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  • 1
    Language: English
    In: Bioorganic & Medicinal Chemistry Letters, 01 November 2012, Vol.22(21), pp.6766-6769
    Description: We investigated several 2-phenylquinazolines with different substitutions at position 4 for their BCRP inhibition. Compounds with phenyl ring attached via an amine-containing linker at position 4 were found to be potent inhibitors of BCRP. In general compounds with substitution of phenyl ring at position 4 were found to have higher inhibitory effect, compound being the most potent and selective towards BCRP.
    Keywords: Bcrp ; Inhibitors ; Multidrug Resistance ; Quinazolines ; Hoechst 33342 ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
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  • 2
    Language: English
    In: Bioorganic & Medicinal Chemistry, 15 December 2013, Vol.21(24), pp.7858-7873
    Description: Chemotherapy is one of the major forms of cancer treatment. Unfortunately, tumors are prone to multidrug resistance leading to failure of treatment. Breast cancer resistance protein (BCRP), the second member of ABC transporter subfamily G, has been found to play a major role in drug efflux and hence multidrug resistance. Until now, very few potent and selective BCRP inhibitors like Ko143 have been identified. In the search for more potent and selective BCRP inhibitors, we synthesized and investigated a series of differently substituted quinazoline compounds. Several variations at positions 2, 4, 6 and 7 of the quinazoline scaffold were carried out to develop a structure–activity-relationship analysis for these compounds. It was found that compounds bearing a phenyl substituent at position 2 of the 4-anilinoquinazoline scaffold were most potent. On the aniline ring at position 4 of the quinazoline moiety substituents like NO , CN, CF led to very high BCRP inhibition potencies. The most potent compounds were further investigated for their intrinsic cytotoxicity and their ability to reverse the multidrug resistance. Compound , an anilinoquinazoline bearing a phenyl ring at position 2 and -nitro substitution on the 4-anilino ring, was found to have the highest therapeutic ratio. The most active compounds from each variation were also investigated for their effect on BCRP expression. It was found that compound has no significant effect on BCRP expression, while compound decreased the surface BCRP expression. The only difference in the two compounds was the presence of a 3,4-dimethoxyphenyl ring in compound instead of phenyl substitution at position 2 of the quinazoline moiety. From the study of all target compounds, compound was the most prominent compound having inhibitory potency even higher than Ko143, the most potent BCRP inhibitor known. Compound was also found to be selective towards BCRP with a very high therapeutic ratio.
    Keywords: ATP Binding Cassette (ABC) Transporter ; Breast Cancer Resistance Protein (Bcrp/Abcg2) ; Multidrug Resistance ; Quinazolines ; Hoechst 33342 Accumulation Assay ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 3
    Language: English
    In: Bioorganic & Medicinal Chemistry, 01 January 2012, Vol.20(1), pp.346-355
    Description: Breast cancer resistance protein (BCRP/ABCG2) belongs to the ATP binding cassette family of transport proteins. BCRP has been found to confer multidrug resistance in cancer cells. A strategy to overcome resistance due to BCRP overexpression is the investigation of potent and specific BCRP inhibitors. The aim of the current study was to investigate different multi-substituted chalcones for their BCRP inhibition. We synthesized chalcones and benzochalcones with different substituents (viz. OH, OCH , Cl) on ring A and B of the chalcone structure. All synthesized compounds were tested by Hoechst 33342 accumulation assay to determine inhibitory activity in MCF-7 MX and MDCK cells expressing BCRP. The compounds were also screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity in the calcein AM accumulation assay and were found to be selective towards inhibition of BCRP. Substituents at position 2′ and 4′ on chalcone ring A were found to be essential for activity; additionally there was a great influence of substituents on ring B. Presence of 3,4-dimethoxy substitution on ring B was found to be optimal, while presence of 2- and 4-chloro substitution also showed a positive effect on BCRP inhibition.
