Design, synthesis and evaluation of a novel series of inhibitors reversing P‐glycoprotein‐mediated multidrug resistance

Abstract

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.

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).…”

Multidrug resistance reversing activity of organoselenium compounds

“…An emerging research approach and therapeutic strategy is the use of efflux pump inhibitors (EPIs) as adjuvant compounds (so-called 'chemosensitizers') to improve the efficacy of antitumor therapy, by co-administering them with chemotherapeutic agents [40,65,[73][74][75]. Considerable number of compounds have been described capable of inhibiting the function of the ABCB1 efflux pump, therefore reversing the MDR phenotype associated with these cancer cells [76,77]. Efflux pump modulators of the ABCB1 pump can be assigned to three different generations of compounds:…”

“…Taking this into consideration, these drugs would need to be administered in high doses to produce adequate concentration in vivo for adequate clinical activity. Because most of these compounds cause serious toxic side effects, their potential use as MDR reversing agents in clinical practice was discarded [76,[78][79][80] (Figure 7. ).…”

“…The disadvantage of these compounds is that they are substrates of the cytochrome P450 enzymes (particularly CYP3A4), resulting in peculiar pharmacokinetic patterns, making the dose adjustments during chemotherapy difficult. In addition, these molecules also inhibited other efflux pumps in the body that are required for physiological integrity, thus causing some offtarget responses (e.g., neurological toxicity) [76,78,81,82] (Figure 7. ).…”

“…They do not possess the limitations of previous generation compounds; they have no other pharmacological activity, they do not influence the pharmacokinetic parameters of antitumor drugs and they specifically inhibit ABCB1, without being a substrate of this pump or affecting other ABCtransporters. Another advantage of compounds, such as tariquidar (XR9576; an anthranilamide derivative), zosuquidar (LY335979; cyclopropyl-dibenzosuberane derivative) and laniquidar (R101933; a chemically modified derivative of verapamil) is that they exhibit efflux pump modulatory activity in very low concentrations (in the nanomolar range), which is advantageous for in vivo dosage [56,76,78] (Figure 7.). The pharmacokinetic properties of these compounds were studied in several Phase I clinical trials and they were well tolerated by the participants, no dose-limiting toxicity (DLT) was observed in a wide therapeutic dose range (50-400 mg/day) [83][84][85][86].…”