Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents

Abstract

Chemotherapy remains a pillar in the treatment and management of various cancers. However, multidrug resistance (MDR) becomes a severe problem after long‐term administration of chemotherapy drugs. Overexpression of P‐glycoprotein (P‐gp) is a significant cause for tumor MDR. Therefore, P‐gp inhibition is considered as an effective strategy to reverse MDR. A third‐generation P‐gp inhibitor tariquidar was selected as a lead compound, and a new series of triazol‐N‐ethyl tetrahydroisoquinoline based compounds were designed as novel P‐gp inhibitors and synthesized through click chemistry. These compounds presented higher reversal activities than the positive‐control verapamil (VRP). Among 18 compounds, compound 11 without cytotoxicity reversed MDR in a dose‐dependent manner, with a persistent longer chemosensitizing effect and reversibility compared to others. Mechanism studies discovered that compound 11 could escalate the intracellular accumulation of rhodamine‐123 and doxorubicin in K562/A02 cells as well as inhibit their efflux from cells. The results obtained suggest that compound 11 is more potent than VRP administered under the same conditions; it may be a potent and safe candidate for P‐gp modulation for further development.

Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

“…Most reported potent tetrahydroisoquinoline-based P-gp inhibitors [64][65][66][67][68][69][70][71][72][73][74][75] were analogs of the third-generation P-gp inhibitor tariquidar (XR9576) 76 (Figure 3). By using various medicinal chemistry strategies 47 including (i) bioisosterism (such as replacing the amide bond in building block 1 of tariquidar with an easily-accessible triazole moiety which bears similar plane structure and bond length) 77,78 ; (ii) hybridization strategy 79,80 that has been frequently used in the drug design of P-gp inhibitors to obtain the desired scaffold; (iii) computer-aided drug design (CADD) strategy; (iv) late-stage functionalization 81,82 that utilizes the C−H bonds in the molecule as sites of diversification to rapidly promote the synthesis of new analogs; (v) ring fusing strategy; (vi) ring splitting strategy, (vii) scaffold hopping strategy (such as N-walking strategy), and (viii) amide reversal strategy, numerous tariquidar analogs have been designed and synthesized which can be divided into three series: Series 1, 2, and 3, where ethylphenylamine, ethyl(1-phenyl-1H-1,2,3-triazol-4-yl)methanamine, and ethyl(1H-1,2,3-triazol-4-yl)methanamine were used as building block 1, respectively ( Figure 3A).…”

Sinensetin: An Insight on Its Pharmacological Activities, Mechanisms of Action and Toxicity

“…Sinensetin is one of the polymethoxylated flavonoids that has been intensively studied for its anticancer activity. Chemotherapy remains as a standard in the treatment and management of cancer ( Qiu et al, 2019 ). However, the major obstacle to successful chemotherapy is the development of multidrug resistance (MDR) by tumor cells after long term administration of chemotherapy drugs ( Choi et al, 2002 ; Qiu et al, 2019 ).…”

“…Chemotherapy remains as a standard in the treatment and management of cancer ( Qiu et al, 2019 ). However, the major obstacle to successful chemotherapy is the development of multidrug resistance (MDR) by tumor cells after long term administration of chemotherapy drugs ( Choi et al, 2002 ; Qiu et al, 2019 ). Prominent group of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), Multiresistance Protein (MRP) and ATP Binding Cassette Subfamily G Member or also known as breast cancer resistance protein (ABCG2 or BCRP) have been characterized in relation to MDR, limiting the exposure to anticancer drugs ( Choi and Yu, 2014 ; Wilkens, 2015 ; Waghray and Zhang, 2018 ).…”

“…Sinensetin has been reported to inhibit P-glycoprotein (P-gp) in several studies. Elevated expression of P-glycoprotein (P-gp) due to regulation of human gene expression of MDR1 is a significant cause for tumor multidrug resistance (MDR) ( Qiu et al, 2019 ). Overexpression of P-gp has been linked to reduced chemotherapeutic responses and poor clinical outcomes in various cancer types ( Waghray and Zhang, 2018 ).…”

“…Overexpression of P-gp has been linked to reduced chemotherapeutic responses and poor clinical outcomes in various cancer types ( Waghray and Zhang, 2018 ). Therefore, P-gp inhibition is nominated as an effective strategy to reverse MDR ( Qiu et al, 2019 ). Sinensetin, was found to significantly inhibit P-gp in a few cell types such as MDR1-MDCK II cells, Caco 2 cells and K562/ADM cells ( Mertens-Talcott et al, 2007 ; Ohtani et al, 2007 ; Bai et al, 2019 ).…”