    Keywords: Chalcones ; Multidrug Resistance ; Breast Cancer Resistance Protein ; Inhibitors ; Hoechst 33342 Assay ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 4
    Language: English
    In: European Journal of Medicinal Chemistry, Sept, 2013, Vol.67, p.115(12)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ejmech.2013.06.035 Byline: Kapil Juvale, Katja Stefan, Michael Wiese Abstract: Multidrug resistance (MDR) often leads to a failure of cancer chemotherapy. Breast Cancer Resistance Protein (BCRP/ABCG2), a member of the superfamily of ATP binding cassette proteins has been found to confer MDR in cancer cells by transporting molecules with amphiphilic character out of the cells using energy from ATP hydrolysis. Inhibiting BCRP can be a solution to overcome MDR. We synthesized a series of flavones, 7,8-benzoflavones and 5,6-benzoflavones with varying substituents at positions 3, 3' and 4' of the (benzo)flavone structure. All synthesized compounds were tested for BCRP inhibition in Hoechst 33342 and pheophorbide A accumulation assays using MDCK cells expressing BCRP. All the compounds were further screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity by calcein AM accumulation assay to check the selectivity towards BCRP. In addition most active compounds were investigated for their cytotoxicity. It was observed that in most cases 7,8-benzoflavones are more potent in comparison to the 5,6-benzoflavones. In general it was found that presence of a 3-OCH.sub.3 substituent leads to increase in activity in comparison to presence of OH or no substitution at position 3. Also, it was found that presence of 3',4'-OCH.sub.3 on phenyl ring lead to increase in activity as compared to other substituents. Compound 24, a 7,8-benzoflavone derivative was found to be most potent being 50 times selective for BCRP and showing very low cytotoxicity at higher concentrations. Author Affiliation: Pharmaceutical Institute, University of Bonn, Pharmaceutical Chemistry II, An der Immenburg 4, 53121 Bonn, Germany Article History: Received 31 October 2012; Revised 12 June 2013; Accepted 13 June 2013
    Keywords: Drug Resistance -- Analysis ; Proteins -- Analysis ; Protein Binding -- Analysis ; Hydrolysis -- Analysis ; Chemotherapy -- Analysis
    ISSN: 0223-5234
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: BBA - Biomembranes, November 2014, Vol.1838(11), pp.2929-2938
    Description: Breast Cancer Resistance Protein (BCRP/ABCG2) belongs to the superfamily of ATP binding cassette (ABC) transporters. Characteristic of some of these transporter proteins is the transport of a variety of structurally unrelated substances against a concentration gradient by using the energy of ATP hydrolysis. ABCG2 has been found to confer multidrug resistance (MDR) in cancer cells. Several anticancer drugs have been identified as ABCG2 substrates including mitoxantrone, etoposide and topotecan. As inhibition of the transporter is one of the strategies to overcome MDR, we have synthesized and tested several 3-methoxy flavones and investigated them for their ABCG2 inhibition. Among these, pentamethyl quercetin (compound ) and pentamethyl morin (compound ) were found to be fluorescent and hence screened for their possible transport by ABCG2 using confocal microscopy. This study showed that pentamethyl quercetin was far less accumulated in ABCG2 overexpressing MDCK BCRP cells as compared to MDCK sensitive cells, suggesting possible efflux of this compound by ABCG2. Pentamethyl morin showed no visible difference in both cell lines. Based on this observation, we studied several other fluorescent 3-methoxy flavones for their accumulation in ABCG2 overexpressing cells. To confirm the substrate or inhibitor nature of the tested compounds, these compounds were further investigated by ATPase assay. If stimulation of the transporter ATPase activity is detected, one can conclude that the compound is probably a transported substrate. All compounds except pentamethyl morin (compound ) and tetramethyl quercetin (compound ) were found to stimulate ATPase activity pointing to possible substrates despite being potent inhibitors of ABCG2.
    Keywords: Abcg2 ; Bcrp ; Flavonoids ; Substrate ; Atpase ; Chemistry
    ISSN: 0005-2736
    E-ISSN: 1879-2642
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  • 6
    Language: English
    In: Future medicinal chemistry, August 2015, Vol.7(12), pp.1521-7
    Description: BCRP/ABCG2, a second member of ABC transporter subclass G, has been shown to be overexpressed in several solid tumors, acute myelogenous leukemia and chronic myeloid leukemia. A variety of chemically unrelated anticancer drugs have been found to be transported by ABCG2 leading to their lower intracellular accumulation and hence causing chemoresistance. Until now several efforts have been taken to identify potent and selective inhibitors of ABCG2. Recent studies carried out to deign BCRP inhibitors have been able to point out the effect of the substitution pattern in compound scaffolds on the potency, selectivity and cytotoxicity of ABCG2 inhibitors.
    Keywords: Drug Design ; ATP-Binding Cassette Transporters -- Antagonists & Inhibitors ; Drug Resistance, Neoplasm -- Drug Effects ; Neoplasm Proteins -- Antagonists & Inhibitors ; Neoplasms -- Drug Therapy
    ISSN: 17568919
    E-ISSN: 1756-8927
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  • 7
    Language: English
    In: European Journal of Pharmaceutical Sciences, Sept 18, 2015, Vol.77, p.1(8)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ejps.2015.04.027 Byline: Manu Smriti Singh, Kapil Juvale, Michael Wiese, Alf Lamprecht Abstract: Display Omitted Article History: Received 24 February 2015; Revised 19 April 2015; Accepted 23 April 2015
    Keywords: General Practitioners – Analysis
    ISSN: 0928-0987
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: European Journal of Medicinal Chemistry, September 2013, Vol.67, pp.115-126
    Description: Multidrug resistance (MDR) often leads to a failure of cancer chemotherapy. Breast Cancer Resistance Protein (BCRP/ABCG2), a member of the superfamily of ATP binding cassette proteins has been found to confer MDR in cancer cells by transporting molecules with amphiphilic character out of the cells using energy from ATP hydrolysis. Inhibiting BCRP can be a solution to overcome MDR. We synthesized a series of flavones, 7,8-benzoflavones and 5,6-benzoflavones with varying substituents at positions 3, 3′ and 4′ of the (benzo)flavone structure. All synthesized compounds were tested for BCRP inhibition in Hoechst 33342 and pheophorbide A accumulation assays using MDCK cells expressing BCRP. All the compounds were further screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity by calcein AM accumulation assay to check the selectivity towards BCRP. In addition most active compounds were investigated for their cytotoxicity. It was observed that in most cases 7,8-benzoflavones are more potent in comparison to the 5,6-benzoflavones. In general it was found that presence of a 3-OCH substituent leads to increase in activity in comparison to presence of OH or no substitution at position 3. Also, it was found that presence of 3′,4′-OCH on phenyl ring lead to increase in activity as compared to other substituents. Compound , a 7,8-benzoflavone derivative was found to be most potent being 50 times selective for BCRP and showing very low cytotoxicity at higher concentrations.
