Multidrug Resistance Reversal Activity Research Articles

Soloxolone N-3-(Dimethylamino)propylamide Restores Drug Sensitivity of Tumor Cells with Multidrug-Resistant Phenotype via Inhibition of P-Glycoprotein Efflux Function.

Multidrug resistance (MDR) remains a significant challenge in cancer therapy, primarily due to the overexpression of transmembrane drug transporters, with P-glycoprotein (P-gp) being a central focus. Consequently, the development of P-gp inhibitors has emerged as a promising strategy to combat MDR. Given the P-gp targeting potential of soloxolone amides previously predicted by us by an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, the aim of the current study was to experimentally verify their P-gp inhibitory and MDR reversing activities in vitro. Screening of soloxolone amides as modulators of P-gp using molecular docking and cellular P-gp substrate efflux assays revealed the ability of compound 4 bearing a N-3-(dimethylamino)propylamide group to interact with the active site of P-gp and inhibit its transport function. Blind and site-specific molecular docking accompanied by a kinetic assay showed that 4 directly binds to the P-gp transmembrane domain with a binding energy similar to that of zosuquidar, a third-generation P-gp inhibitor (ΔG = -10.3 kcal/mol). In vitro assays confirmed that compound 4 enhanced the uptake of Rhodamine 123 (Rho123) and doxorubicin (DOX) by the P-gp-overexpressing human cervical carcinoma KB-8-5 (by 10.2- and 1.5-fold, respectively (p < 0.05, unpaired t-test)) and murine lymphosarcoma RLS40 (by 15.6- and 1.75-fold, respectively (p < 0.05, unpaired t-test)) cells at non-toxic concentrations. In these cell models, 4 showed comparable or slightly higher activity than the reference inhibitor verapamil (VPM), with the most pronounced effect of the hit compound in Rho123-loaded RLS40 cells, where 4 was 2-fold more effective than VPM. Moreover, 4 synergistically restored the sensitivity of KB-8-5 cells to the cytotoxic effect of DOX, demonstrating MDR reversal activity. Based on the data obtained, 4 can be considered as a drug candidate to combat the P-gp-mediated MDR of tumor cells and semisynthetic triterpenoids, with amide moieties in general representing a promising scaffold for the development of novel therapeutics for tumors with low susceptibility to antineoplastic agents.

Synthesis and evaluation of novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors for overcoming MDR in cancer

The emergence of multidrug resistance (MDR) in malignant tumors is one of the major threats encountered currently by many chemotherapeutic agents. Among the various mechanisms involved in drug resistance, P-glycoprotein (P-gp, ABCB1), a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells, and the metabolic enzyme CYP1B1 are widely considered to be two critical targets for overcoming MDR. Unfortunately, no MDR modulator has been approved by the FDA to date. In this study, based on pharmacophore hybridization, bioisosteric and fragment-growing strategies, we designed and synthesized 11 novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors. Among them, the preferred compound A10 exhibited the best MDR reversal activity (IC50 = 0.25 μM, RF = 44.4) in SW620/AD300 cells, being comparable to one of the most potent third-generation P-gp inhibitors WK-X-34. In parallel, this dual ABCB1/CYP1B1 inhibitory effect drives compound A10 exhibiting prominent drug resistance reversal activity to doxorubicin (IC50 = 4.7 μM, RF = 13.7) in ABCB1/CYP1B1-overexpressing DOX-SW620/AD300-1B1 resistant cells, which is more potent than that of the CYP1B1 inhibitor ANF. Furthermore, although compound A2 possessed moderate ABCB1/CYP1B1 inhibitory activity, it showed considerable antiproliferative activity towards drug-resistant SW620/AD300 and MKN45-DDP-R cells, which may be partly related to the increase of PUMA expression to promote the apoptosis of the drug-resistant MKN45-DDP-R cells as confirmed by proteomics and western blot assay. These results indicated that the tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates may provide a fundamental scaffold reference for further discovery of MDR reversal agents.

