChem, May 2013, Vol.8(5), pp.748-762
    Description: The primary aim of this work was to analyze the contacts between residues in the nucleotide binding domains (NBDs) and at the interface between the transmembrane domains (TMDs) and the NBDs in the inward‐open homology model of human P‐glycoprotein (P‐gp). The analysis revealed communication nets through hydrogen bonding in the NBD and at the NBD–TMD interface of each half involving residues from the adenosine triphosphate (ATP) motifs and the coupling helices of the intracellular loops. Similar networks have been identified in P‐gp conformations generated by molecular dynamics simulation. Differences have been recorded in the networking between both halves of P‐gp. Many of the residue contacts have also been observed in the X‐ray crystal structures of other ATP binding cassette (ABC) transporters, which confirms their validity. Next, possible binding pockets involving residues of importance for the TMD–NBD communication were identified. By studying these pockets, binding sites were suggested for rhodamine 123 (R‐site) and prazosin (regulatory site) at the NBD–TMD interface that agreed with the experimental data on their location. Additionally, one more R‐site in the protein cavity was proposed, in accordance with the available biochemical data. Together with the previously suggested Hoechst 33342 site (H‐site), all sites were interpreted with respect to their effects on the protein ATPase activity, in correspondence with the experimental observations. Several residues involved in key contacts in the P‐gp NBDs were proposed for further targeted mutagenesis experiments. Contacts were analyzed between residues in the nucleotide binding domains (NBDs) and at the NBD–transmembrane domain (TMD) interfaces in the inward‐facing structural model of human P‐glycoprotein. The results reveal possible ways of communication between NBDs and TMDs through the intracellular, X‐, and Q‐loops and point to differences between both NBDs in the way of networking. Several binding pockets involving residues important for interdomain communication were identified, and binding sites were proposed for rhodamine 123 (R‐site) and prazosin (regulatory site), in agreement with experimental data.
    Keywords: Abc Transporters ; Glycoproteins ; Protein Structures ; Rhodamine ; Structure–Activity Relationships
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 8
    Language: English
    In: ChemMedChem, 21 November 2016, Vol.11(22), pp.2547-2558
    Description: ABCG2 belongs to the superfamily of ATP binding cassette (ABC) proteins and is associated with the limited success of anticancer chemotherapy, given its responsibility for the cross‐resistance of tumor cells, known as multidrug resistance (MDR). Several classes of ABCG2 inhibitors were developed for increasing the efficacy of chemotherapy. A series of chalcones coupled to an additional aromatic residue was synthesized and investigated for their inhibition of ABC transporters. In our previous work we determined the preferred position of the linker on the A‐ring to be , and found several substitution patterns at the additional ring that improved potency. In this study we investigated whether a methoxy group that improved the inhibitory activity of chalcones would also be beneficial for the acryloylphenylcarboxamide scaffold. Indeed, this modification led to highly potent ABCG2 inhibitors. To support the hypothesis of a beneficial effect of the amide linker, six acryloylphenylcarboxylates were synthesized and investigated for their inhibitory activity. Replacement of the amide linker with an ester group resulted in decreased inhibition. Molecular modeling showed that the conformational preference of both series differs, thereby explaining the positive effect of the amide linker. Several compounds were characterized in detail by investigating their intrinsic cytotoxicity and capacity to reverse MDR in MTT assays and their effect on vanadate‐sensitive ATPase activity. : Methoxy‐substituted acryloylphenylcarboxamides are a class of highly potent inhibitors of the ATP binding cassette G2 (ABCG2). A comparison with acryloylphenylcarboxylates highlighted the beneficial effect of an amide function for inhibitory activity toward this drug efflux pump, which plays a role in multidrug resistance.
    Keywords: Abcg2 ; Cancer ; Chalcones ; Membrane Proteins ; Multidrug Resistance
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 9
    Language: English
    In: ChemMedChem, October 2013, Vol.8(10), pp.1701-1713
    Description: Tariquidar and elacridar are among the most potent inhibitors of the multidrug resistance transporter P‐glycoprotein (P‐gp), but how they interact with the protein is yet unknown. In this work, we describe a possible way in which these inhibitors interact with P‐gp. We rely on structure–activity relationship analysis of a small group of tariquidar and elacridar analogues that was purposefully selected, designed, and tested. Structural modifications of the compounds relate to the presence or absence of functional groups in the tariquidar and elacridar scaffolds. The activity of the compounds was evaluated by their effects on the accumulation of P‐gp substrates rhodamine 123 and Hoechst 33342 in resistant tumor cells. The data allow estimation of the ability of the compounds to interact with the experimentally proposed R‐ and H‐sites to which rhodamine 123 and Hoechst 33342 bind, respectively. Using an inward‐facing homology model of human P‐gp based on the crystallographic structure of mouse P‐gp, we demonstrate that these binding sites may overlap with the binding sites of the QZ59 ligands co‐crystallized with mouse P‐gp. Based on this SAR analysis, and using flexible alignment and docking, we propose possible binding modes for tariquidar and elacridar. Our results suggest the possibility for the studied compounds to bind to sites that coincide or overlap with the binding sites of rhodamine 123 and Hoechst 33342. These results contribute to further understanding of structure–function relationships of P‐gp and can help in the design of selective and potent P‐gp inhibitors with potential clinical use. Tariquidar (magenta) and elacridar (green) are two of the most potent known inhibitors of P‐glycoprotein (P‐gp), but the way in which they interact with this target has not been determined. We pursued structure–activity relationship analyses of tariquidar and elacridar analogues and evaluated their effects on cellular P‐gp substrate accumulation to produce results useful for the future design of selective P‐gp inhibitors.
    Keywords: Binding Sites ; Elacridar ; Interactions ; P‐Glycoprotein ; Tariquidar
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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  • 10
    Language: English
    In: ChemMedChem, August 2014, Vol.9(8), pp.1704-1724
    Description: 8‐Benzyl‐substituted tetrahydropyrazino[2,1‐]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual‐target‐directed A/A adenosine receptor antagonists were identified. Several compounds showed triple‐target inhibition; one of the best compounds was 8‐(2,4‐dichloro‐5‐fluorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐]purine‐2,4(1,3)‐dione () (human AR:  A 217 n, A 233 n; IC MAO‐B: 508 n). Dichlorinated compound [8‐(3,4‐dichlorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐]purine‐2,4(1,3)‐dione] was found to be the best triple‐target drug in rat ( A 351 n, A 322 n IC MAO‐B: 260 n), and may serve as a useful tool for preclinical proof‐of‐principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease‐modifying treatment of neurodegenerative diseases are expected to show advantages over single‐target therapeutics. To help address Alzheimer′s and Parkinson′s diseases, tricyclic xanthine derivatives were developed by formally shifting N9 in to N8 in to improve water solubility at physiological pH. This resulted in potent dual‐target A/A adenosine receptor (AR) antagonists as well as triple‐target drugs with A/A AR antagonistic and MAO‐B inhibitory activities. Such compounds may be superior to single‐target drugs for complex neurodegenerative diseases.
    Keywords: Adenosine Receptors ; Antagonists ; Inhibitors ; Monoamine Oxidases ; Multitarget Drugs ; Neurodegenerative Diseases
    ISSN: 1860-7179
    E-ISSN: 1860-7187
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