- Design, synthesis and evaluation of a novel series of inhibitors reversing P-glycoprotein-mediated multidrug resistance
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Multidrug resistance (MDR) is still the main barrier to attaining effective results with chemotherapy. Discovery of new chemo-reversal agents is needed to overcome MDR. Our study focused on a better way to obtain novel drugs with triazole rings that have an MDR reversal ability through click chemistry. Among 20 developed compounds, compound 19 had a minimal cytotoxic effect compared to tariquidar and verapamil (VRP) and showed a higher reversal activity than VRP through increased accumulation in K562/A02 cells. Compound 19 also played an important role in the P-gp efflux function of intracellular Rh123 and doxorubicin (DOX) accumulation in K562/A02 cells. Moreover, compound 19 exhibited a long lifetime of approximately 24?hr. These results indicated that compound 19 is a potential lead compound for the design of new drugs to overcome cancer MDR.
- Ghaleb, Hesham,Li, Huilan,Kairuki, Mutta,Qiu, Qianqian,Bi, Xinzhou,Liu, Chunxia,Liao, Chen,Li, Jieming,Hezam, Kamal,Huang, Wenlong,Qian, Hai
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Read Online
- Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance
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P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major impediment for clinical cancer therapy. 19 novel aromatic amides with triazole-core as MDR reversal agents were designed and synthesized via click chemistry to reverse MDR. Among them, compound 42 was identified as the most promising candidate with high potency (EC50 = 78.1 ± 5.4 nM), low cytotoxity (SI > 1282) and persistent duration in reversing doxorubicin (DOX) resistance in K562/A02 cells. 42 also enhanced the potency of other P-gp associated cytotoxic agents with different structures. In further study, remarkably increased intracellular accumulation of Rh123 and DOX in K562/A02 cells was achieved by compound 42, while CYP3A4 activity had no change by compound 42. These results indicate that compound 42 as a relatively safe modulator of P-gp-mediated MDR has good potential for further development.
- Qiu, Qianqian,Zhu, Jilan,Chen, Qiutong,Jiang, Ziqian,Xu, Jiting,Jiang, Xueting,Huang, Wenlong,Liu, Zhongquan,Ye, Jing,Xu, Xiaojuan
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Read Online
- Water-soluble inhibitors of ABCG2 (BCRP) – A fragment-based and computational approach
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A good balance between hydrophilicity and lipophilicity is a prerequisite for all bioactive compounds. If the hydrophilicity of a compound is low, its solubility in water will be meager. Many drug development failures have been attributed to poor aqueous solubility. ABCG2 inhibitors are especially prone to be insoluble since they have to address the extremely large and hydrophobic multidrug binding site in ABCG2. For instance, our previous, tariquidar-related ABCG2 inhibitor UR-MB108 (1) showed high potency (79 nM), but very low aqueous solubility (78 nM). To discover novel potent ABCG2 inhibitors with improved solubility we pursued a fragment-based approach. Substructures of 1 were optimized and the fragments ‘enlarged’ to obtain inhibitors, supported by molecular docking studies. Synthesis was achieved, i.a., via Sonogashira coupling, click chemistry and amide coupling. A kinetic solubility assay revealed that 1 and most novel inhibitors did not precipitate during the short time period of the applied biological assays. The solubility of the compounds in aqueous media at equilibrium was investigated in a thermodynamic solubility assay, where UR-Ant116 (40), UR-Ant121 (41), UR-Ant131 (48) and UR-Ant132 (49) excelled with solubilities between 1 μM and 1.5 μM – an up to 19-fold improvement compared to 1. Moreover, these novel N-phenyl-chromone-2-carboxamides inhibited ABCG2 in a Hoechst 33342 transport assay with potencies in the low three-digit nanomolar range, reversed MDR in cancer cells, were non-toxic and proved stable in blood plasma. All properties make them attractive candidates for in vitro assays requiring long-term incubation and in vivo studies, both needing sufficient solubility at equilibrium. 41 and 49 were highly ABCG2-selective, a precondition for developing PET tracers. The triple ABCB1/C1/G2 inhibitor 40 qualifies for potential therapeutic applications, given the concerted role of the three transporter subtypes at many tissue barriers, e.g. the BBB.
