Figure 1 - uploaded by Joseph ( Jozsef in Hungarian) -- Molnar
Content may be subject to copyright.
Chemical structures of chalcones 1-11.
Source publication
The ability of 11 chalcones with 3,4,5-trimethoxy substitution on ring A to inhibit the transport activity of P-glycoprotein was studied. Flow cytometry was applied in multidrug-resistant human mdr1 gene-transfected mouse lymphoma cells (L 5178 Y). The reversal of multidrug resistance (MDR) was investigated by measuring the accumulation of rhodamin...
Context in source publication
Similar publications
The development of multidrug resistance (MDR) causes difficulties in the chemotherapy of of human cancer. Investigation of the possibility of reversal of MDR has been greatly aided by the use of cell lines with acquired resitance to anticancer agents in vitro or transfected with the mdrl gene. The aim of this study was to examine new perspectives o...
Multidrug resistance (MDR) has a potentially serious influence on cancer treatment and should be taken into consideration in the design and application of therapeutic regimens. It is mediated through the activity of cellular pumps.
To investigate whether furosemide, itself a pump-blocker, reverses MDR in an in vitro model.
An MDR bladder cancer cel...
Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemothera...
In the search for new derivatives of anthracycline antibiotics with the ability to overcome the drug resistance barrier, a series of new analogs of these antibiotics, containing the amidino group at C-3' position of the daunosamine moiety, have been synthesized. The new compounds were tested for their cytotoxic activity in vitro against the sensiti...
Induced expression of the Abcb1 drug transporter often occurs in tumors in response to chemotherapy. The role that epigenetic modifications within the ABCB1 promoter play in Abcb1 expression remains unclear. We selected MCF-7 cells for survival in increasing doses of chemotherapy drugs, and assessed the methylation status of 66 CpG sites within the...
Citations
... The physical state of the surrounding lipids and the composition of the lipid bilayer can modulate membrane transport proteins such as P-glycoprotein (P-gp) [4]. Hydrophobicity and other factors, such as the size and shape of molecules, can interfere with the ability of chalcones to interact with P-gp and change the inflow / efflux pump, reducing its absorption or promoting its bioaccumulation [62]. Di Pietro et al. [63] investigated the binding capacity of flavonoids, including chalcones, to the P-gp domain and found that halogenated chalcones have high affinity for P-gp. ...
... Di Pietro et al. [63] investigated the binding capacity of flavonoids, including chalcones, to the P-gp domain and found that halogenated chalcones have high affinity for P-gp. Furthermore, Ivanova et al. [62] demonstrated that 4-chloro-substituted chalcones in combination with cytotoxic compound have similar properties to the response observed with the highest concentration of 4-CL co-treated with SA, in the Ames test, and all doses co-administered with MMC in 48 h, in the micronucleus test, where an increase in mutagenicity and genotocicity was observed in relation to the positive controls SA and MMC, respectively. Some authors also observed that the cytotoxic effect of the association, chalcone and cytotoxic compounds, such as MMC, were greater than that presented by each compound alone, due, at least in part, to the decrease in cell membrane fluidity [64,65]. ...
The chalcones (E)-3-(4-chlorophenyl)-1-phenyl-2-propen-1-one (4-CL) and (E)-3-(3,4-dimethoxyphenyl)-1-phenyl-2 -propen-1-one (DMF) are versatile and easily synthesized into low-cost compounds that have a wide spectrum of biological activities. In this study, the cytotoxic, genotoxic and modulatory activities of 4-CL and DMF were evaluated using the Ames test and the mouse micronucleus assay. The results of the Ames test revealed that both chalcones did not show mutagenic activity in Salmonella typhimurium strains TA98 and TA100, and demonstrated significant antimutagenicity (p< 0.05) when co-administered with sodium azide (SA) in strain TA100. In the micronucleus assay, both showed a significant increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) at 24 h and 48 h, revealing a genotoxic effect. In the co-treatment with mitomycin C (MMC) there was a significant decrease (p< 0.05) in the frequency of MNPCE both in chalcones at 24h and in the less concentrated dose of DMF at 48h, demonstrating its antigenotoxic activity. 4-CL showed a significant decrease in the polychromatic/ normochromatic erythrocyte (PCE/ NCE) ratio at 24 and 48 h (p< 0.05), indicating cytotoxicity. However, 4-CL and DMF when co-administered with MMC showed a significant increase in the PCE/NCE ratio within 24 hours, demonstrating anticytotoxicity. Furthermore, a biphasic dose-response behavior was observed in both chalcones, 4-CL in the co-administration with SA, in the Ames Test and DMF in the co-treatment with MMC, at 48 hours of exposure, in the micronucleus assay. In this study, 4-CL and DMF showed genotoxic, cytotoxic, antigenotoxic, anticytotoxic and no mutagenic properties.
