Functional assay and structure–activity relationships of new third-generation P-glycoprotein inhibitors

Müller, Henrik; Pajeva, Ilza; Globisch, Christoph; Wiese, Michael

doi:10.1016/j.bmc.2007.11.057

Cited by 58 publications

(63 citation statements)

References 23 publications

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“…A number of tariquidar analogs have been synthesized and tested by Wiese and coworkers (23)(24)(25)(26)(27). Recently, a small molecule library has been reported (28) with 39 compounds that possess a tetrahydroisoquinoline-ethyl-phenylamine substructure as in XR9576.…”

Section: Other Tariquidar Analogsmentioning

confidence: 99%

“…A high correlation between the pIC 50 values in both assays was observed, and it was shown that at the low substrate concentrations used in the assays, the type of interaction of the compounds with P-gp (competitive or non-competitive) could not be distinguished from the IC 50 values only. When additional experiments were performed with different substrate concentrations to appraise the type of inhibition, noncompetitive inhibition was found with calcein AM and competitive inhibition was observed for Hoechst 33342 (27).…”

Section: Other Tariquidar Analogsmentioning

confidence: 99%

“…Tariquidar belongs to a series of compounds, called XR compounds, which have been developed by Xenova Group Ltd. (21,22). A number of new tariquidar analogs have been synthesized and pharmacologically tested (23)(24)(25)(26)(27)(28)(29)(30)(31)(32), thus supplying good data for a profound structure-activity investigation of this promising class of MDR modulators.…”

Section: Introductionmentioning

confidence: 99%

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Structure–Activity Relationships of Tariquidar Analogs as Multidrug Resistance Modulators

Pajeva

Wiese

2009

AAPS J

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Abstract. The review summarizes the most recent achievements in structure-activity relationship (SAR) studies of tariquidar and its analogs. Tariquidar is one of the most promising representatives of the third generation of multidrug resistance (MDR) modulators created so far. This fact determines the strong interest of different research groups in the development of tariquidar-like structures as selective inhibitors of MDR transporters in resistant human cancer cells. After the discovery of tariquidar, a number of analogs have been synthesized and pharmacologically tested, thus supplying good data for comprehensive analyses of their structure-activity relationships. In the review, the structural and pharmacological data of newly synthesized tariquidar-like compounds are first presented. Next, the main achievements in the SAR studies are described focusing on two main transport proteins: P-glycoprotein and breast cancer resistance protein. The reported results are discussed from the point of view of their significance and importance for future directions in the rational design of effective MDR modulators.

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Section: Other Tariquidar Analogsmentioning

confidence: 99%

Section: Other Tariquidar Analogsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure–Activity Relationships of Tariquidar Analogs as Multidrug Resistance Modulators

Pajeva

Wiese

2009

AAPS J

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“…[6][7][8][9] However, none of them was approved for clinical use due to their unwanted side effects.…”

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confidence: 99%

Icariin Enhances Cytotoxicity of Doxorubicin in Human Multidrug-Resistant Osteosarcoma Cells by Inhibition of ABCB1 and Down-Regulation of the PI3K/Akt Pathway

Wang

Yang

Xia

et al. 2015

Biological & Pharmaceutical Bulletin

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Multidrug resistance is one of the major causes limiting the efficacy of chemotherapeutic agents used to control osteosarcoma. Multidrug resistance protein 1 (MDR1 or ABCB1) was considered to play a critical role in multidrug resistance. Agents from traditional Chinese medicines (TCMs) have great potential to prevent the onset or delay the progression of the carcinogenic process, and also to enhance the efficacy of mainstream antitumor agents. Herein, we investigated the effect and mechanism of icariin in the human osteosarcoma doxorubicin ( Key words osteosarcoma; icariin; multidrug resistance (MDR); phosphatidyl inositol 3-kinase (PI3K)/Akt pathwayChemotherapy is regarded as an important line of defense against osteosarcoma which is the most common primary mesenchymal malignant tumor of bone tissue in human, especially in children and adolescents. However, on account of drug resistance especially multidrug resistance (MDR), only a limited proportion of cancer patients respond favorably to commonly used chemotherapeutic drugs.1) With respect to the mechanisms of multidrug resistance, ATP-binding cassette transporters, such as ABCB1 (MDR1, P-glycoprotein (P-gp)), ABCC1/multidrug resistance-associated protein 1 (MRP1) and ABCG2/breast cancer resistance protein (BCRP), mediate energy-dependent drug efflux and play a main role in chemoresistance.2,3) And central to the mechanism is the overexpression of MDR1, which extrudes (certainly but not only) Vinca alkaloids, anthracyclines, epipodophyllotoxins, and taxanes out of cancer cells. 4)Inhibiting drug transporter and modulating MDR are one of the most important strategies in the field of cancer chemotherapy. First-generation inhibitors of P-gp such as verapamil (VPL) and cyclosporine were combined with a range of chemotherapy regimens for many cancers, but the results were not convincing. The second-generation inhibitors of P-gp such as PSC 833 and VX-710 were attempted in subsequent clinical trials, but the results of these trialswere largely negative, failing in some cases because of pharmacokinetic interaction between the chemotherapeutic agents and the P-gp inhibitors.5) The third-generation inhibitors of P-gp and MRP1 such as tariquidar (XR9576), Zosuquiar (LY335979), Laniquidar (R102933), and may be more effective in certain patients with MDR. [6][7][8][9] However, none of them was approved for clinical use due to their unwanted side effects.Therefore, the screening of more potent chemosensitizers with desirable pharmacology is of paramount clinical importance.Agents derived from plant origin are being increasingly utilized in drug discovery and drug development programs. 10,11) Identification of natural compounds capable of circumventing MDR with minimal adverse side effects is an attractive goal. For example, flavonoids are a group of compounds which have been extensively studied as chemosensitizers in a number of cancer cell lines. 12) Icariin (Fig. 1), one of the most abundant flavonoids in Herba Epimedii, has lots of pharmacological and biological acti...

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“…The method with Hoechst 33342 determines the specifi ty of ABC pump inhibitors. If the modulator infl uences the binding site of Hoechst 33342 in the protein, the fl uorescence intensity of this fl uorochrome increases (Muller et al, 2007(Muller et al, , 2008.…”

Section: Acetoxymethyl Derivatives As Fl Uorescent Markers Determinatmentioning

confidence: 99%

Inhibitors of ABC Transporters and Biophysical Methods to Study their Activity

Bartosiewicz

Krasowska

2009

Zeitschrift Für Naturforschung C

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Functional assay and structure–activity relationships of new third-generation P-glycoprotein inhibitors

Cited by 58 publications

References 23 publications

Structure–Activity Relationships of Tariquidar Analogs as Multidrug Resistance Modulators

Structure–Activity Relationships of Tariquidar Analogs as Multidrug Resistance Modulators

Icariin Enhances Cytotoxicity of Doxorubicin in Human Multidrug-Resistant Osteosarcoma Cells by Inhibition of ABCB1 and Down-Regulation of the PI3K/Akt Pathway

Inhibitors of ABC Transporters and Biophysical Methods to Study their Activity

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