    Keywords: Flavonoids ; Benzoflavones ; Breast Cancer Resistance Protein (Bcrp) ; P-Gp ; Mrp1 ; Multidrug Resistance (Mdr) ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0223-5234
    E-ISSN: 1768-3254
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  • 9
    Language: English
    In: European Journal of Pharmaceutical Sciences, 18 September 2015, Vol.77, pp.1-8
    Description: Overcoming multidrug resistance (MDR) in cancer is a major challenge and efforts are on-going to develop inhibitors against the most characterized and ubiquitous MDR transporters: P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP1) and breast cancer resistance protein (BCRP). Recently reported, two 4-anilinoquinazolines (compounds 1 and 2), demonstrate potential MDR reversal activity against BCRP and to a lesser extent, P-gp. In this work, we formulated the compounds as polymeric nanoparticles (NPs) and assessed their MDR inhibitory activity in relevant BCRP and P-gp over-expressing cell line models. Particles in the size range 300–365 nm with a loading efficiency of 69% (compound 1 NP) and 77% (compound 2 NP) respectively were obtained. BCRP inhibition was observed in Hoechst 33342 and pheophorbide A assays while P-gp inhibition was evaluated in calcein AM and rhodamine-123 assays. In cytotoxicity studies, while BCRP expressing cells showed complete reversal of drug resistance in nearly all treatment groups (both compounds and their respective NP); a higher reversal in NP treated group was obtained as compared with inhibitory compound treated group in P-gp expressing cells. These results demonstrate promising inhibitory activity of both formulations, especially against P-gp expressing cells; which is possibly due to a prolonged presence of encapsulated compounds in NPs and consequently a prolonged sensitization of transmembrane drug transporter. These formulations can therefore be considered as dual-transporter inhibitors and it is imperative to investigate both inhibitors in animal models of MDR owing to the presence of multiple efflux transporters in several cancer models.
    Keywords: Cancer ; Mdr ; P-Gp ; Bcrp ; Nanoparticle ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0928-0987
    E-ISSN: 1879-0720
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  • 10
    In: Acta Crystallographica Section C, 01 January 2017, Vol.73(1), pp.20-27
    Description: The syntheses of new ‐inositol derivatives have received much attention due to their important biological activities. 1,2‐‐Cyclohexylidene‐‐inositol is an important intermediate formed during the syntheses of certain ‐inositol derivatives. We report herein the crystal structure of 1,2‐‐cyclohexylidene‐‐inositol dihydrate, CHO·2HO, which is an intermediate formed during the syntheses of ‐inositol phosphate derivatives, to demonstrate the participation of water molecules and hydroxy groups in the formation of several intermolecular O—H…O interactions, and to determine a low‐energy conformation. The title ‐inositol derivative crystallizes with two water molecules in the asymmetric unit in the space group 2/, with = 8. The water molecules facilitate the formation of an extensive O—H…O hydrogen‐bonding network that assists in the formation of a dense crystal packing. Furthermore, geometrical optimization and frequency analysis was carried out using density functional theory (DFT) calculations with B3LYP hybrid functionals and 6‐31G(d), 6‐31G(d,p) and 6‐311G(d,p) basis sets. The theoretical and experimental structures were found to be very similar, with only slight deviations. The intermolecular interactions were quantitatively analysed using Hirshfeld surface analysis and 2D (two‐dimensional) fingerplot plots, and the total lattice energy was calculated. In 1,2‐‐cyclohexylidene‐‐inositol, the hydroxy groups at positions 4 and 5 are in a configuration and a rationale is suggested for the difficulties in synthesizing 1,2;4,5‐di‐‐cyclohexylidene‐‐inositol. The calculated structure was very similar to that of the experimental structure. Hirshfeld surface analysis with fingerprint plots demonstrated that the O—H…O interactions are the major intermolecular interactions. Lattice energy calculations suggested that dispersion is the major contributor to the crystal packing.
    Keywords: Myo ‐Inositol ; Geometry Optimization ; Crystal Structure ; Hirshfeld Surface Analysis ; Lattice Energy ; Transmembrane Signalling ; Potential Chemotherapeutic Agent
    ISSN: 2053-2296
    ISSN: 01082701
    E-ISSN: 2053-2296
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