... The chalcones were synthesized by Claisen-Schmidt condensation between equimolar quantities of substituted acetophenones and aryl aldehydes (or indole-3-carboxaldehyde) [24,25]. The progress of the reactions was monitored by thin-layer chromatography on silica gel plates. ...
Background:
Malaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming. Plant derived synthetic pharmaceutical compounds are found to be a foremost research to obtain diverse range of potent leads. Amongst them, the chalcone scaffold is a functional template for drug discovery. The present study involves synthesis of ten chalcones with various substitution pattern in rings A and B and assessment of their anti-malarial efficacy against chloroquine sensitive and chloroquine resistant strains as well as of their cytotoxicity and effect on haemozoin production.
Methods:
The chalcones were synthesized by Claisen-Schmidt condensation between equimolar quantities of substituted acetophenones and aryl benzaldehydes (or indole-3-carboxaldehyde) and were screened for anti-malarial activity by WHO Mark III schizont maturation inhibition assay. The cytotoxicity profile of a HeLa cell line was evaluated through MTT viability assay and the selectivity index (SI) was calculated. Haemozoin inhibition assay was performed to illustrate mode of action on a Plasmodium falciparum strain.
Results:
The IC50 values of all compounds were in the range 0.10-0.40 μg/mL for MRC-2 (a chloroquine sensitive strain) and 0.14-0.55 μg/mL for RKL-9 (a chloroquine resistant strain) of P. falciparum. All the chalcones showed low cellular toxicity with minimal haemolysis. The statistically significant reduction (p < 0.05) in the haemozoin production suggests a similar mechanism than that of chloroquine.
Conclusions:
Out of ten chalcones, number 7 was found to be a lead compound with the highest potency (IC50 = 0.11 µg/mL), as compared to licochalcone (IC50 = 1.43 µg/mL) and with high selectivity index of 85.05.
... They exhibit antifungal activity against both different and specific fungal targets, and also play a role as MDR modulators. For example, the inhibition of an MDR efflux pump (P-glycoprotein -P-gp) by chalcones was previously assessed through testing distinct methoxy-chalcones B-ring derivatives in a human mdr1 gene transfected into a mouse lymphoma cell line, which showed a high binding affinity to P-gp, exceeding that of a known MDR blocking agent (Ivanova et al., 2008). Moreover, the use of chalcone analogs also promoted the sensitization of a fluconazole-resistant C. albicans strain mediated by the inhibition of efflux pumps (Lacka et al., 2015;Wang et al., 2016). ...
Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.
... In particular incorporation of multiple electron releasing groups on ring-A with single or multiple electron releasing (or withdrawing) groups on ring-B [16], replacement of aryl rings with heteroaryl(s) [17], rigidification of keto vinyl arrangement to form chalconoids [18]. To the best of our knowledge most of the chalcones reported with anticancer action, both from the nature and synthesis typically contain more than one electron releasing group on ring-A [19][20][21][22][23][24], and even if monosubstitution is present it is either a simple -NH2, -OH, -OCH3 and -CH3 [25][26][27], but not a bulkier hydrophobic isobutyl functionality. Lipophilicity plays a crucial role in cell permeability and presence of such groups increase the penetrability and inhibitory effects of compounds against cancer cells. ...
