Modulation of breast cancer resistance protein (BCRP/ABCG2) by non-basic chalcone analogues

Han, Yi; Riwanto, Meliana; Go, Mei‐Lin; Ee, Pui Lai Rachel

doi:10.1016/j.ejps.2008.06.001

Cited by 41 publications

(26 citation statements)

References 33 publications

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“…As for the flavones, these have been widely reported to be modulators of ABCG2 activity. [19,21,36] Hence, the reasonably good activity of the series 9 flavones was anticipated. In contrast to earlier reports indicating a preference for dihydroxy groups on ring A of the flavone template, [19] the outstanding activities of 9-4 and 9-5, which are as active as FTC, show that a dimethoxylated ring A fares just as well, provided ring B is disubstituted.…”

Section: Discussionmentioning

confidence: 96%

“…On the other hand, an earlier study showed that 2,4-dimethoxychalcones and 2-hydroxychalcones are capable of modulating ABCG2 activity at low sub-micromolar concentrations when investigated for their effects on mitoxantrone accumulation and resensitization to mitoxantrone in ABCG2-overexpressing cells. [36] The contrasting outcomes may be attributed to the intrinsic differences of the in vitro assays employed (PhA accumulation versus mitoxantrone accumulation/resensitization), the type of substitution on ring A (series 8 chalcones with 2-hydroxy-4,6-dimethoxy on ring A were not included in that study) and substitution on ring B (the active chalcones had halogenated or methylated rings B, [36] which were not investigated here). There is a strong likelihood that the ring B substituents play a key role in influencing activity, as both active chalcones 8-4 and 8-5 bear dimethoxy groups on ring B.…”

Section: Discussionmentioning

confidence: 96%

“…Chalcones [36] and flavones [19,21] have been reported to be ABCG2 modulators. These scaffolds provided further insight on the effect of modifying the aurone ring C. Chalcones 8-1 to 8-5 may be viewed as the ring-C-opened forms of dimethoxyaurones, whereas the hydroxylated chalcones 8-6 to 8-8 are analogous to the unsubstituted aurones (series 3).…”

Section: Stereochemical Considerationsmentioning

confidence: 99%

“…This model was validated by determining how well it predicted the activities of the remaining 22 compounds set aside as the test set. Further validation was carried out using an external database of 27 compounds, of which 13 were reported ABCG2 inhibitors, [36,40,41] while the remaining compounds were either non-inhibitors of ABCG2 or have not been associated with ABCG2 inhibition. [40,42,43] Details of the external database are given in the Supporting Information.…”

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confidence: 99%

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Aurones as Modulators of ABCG2 and ABCB1: Synthesis and Structure–Activity Relationships

et al. 2011

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The ability of aurones to modulate the efflux activities of ABCG2 and ABCB1 was investigated by quantifying their effects on the accumulation of pheophorbide A (PhA) in ABCG2-overexpressing MDA-MB-231/R cells and calcein AM in ABCB1-overexpressing MDCKII/MDR1 cells. Key structural features for interactions at both ABCG2 and ABCB1 are a methoxylated ring A, an intact exocyclic double bond, and the location of the carbonyl bond on ring C. Modifications on rings B and C were less critical and served primarily to moderate activity and selectivity for one or both transporters. These SAR trends were quantified by Free-Wilson analyses and are reflected in a pharmacophore model for PhA accumulation. Several compounds were found to be equipotent with fumitremorgin C (FTC) in promoting PhA accumulation, and they also demonstrated strong affinities for ABCB1. These compounds were disubstituted on ring B with methoxy or a combination of methoxy and hydroxy groups. Taken together, our findings highlight the versatility of the aurone template as a lead scaffold for the design of dual-targeting ABCG2 and ABCB1 modulators.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 96%

Section: Stereochemical Considerationsmentioning

confidence: 99%

mentioning

confidence: 99%

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Aurones as Modulators of ABCG2 and ABCB1: Synthesis and Structure–Activity Relationships

et al. 2011

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“…They increased mitoxanthrone accumulation to a greater extent than the established BCRP inhibitor, fumitremorgin C and did not inhibit P-gp. Such selectivity is highly desirable in clinical use because the specific BCRP inhibitor would not interfere with other transporters and cause unwanted drug-drug interactions [80].…”

Section: Adenosine Triphosphate (Atp)-binding Cassette Transportersmentioning

confidence: 99%

Trends in Utilization of the Pharmacological Potential of Chalcones

Batovska

Todorova²

2010

CCP

296

206

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Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. They are important for the pigmentation of flowers and, hence, act as attractants to the pollinators. As flavonoids, chalcones also play an important role in defense against pathogens and insects. A longstanding scientific research has shown that chalcones also display other interesting biological properties such as antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and anti-inflammatory activities. Some lead compounds with various pharmacological properties have been developed based on the chalcone skeleton. Clinical trials have shown that these compounds reached reasonable plasma concentrations and did not cause toxicity. For these reasons, chalcones became an object of continued interest in both academia and industry. Nowadays, several chalcones are used for treatment of viral disorders, cardiovascular diseases, parasitic infections, pain, gastritis, and stomach cancer, as well as like food additives and cosmetic formulation ingredients. However, much of the pharmacological potential of chalcones is still not utilized. The purpose of this review is to describe the recent efforts of scientists in pharmacological screening of natural and synthetic chalcones, studying the mechanisms of chalcone action and relevant structure-activity relationships. Put together, these activities aimed at synthesis of pharmacologically active chalcones and their analogs.