Hyperkouytones A—O, New Polyprenylated Acylphloroglucinols from Hypericum kouytchense with Multidrug Resistance Reversal Activity

Comprehensive SummaryGiven the lack of systematic polyprenylated acylphloroglucinols (PPAPs) research on traditional Chinese medicine of Hypericum kouytchense, this plant was applied for the phytochemical study, which led to fifteen new PPAPs (1—15, PPAPs), along with 36 known PPAP derivatives. Their structures and absolute configurations were established by comprehensive spectral analysis and theoretical ECD and NMR calculations. Structurally, compound 1 possesses a rare fused 6/6/6/5/5 pentacyclic ring system. Eleven compounds exhibited good multidrug resistance reversal activity (RF ranging from 5 to 53) in HepG2/ADR cells. Importantly, compound 34, the most potential MDR modulator, showed better reversal effect (RF: 53) than positive control, verapamil. The primary mechanistic study of compound 34, implied that this compound could prohibit the function of P‐gp transport rather than its expression. The possible recognition mechanism between compound 34 and P‐gp was predicted by molecular docking.

Sesquiterpene dimers with a rare skeleton from Chloranthus holostegius exhibiting multidrug resistance reversal activity in vitro and in vivo

Two previously unreported lindenane sesquiterpene dimers (1 and 2) with a rare skeleton containing an oxaspiro[4.5]decane moiety were isolated from the roots of Chloranthus holostegius var. trichoneurus. Their structures were elucidated by HRESIMS, NMR, ECD, and NMR quantum chemical calculations, along with DP4+ probability analysis. In bioassay, compound 1 exhibited significant activity to reverse the multidrug resistance (MDR)in MCF-7/ADR cells, with an IC50 value of 4.4 μM. Further mechanistic studies revealed that compound 1 combined with doxorubicin could induce apoptosis of MCF-7/ADR cells and block the cell cycle in the G2/M phase. Mechanistically, compound 1 could inhibit the efflux function of P-glycoprotein (P-gp) using the zebrafish model. Finally, the enhanced chemotherapeutic effects of doxorubicin were further confirmed by in vivo zebrafish xenograft experiments.

Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.

Novel pyxinol amide derivatives bearing an aliphatic heterocycle as P-glycoprotein modulators for overcoming multidrug resistance

P-glycoprotein (Pgp) modulators are promising agents for overcoming multidrug resistance (MDR) in cancer chemotherapy. In this study, via structural optimization of our lead compound S54 (nonsubstrate allosteric inhibitor of Pgp), 29 novel pyxinol amide derivatives bearing an aliphatic heterocycle were designed, synthesized, and screened for MDR reversal activity in KBV cells. Unlike S54, these active derivatives were shown to transport substrates of Pgp. The most potent derivative 4c exhibited promising MDR reversal activity (IC50 of paclitaxel = 8.80 ± 0.56 nM, reversal fold = 211.8), which was slightly better than that of third-generation Pgp modulator tariquidar (IC50 of paclitaxel = 9.02 ± 0.35 nM, reversal fold = 206.6). Moreover, the cytotoxicity of this derivative was 8-fold lower than that of tariquidar in human normal HK-2 cells. Furthermore, 4c blocked the efflux function of Pgp and displayed high selectivity for Pgp but had no effect on its expression and distribution. Molecular docking revealed that 4c bound preferentially to the drug-binding domain of Pgp. Overall, 4c is a promising lead compound for developing Pgp modulators.

Cationic anticancer peptide L-K6-modified and doxorubicin-loaded mesoporous silica nanoparticles reverse multidrug resistance of breast cancer

Multidrug resistance (MDR) is the major challenge for chemotherapy of cancer and makes the treatment benefits unsustainable. To overcome this issue, nanotechnology has been introduced and various nanocarriers have been constructed to reverse MDR in drug resistant cancer cells. Here, mesoporous silica nanoparticle (MSN-COOH) were modified with cationic anticancer peptide L-K6 (MSN@L-K6), and further loaded with doxorubicin (DOX) to construct an anticancer nano-system, MSN@L-K6@DOX. Our results showed that MSN@L-K6@DOX released DOX in pH-sensitive manner, which enable to be highly efficient in delivering drugs to tumors, counterbalancing the MDR. In addition, MSN@L-K6@DOX treatment decreased the expression level of P-glycoprotein in MCF-7/ADR cells, enhanced the intracellular accumulation of DOX, and thereafter reversed the MDR of MCF-7/ADR cells to DOX. Moreover, the MDR reversal activity of MSN@L-K6@DOX was further confirmed in xenograft mouse model, as evidenced by the decreased tumor volume and weight. These results indicate the MDR reversal activity of MSN@L-K6@DOX and may provide a novel strategy for the development of nano-based drug delivery system to overcome cancer MDR.