A series of novel isobutylchalcones (A1-A20) were prepared, evaluated for their cytotoxic activity and characterized by FTIR, 1H NMR, 13C NMR, and elemental analysis data. The logic behind the design is to synthesize and compare chalcones containing electron releasing lipophilic isobutyl substituent on aromatic ring A and the B ring with aromatic ring containing a range of electron releasing and electron withdrawing groups as well as heteroaromatic rings for their cytotoxic activity. The compounds were tested against HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer) cell lines using methotrexate (IC50 12 ± 1 (HT-29), 9 ±1 (MCF-7) 5 ± 1 (DU-145)) as reference standard. Compound A6 having 2,4-difluorphenyl moiety was most potent of the series against all the three cell lines and notably A6 was mainly effective against DU-145 cell lines with an IC50 value of 18 µg/mL. The critical structural features required for the activity against all the cell lines were identified through pharmacophore model using PHASETM which has recognised a 5 point AHHRR model and is consistent with the cytotoxic activity of the tested compounds.
... In continuation of our work (Upadhyay et al. 2012(Upadhyay et al. , 2014Maurya et al. 2013;Gupta et al. 2013;Dwivedi et al. 2014Dwivedi et al. , 2015 on synergistic potential of natural products and their derivatives, the present study describes the drug resistance reversal potential of gallic acid and derived compounds in combination with tetracycline and ofloxacin. In the recent past, Ivanova et al. (2008) reported MDR reversal effect of some of the chalcones possessing 3,4,5-trimethoxyphenyl unit. Majority of these compounds enhanced the retention of anticancer drug (epirubicin) by inhibiting the efflux pump activity (human mdr1). ...
... Previously, several chalcones possessing a 3,4,5trimethoxyphenyl unit were synthesized and found to be effective in the reversal of MDR activity of an anticancer drug (Ivanova et al. 2008). In this study, naturally occurring molecule, i.e., gallic acid, has been chemically transformed to get 3, 4,5-trimethoxyphenyl system. ...
The purpose of the present study was to study the synergy potential of gallic acid-based derivatives in combination with conventional antibiotics using multidrug resistant cultures of Escherichia coli. Gallic acid-based derivatives significantly reduced the MIC of tetracycline against multidrug resistant clinical isolate of E. coli. The best representative, 3-(3',4,'5'-trimethoxyphenyl)-4,5,6-trimethoxyindanone-1, an indanone derivative of gallic acid, was observed to inhibit ethidium bromide efflux and ATPase which was also supported by in silico docking. This derivative extended the post-antibiotic effect and decreased the mutation prevention concentration of tetracycline. This derivative in combination with TET was able to reduce the concentration of TNFα up to 18-fold in Swiss albino mice. This derivative was nontoxic and well tolerated up to 300 mg/kg dose in subacute oral toxicity study in mice. This is the first report of gallic acid-based indanone derivative as drug resistance reversal agent acting through ATP-dependent efflux pump inhibition.
... Like for other flavonoids, the SAR studies of chalcones on P-gp inhibitory activity revealed the relevance of the hydrophobic environment on A and B ring of chalcones [186]. Presence of methoxy groups on these rings leads to enhanced potency. ...
A major impediment for cancer chemotherapy is the development of multidrug-resistance (MDR). Continuous use of chemotherapeutic drugs during cancer therapy induces the expression of P-Glycoprotein (P-gp, MDR1), an ATP dependant transporter, which in turn reduces the intracellular accumulation of chemotherapeutic drugs leading to MDR. Extensive research over the years has identified several potential P-gp inhibitors, both synthetic as well as natural origin, to overcome the MDR during cancer chemotherapy. In this review, we discuss the cellular pathways involved and transcription factors regulating the expression of P-gp. A number of phytochemicals are reported to inhibit P-gp activity and MDR1 expression; the structure-activity relationship (SAR) among the phytochemicals for P-gp inhibition and the effect of these phytochemicals on cellular signaling pathways regulating P-gp expression are discussed in detail. Moreover, structural biology and mutagenesis studies on P-gp along with docking studies throw light on the structural requirements for P-gp inhibition. Insight provided in the review about the phytochemicals molecular mechanism and SAR could catalyze the design of potent P-gp inhibitors in the future and could help to overcome MDR in cancer chemotherapy.
