1610805-19-0Relevant articles and documents
Design, synthesis and evaluation of a novel series of inhibitors reversing P-glycoprotein-mediated multidrug resistance
Ghaleb, Hesham,Li, Huilan,Kairuki, Mutta,Qiu, Qianqian,Bi, Xinzhou,Liu, Chunxia,Liao, Chen,Li, Jieming,Hezam, Kamal,Huang, Wenlong,Qian, Hai
, p. 1708 - 1716 (2018)
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.
Water-soluble inhibitors of ABCG2 (BCRP) – A fragment-based and computational approach
Antoni, Frauke,Wifling, David,Bernhardt, Günther
supporting information, (2020/11/20)
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.
Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562/A02 cells
Kairuki,Qiu, Qianqian,Pan, Miaobo,Li,Zhou,Ghaleb, Hesham,Huang, Wenlong,Qian, Hai,Jiang
, p. 3347 - 3357 (2019/06/17)
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.