- Antoni, Frauke,Wifling, David,Bernhardt, Günther
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supporting information
(2020/11/20)
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- Tariquidar-related triazoles as potent, selective and stable inhibitors of ABCG2 (BCRP)
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Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current study comprises the synthesis and characterization of novel tariquidar-related inhibit
- Antoni, Frauke,Bauer, Stefanie,Bause, Manuel,Bernhardt, Günther,Buschauer, Armin,Jackson, Scott M.,K?nig, Burkhard,Locher, Kaspar P.,Manolaridis, Ioannis,Scholler, Matthias,Stark, Simone A.
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supporting information
(2020/02/26)
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- Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562/A02 cells
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Multidrug resistance (MDR) refers to the cross-resistance of cancer cells to one drug, accompanied by other drugs with different mechanisms and structures, which is one of the main obstacles of clinical chemotherapy. Overexpression of P-glycoprotein (P-gp) was an extensively studied cause of MDR. Therefore, inhibiting P-gp have become an important strategy to reverse MDR. In this study, two series of triazole-tetrahydroisoquinoline-core P-gp inhibitors were designed and synthesized. Among them, compound I-5 had a remarkable reversal activity of MDR activity and the preliminary mechanism study was also carried out. All the results proved that compound I-5 was considered as a promising P-gp-mediated MDR reversal candidate.
- Kairuki,Qiu, Qianqian,Pan, Miaobo,Li,Zhou,Ghaleb, Hesham,Huang, Wenlong,Qian, Hai,Jiang
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p. 3347 - 3357
(2019/06/17)
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- Triazole-N-tetrahydroisoquinoline compounds as well as preparation method and application thereof
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The invention relates to compounds shown in a general formula (I) and salt thereof. The compounds have stronger functions of reversing multiple drug resistance (MDR) of tumor, the activity of a part of the compounds is much higher than that of verapamil, and the compounds have lower cell toxicity. The invention also relates to a preparation method of the compounds and a pharmaceutical preparationcontaining the compounds. According to the compounds as well as the preparation and application thereof disclosed by the invention, a series of compounds shown in the general formula (1) and the pharmaceutically acceptable salt are synthesized. The formula (1) is shown in the description.
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Paragraph 0206; 0212; 0213
(2018/03/26)
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- Triazole-N-phenethyl tetrahydronaphthalene isoquinoline compounds and, preparation method and application thereof
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The invention relates to compounds as shown in a formula (I) and salt thereof. The compounds have relatively high action of reserving multidrug resistance (MDR) of tumors and the activity of part of the compounds is higher than that of verapamil, and the
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Paragraph 0078-0081
(2018/01/14)
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- Design, synthesis and biological evaluation of novel triazole-core reversal agents against P-glycoprotein-mediated multidrug resistance
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We designed and synthesized a novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors bearing a triazolphenethyl-tetrahydroisoquinoline scaffold through click chemistry. Then those synthesized compounds were tested on doxorubi
- Zhang, Bo,Zhao, Tianxiao,Zhou, Jie,Qiu, Qianqian,Dai, Yuxuan,Pan, Miaobo,Huang, Wenlong,Qian, Hai
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p. 25819 - 25828
(2016/03/25)
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- Discovery of novel P-glycoprotein-mediated multidrug resistance inhibitors bearing triazole core via click chemistry
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A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors bearing a triazol-phenethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 5 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity (IC50s > 100 μm). Compared with VRP, compound 5 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 5 persisted longer chemo-sensitizing effect (>24 h) than VRP (6 h) with reversibility. Given the low intrinsic cytotoxicity and the potent reversal activity, compound 5 may represent a promising candidate for developing P-gp-mediated MDR inhibitor.
- Liu, Baomin,Qiu, Qianqian,Zhao, Tianxiao,Jiao, Lei,Hou, Jianyu,Li, Yunman,Qian, Hai,Huang, Wenlong
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p. 182 - 191
(2014/07/22)
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