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library.

The discovery of novel and highly effective P-gp inhibitors is considered to be an effective strategy for overcoming tumor drug resistance. In this paper, a phenotypic screening via a self-constructed synthetic methodology-based library identified a new class of tricyclic spiroindole derivatives with excellent tumor multidrug resistance reversal activity. A stereospecific compound OY-103-B with the best reversal activity was obtained based on a detailed structure-activity relationship study, metabolic stability optimization and chiral resolution. For the VCR-resistant Eca109 cell line (Eca109/VCR), co-administration of 5.0 μM OY-103-B resulted in a reversal fold of up to 727.2, superior to the typical third-generation P-gp inhibitor tariquidar. Moreover, the compound inhibited the proliferation of Eca109/VCR cells in a concentration-dependent manner in plate cloning and flow cytometry. Furthermore, fluorescence substrate accumulation assay and chemotherapeutic drug reversal activity tests demonstrated that OY-103-B reversed tumor drug resistance via P-gp inhibition. In conclusion, this study provides a novel skeleton that inspires the design of new P-gp inhibitors, laying the foundation for the treatment of drug-resistant tumors.

Synthesis and evaluation of WK-X-34 derivatives as P-glycoprotein (P-gp/ABCB1) inhibitors for reversing multidrug resistance.

The emergence of multidrug resistance (MDR) in malignant tumors is one of the leading threats encountered currently by many chemotherapeutic agents. A proposed strategy to overcome MDR is to disable the efflux function of P-glycoprotein (P-gp/ABCB1), a critical member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells. In this study, structural modification of a third-generation P-gp inhibitor WK-X-34 based on bioisosteric and fragment-growing strategies led to the discovery of the adamantane derivative PID-9, which exhibited the best MDR reversal activity (IC50 = 0.1338 μM, RF = 78.6) in this series, exceeding those of the reported P-gp inhibitors verapamil and WK-X-34. In addition, compared with WK-X-34, PID-9 showed decreased toxicity to cells. Furthermore, the mechanism studies revealed that the reversal activity of adamantane derivatives PID-5, PID-7, and PID-9 stemmed from the inhibition of P-gp efflux. These results indicated that compound PID-9 is the most effective P-gp inhibitor among them with low toxicity and high MDR reversal activity, which provided a fundamental structural reference for further discovery of novel, effective, and non-toxic P-gp inhibitors.

Myrsinane-Type Diterpenes: A Comprehensive Review on Structural Diversity, Chemistry and Biological Activities.

Euphorbia species are important sources of polycyclic and macrocyclic diterpenes, which have been the focus of natural-product-based drug research due to their relevant biological properties, including anticancer, multidrug resistance reversal, antiviral, and anti-inflammatory activities. Premyrsinane, cyclomyrsinane, and myrsinane diterpenes are generally and collectively designated as myrsinane-type diterpenes. These compounds are derived from the macrocyclic lathyrane structure and are characterized by having highly oxygenated rearranged polycyclic systems. This review aims to describe and summarize the distribution and diversity of 220 myrsinane-type diterpenes isolated in the last four decades from about 20 Euphorbia species. Some myrsinane diterpenes obtained from Jatropha curcas are also described. Discussion on their plausible biosynthetic pathways is presented, as well as isolation procedures and structural elucidation using nuclear magnetic resonance spectroscopy. Furthermore, the most important biological activities are highlighted, which include cytotoxic and immunomodulatory activities, the modulation of efflux pumps, the neuroprotective effects, and the inhibition of enzymes such as urease, HIV-1 reverse transcriptase, and prolyl endopeptidase, among other biological effects.