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C

2010

Handbook of Biological Dyes and Stains

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Chemical Structure CA Index Name Glycine, N,N 0 -[(3 0 ,6 0 -dihydroxy-3-oxospiro[isobenzofuran-1(3H),9 0 -[9H]xanthene]-2 0 ,7 0 -diyl) bis(methylene)]bis[N-(carboxymethyl)-Other Names Bis [N, N-bis(carboxymethyl)aminomethyl] fluorescein; Fluorescein, 2 0 ,7 0 -bis[[bis(carboxymethyl) amino]methyl]-; Fluorescein-bis(methyliminodiacetic acid); Spiro[isobenzofuran-1(3H),9 0 -[9H]xanthene], glycine derivative; 2,7-Bis[N,N-bis(carboxymethyl)aminomethylene]fluorescein; Acetic acid, [(3 0 ,6 0 -dihydroxy-2 0 ,7 0 -fluorandiyl)bis(methylenenitrilo)]tetra-; Calcein; Fluorescein complexon; Fluorexon; NSC 298193; Oftasceine Merck Index Number Not listed Chemical/Dye Class Xanthene Molecular Formula C 30 H 26 N 2 O 13 Molecular Weight 622.53 Physical Form Yellow-orange to brown powder Solubility Soluble in water, ethanol, N,N-dimethyl formamide, dimethyl sulfoxide Melting Point 200 C Boiling Point (Calcd.) 952.7 AE 65.0 C, pressure: 760 Torr pH Range 6.0-7.2Color Change at pH Weak green fluorescence (6.0) to strong green fluorescence (7.2) pK a 6.67 Absorption (l max ) 494 nm Emission (l max ) 517 nm Synthesis Synthetic methods 1-7 Staining Applications Calcium ions; 8,9 fluoride ions; 10 iron ions; 11-13 mercury ions; 14 peptides; 2 proteins; 2 antibodies; 2 atherosclerotic plaque; 1,15 bone; 16,17 cells; 18-20 fish; 21 liposomes; 22,23 neurons; 8 skin; 24 tumor cells; 1,25 inflammations; 1 lymphokines; 1 hepatocytes 3,4 Biological Applications Calcium indicator; 8,9 fluoride indicator; 10 iron indicator; 11-13 mercury indicator; 14 detecting nucleic acids, 1,26 proteins; 27 treating osteoporosis; 28 drug delivery systems 1,29 Industrial Applications Chemical mechanical polishing; 1,30 coatings; 31 photoresists 32 Safety/Toxicity Acute toxicity; 33 cytotoxicity; 1,34 mutagenicity; 35 neurotoxicity; 36 ophthalmotoxicity 37 2. Hahn, K. M.; Toutchkine, A.; Muthyala, R.; Kraynov, V.; Bark, S. J.; Burton, D. R.; Chamberlain, C. Labeled peptides, proteins and antibodies and processes and intermediates useful for their preparation. O OH HO N N COOH COOH HOOC HOOC O O 71 3. Horiuchi, K.; Saji, H.; Arano, Y.; Yokoyama, A. Ligandin binding phthalein complexone complex of technetium for hepatic function studies. Eur. J. Nucl. Med. 1990, 16, 137-142. 4. Saji, H.; Yokoyama, A.; Arano, Y.; Tanaka, H.; Odori, T.; Morita, R.; Torizuka, K. Phthalein and fluorescein derivatives with an effective technetium-99m labeled state for a hepatobiliary transport: 99mTc-PC, a new hepatobi-liary radiopharmaceutical. Pribil, R. New metallochromic indicators of the complexon type. Chem. Ind. 1957, 233-234. 8. Dravid, S. M.; Murray, T. F. Fluorescent detection of Ca 2 þ -permeable AMPA/kainate receptor activation in murine neocortical neurons. Neurosci. Lett. 2003, 351, 145-148. 9. Sugita, M.; Hirono, C.; Tanaka, S.; Nakahari, T.; Imai, Y.; Kanno, Y.; Shiba, Y. Visualization of the secretory process involved in Ca 2 þ -activated fluid secretion from rat submandibular glands using the fluorescent dye, calcein. Eur. J. Cell Biol. 2000, 79, 182-191. 10. Li...

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Modulation of breast cancer resistance protein (BCRP/ABCG2) by non-basic chalcone analogues

Cited by 41 publications

References 33 publications

Aurones as Modulators of ABCG2 and ABCB1: Synthesis and Structure–Activity Relationships

Aurones as Modulators of ABCG2 and ABCB1: Synthesis and Structure–Activity Relationships

Trends in Utilization of the Pharmacological Potential of Chalcones

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