... Some natural flavonoids and their synthetic derivatives were reported to be effective modulators of microbial multidrug resistance (Ivanova et al., 2008;Liu et al., 2008;Sharma et al., 2010). To check whether chalcones tested in this work were able to restore the antifungal potency of FLC against FLC-resistant human pathogenic yeasts, an in vitro assay was performed employing C. albicans clinical isolates resistant to fluconazole, due to the FLC-induced overexpression of genes encoding multidrug efflux pumps. ...
Three structurally related oxathiolone fused chalcone derivatives appeared effective chemosensitizers, able to restore in part sensitivity to fluconazole of multidrug-resistant C. albicans strains. Compound 21 effectively chemosensitized cells resistant due to the overexpression of the MDR1 gene, compound 6 reduced resistance of cells overexpressing the ABC-type drug transporters CDR1/CDR2 and derivative 18 partially reversed fluconazole resistance mediated by both types of yeast drug efflux pumps. The observed effect of sensitization of resistant strains of Candida albicans to fluconazole activity in the presence of active compounds most likely resulted from inhibition of the pump-mediated efflux, as was revealed by the results of studies involving the fluorescent probes, Nile Red, Rhodamine 6G and diS-C3(3).
... Chalcones with 3´,4´,5´-trimethoxy substitution in ring A has shown the ability to inhibit P-gp efflux pump. Chalcones activity is improved with increase of their hydrophobicity [79]. Parveen et al. performed 2D-and 3D-QSAR studies indicating the importance of H-bond acceptors, methoxy groups, hydrophobic groups as well as the number of rotatable bonds as pharmacophoric features influencing P-gp inhibitory activity of chalcones [80]. ...
Chalcones constitute a group of phenolic compounds that command an increasing interest on cancer research. Natural chalcones are widespread through the plant kingdom. The most abundant and investigated chalcones are isoliquiritigenin, flavokawain and xanthohumol, which are present in the Fabaceae, Piperaceae, Cannabaceae, and Moraceae families. These chalcones have been shown to be promising lead antitumor-chemopreventive drugs by three different activities: antioxidants, cytotoxic and apoptosis inducers. In recent years, SAR (structure-activity relationship) has contributed towards the improvement of anticancer properties of chalcones by substituting aryl rings and introducing heterocyclic moieties. This review summarizes the anticancer activities shown by natural chalcones and the SAR and describes how different chemical moiety modifications could lead them to be therapeutically useful in the treatment of cancer.
... In both studies, the hydrophobicity of chalcones was important for activity [85,86]. Other studies evaluated the effect of chalcones on P-gp [61,87]. Liu et al. screened a library of chalcones with basic functionalities for P-gp inhibition. ...
Chalcones are natural compounds found in plants, fruits and vegetables.This class of compounds has shown many biological activities including antioxidant, antimicrobial, anti-inflammatory, antifungal and antihypertensive,among others. In cancer, it has been reported that chalcones interfere in several points of the signal transduction pathways related to cellular proliferation, angiogenesis, metastasis, apoptosis and the reversal of multidrug resistance. The largenumber of research articles and patents related to chalcones is already an indication of their importance as a lead class of compounds. This articlegathers recent efforts to elucidate the molecular mechanisms of action of chalcones,associatedwith their anticancer and antiresistance potential.
... Even minor structural modification can result in distinct cellular and molecular alterations. The diversity of the chalcone family also lends *Address correspondence to this author at the Department of Urology, University of California, Irvine, 101 itself to broad-spectrum biologic applications in oncology, particularly for the development of novel targeted therapies. Molecular targeted and "biologic" agents in cancer therapy are the result of a rapidly growing understanding of the molecular events which are involved in carcinogenesis, including crucial aberrations in the regulation of apoptosis, cell-cycle control, metastasis and tumor angiogenesis. ...
... Other authors have looked at the ability of their chalcone derivatives to modulate increased drug accumulation via effects on P-gp. Ivanova et al., [101] demonstrated a 100-fold increase in drug accumulation via inhibition of P-gp in lymphoma cells, most effective in a chalcone with a -chloro group on Ring B, with IC 50 concentrations in the low-micromolar range. Similarly, Liu et al., [102] demonstrated that chalcones with basic moieties on Ring A increased drug accumulation in breast cancer cells by inhibition of P-gp using the calcein assay. ...
There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy.