Discovery of (quinazolin-6-yl)benzamide derivatives containing a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety as potent reversal agents against P-glycoprotein-mediated multidrug resistance

P-glycoprotein (P-gp) is an important factor leading to multidrug resistance (MDR) in cancer treatment. The co-administration of anticancer drugs and P-gp inhibitors has been a treatment strategy to overcome MDR. In recent years, tyrosine kinase inhibitor Lapatinib has been reported to reverse MDR through directly interacting with ABC transporters. In this work, a series of P-gp inhibitors (1–26) was designed and synthesized by integrating the quinazoline core of Lapatinib into the molecule framework of the third-generation P-gp inhibitor Tariquidar. Among them, compound 14 exhibited better MDR reversal activity than Tariquidar. The docking results showed compound 14 displayed the L-shaped molecular conformation. Importantly, compound 14 increased the accumulation of Adriamycin (ADM) and rhodamine 123 (Rh123) in MCF7/ADM cells. Besides, compound 14 significantly increased ADM-induced apoptosis and inhibited the proliferation, migration and invasion of MCF7/ADM cells. It was also demonstrated that compound 14 significantly inhibited the growth of MCF7/ADM xenograft tumors by increasing the sensitivity of ADM. In summary, compound 14 has the potential to overcome MDR caused by P-gp.

A Novel 3-meta-Pyridine-1,2,4-oxadiazole Derivative of Glycyrrhetinic Acid as a Safe and Promising Candidate for Overcoming P-Glycoprotein-Mediated Multidrug Resistance in Tumor Cells.

Given the pharmacophore properties of the nitrogen-containing moiety in the molecular structure of P-glycoprotein (P-gp) inhibitors, we report the evaluation of the P-gp inhibitory and MDR reversal activities of 2g, a 3-meta-pyridin-1,2,4-oxadiazole derivative of 18βH-glycyrrhetinic acid. Through molecular docking, we have shown that 2g has the potential to directly interact with the transmembrane domain of P-gp with a low free binding energy (-10.2 kcal/mol). Using KB-8-5 human cervical carcinoma cells and RLS40 murine lymphosarcoma cells, both of which exhibit a multidrug-resistant (MDR) phenotype mediated by P-gp activation, we have shown that 2g, at nontoxic concentrations, effectively increased the intracellular accumulation of fluorescent P-gp substrates (rhodamine 123 or doxorubicin (DOX)), leading to a marked sensitization of the model cells to the cytotoxic effect of DOX. Considering the comparable activity of 2g with verapamil, a known P-gp inhibitor, 2g can be considered as a promising candidate for the development of agents capable of overcoming P-gp-mediated MDR in tumor cells.

Cycloartane-type triterpenoids and steroids from Trichilia connaroides and their multidrug resistance reversal activities

Four undescribed cycloartane-type triterpenoids (1−4) and seven undescribed steroids (6−12), along with five known analogues (5 and 13−16), were isolated from the leaves of Trichilia connaroides. Their structures were identified based on the NMR data and HRESIMS, and the absolute configurations were determined through single-crystal X-ray diffraction analysis, Mosher's method, and ECD calculations. The multidrug resistance (MDR) reversal activities of all the isolates were assessed, and compounds 10 and 11 showed significant activities to reverse the MDR of MCF-7/DOX cells with IC50 values of 2.90 and 3.76 μM, respectively. These bioactive compounds may bring fresh insights into the research and development of MDR reversal agents.

Pregnane steroid glycosides with multidrug resistance reversal activity from the stems of Marsdenia tenacissima

Eighteen previously unreported pregnane glycosides, namely marsdenosides S1–S18, along with 15 known analogues, have been isolated from the stems of Marsdenia tenacissima. The structures of the undescribed compounds were elucidated by spectroscopic means, and their absolute configurations were established on the basis of time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculation, X-ray crystallography and acid hydrolysis. All the isolates were evaluated for their chemo-reversal ability against P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MCF-7/ADR cell line, and nine ones displayed moderate MDR reversal activity with reversal folds in the range of 2.45–9.01. The most active 12-O-acetyl-20-O-benzoyl-(14,17,18-orthoacetate)-dihydrosarcostin-3-O-β-d-thevetopyranosyl-(1 → 4)-O-β-d-oleandropyranosyl-(1 → 4)-O-β-d-cymaropyranoside increased the sensitivity of MCF-7/ADR cell to adriamycin comparably to the reference drug verapamil (RF = 8.93).

Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance

Multidrug resistance (MDR) caused by ATP-Binding Cassette Subfamily B Member 1 (ABCB1, P-glycoprotein, P-gp) is a major barrier for the success of chemotherapy in clinics. In this study, we designed and synthesized a total of 19 Lissodendrins B analogues and tested their ABCB1-mediated MDR reversal activity in doxorubicin (DOX)-resistant K562/ADR and MCF-7/ADR cells. Among all derivatives, compounds D1, D2, and D4 with a dimethoxy-substituted tetrahydroisoquinoline fragment possessed potent synergistic effects with DOX and reversed ABCB1-mediated drug resistance. Notably, the most potent compound D1 merits multiple activities, including low cytotoxicity, the strongest synergistic effect, and effectively reversing ABCB1-mediated drug resistance of K562/ADR (RF = 1845.76) and MCF-7/ADR cells (RF = 207.86) to DOX. As a reference substance, compound D1 allows for additional mechanistic studies on ABCB1 inhibition. The synergistic mechanisms were mainly related to the increased intracellular accumulation of DOX via inhibiting the efflux function of ABCB1 rather than from affecting the expression level of ABCB1. These studies suggest that compound D1 and its derivatives might be potential MDR reversal agents acting as ABCB1 inhibitors in clinical therapeutics and provide insight into a design strategy for the development of ABCB1 inhibitors.

D-chiro-Inositol Derivatives with Multidrug Resistance Reversal Activities from the Fruits of Chisocheton siamensis.

Chisosiamols A-K (1-11), 11 new d-chiro-inositol derivatives, along with a known analogue (12) were isolated from the fruits of Chisocheton siamensis. Their planar structures and relative configurations were elucidated by the comprehensive application of spectroscopic methods, especially from the characteristic coupling constants, and 1H-1H COSY spectra. The absolute configurations of the d-chiro-inositol core were determined using the ECD exciton chirality and X-ray diffraction crystallographic analytical methods. This is the first crystallographic data reported for the d-chiro-inositol derivatives. A structural elucidation strategy mainly combining 1H-1H COSY correlations and ECD exciton chirality for determining the structure of d-chiro-inositol derivatives was developed, which also led to the revisions of previously reported structures. Bioactivity evaluation indicated that chisosiamols A, B, and J can reverse multidrug resistance in MCF-7/DOX cells in the IC50 range of 3.4-6.5 μM (RF: 3.6-7.0).

5-Oxohexahydroquinolines bearing 4-pyridyl methyl carboxylate as P-glycoprotein inhibitors and multidrug resistance reversal agents in cancer cells

Multidrug resistance (MDR) limits the therapeutic effect of conventional chemotherapeutic agents as well as novel targeted anticancer drugs. An important mechanism of MDR is the overexpression of ATP-binding cassette (ABC) transporters in cancer cells, among which P-glycoprotein (P-gp) has one of the highest contributions to drug resistance. In this study, 10 novel 5-oxo-hexahydroquinoline (5-oxo-HHQ) derivatives bearing 4-pyridyl methyl carboxylate moiety (G1-G10) were synthesized and examined for their MDR reversal activity in P-gp overexpressing MES-SA-DX5 cells. Moreover, all synthesized compounds were evaluated for their cell growth inhibitory effect in several cancer cell lines. Most of the tested compounds significantly enhanced the intracellular accumulation of rhodamine 123, a P-gp substrate, in MDR cells, some of them showing better results than verapamil, a well-established P-gp inhibitor. Moreover, most compounds, especially G2, G3, G7, and G8, bearing 2-chlorophenyl, 3-bromophenyl, 3-nitrophenyl and pyridin-4-yl moieties were effective in reversing resistance to doxorubicin when co-incubated with this chemotherapeutic agent in MES-SA-DX5 cells. Our results also showed that compounds G3 and G7 exhibited considerable cytotoxic effects against leukemia and colon cancer cells. In silico docking analysis also confirmed the interaction of compounds G2, G3, G7, and G8 with the drug-substrate binding site of P-gp. Molecular dynamic simulation study was performed to gain insight into the binding mode of compound G3 with P-gp. According to the results, hydrophobic interactions played a more prominent role than hydrogen-binding interactions. Taken together, our findings showed that designed 5-oxo-HHQ compounds are promising MDR reversal agents.

New Guaiane-Type Sesquiterpenoids Biscogniauxiaols A-G with Anti-Fungal and Anti-Inflammatory Activities from the Endophytic Fungus Biscogniauxia Petrensis.

Seven undescribed guaiane-type sesquiterpenoids named biscogniauxiaols A-G (1-7) were isolated from the endophytic fungus Biscogniauxia petrensis on Dendrobium orchids. Their structures were determined by extensive spectroscopic analyses, electronic circular dichroism (EC) and specific rotation (SR) calculations. Compound 1 represented a new family of guaiane-type sesquiterpenoids featuring an unprecedented [5/6/6/7] tetracyclic system. A plausible biosynthetic pathway for compounds 1-7 was proposed. The anti-fungal, anti-inflammatory and multidrug resistance reversal activities of the isolates were evaluated. Compounds 1, 2 and 7 exhibited potent inhibitory activities against Candida albicans with MIC values ranging from 1.60 to 6.30 μM, and suppressed nitric oxide (NO) production with IC50 ranging from 4.60 to 20.00 μM. Additionally, all compounds (100 μg/mL) enhanced the cytotoxicity of cisplatin in cisplatin-resistant non-small cell lung cancer cells (A549/DDP). This study opened up a new source for obtaining bioactive guaiane-type sesquiterpenoids and compounds 1, 2, and 7 were promising for further optimization as multifunctional inhibitors for anti-fungal (C. albicans) and anti-inflammatory purposes.

Design, synthesis and biological evaluation of seco-DSP/DCK derivatives reversing P-glycoprotein-mediated paclitaxel resistance in A2780/T cells

P-glycoprotein transporter (P-gp, ABCB1) is a major contributor to multidrug resistance, making it a valuable target for the development of novel P-gp inhibitor to overcome multidrug resistance. In this study, forty-nine novel seco-DSPs and seco-DMDCK derivatives were synthesized and evaluated their chemo-sensitize abilities to paclitaxel in A2780/T cell lines. Most of them exhibited a comparable reversal multidrug-resistance activity than verapamil. Especially, compound 27f showed a remarkable chemo-sensitization with more than 425-fold reversal ratio in A2780/T cells. The study of preliminary pharmacological mechanism displayed that compound 27f was more effective to increase the accumulation of paclitaxel and Rhodamine 123 than verapamil via inhibiting P-gp for reversing multidrug-resistance. In addition, a higher than 40 μM IC50 values of hERG potassium channel inhibition concentration suggested that compound 27f hardly had relevant cardiac toxicity. These results indicated that compound 27f might be a potential candidate to further investigate for the development of chemosensitizer with MDR reversal activity.

Design, synthesis and biological evaluation of novel phenylfuran-bisamide derivatives as P-glycoprotein inhibitors against multidrug resistance in MCF-7/ADR cell

The co-administration of anticancer drugs and P-glycoprotein (P-gp) inhibitors was a treatment strategy to surmount multidrug resistance (MDR) in anticancer chemotherapy. In this study, novel phenylfuran-bisamide derivatives were designed as P-gp inhibitors based on target-based drug design, and 31 novel compounds were synthesized and screened on MCF-7/ADR cells. The result of bioassay revealed that compound y12d exhibited low cytotoxicity and promising MDR reversal activity (IC50 = 0.0320 μM, reversal fold = 1163.0), 3.64-fold better than third-generation P-gp inhibitor tariquidar (IC50 = 0.1165 μM, reversal fold = 319.3). The results of Western blot and rhodamine 123 accumulation verified that compound y12d exhibited excellent MDR reversal activity by inhibiting the efflux function of P-gp but not expression. Furthermore, molecular docking showed that compound y12d bound to target P-gp by forming the double H-bond interactions with residue Gln 725. These results suggest that compound y12d might be a potential MDR reveal agent acting as a P-gp inhibitor in clinical therapeutics, and provide insight into design strategy and skeleton optimization for the development of P-gp inhibitors.