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  • Elsevier (CrossRef)  (124)
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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: Bioorganic & Medicinal Chemistry Letters, 2010, Vol.20(1), pp.180-183
    Description: Compound is a novel lead for the design of new and potent BCRP modulators. From our modulator library an interesting inhibitor of breast cancer resistance protein (BCRP) was identified. Due to its high inhibitory potency, this compound may serve as a promising novel lead for the design of new and potent modulators. This adds a new structural class to the few known highly active BCRP inhibitors.
    Keywords: Abcg2 ; Inhibitors ; Multidrug Resistance ; Bcrp ; Hoechst 33342 ; Pheophorbide A ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
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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: Bioorganic & Medicinal Chemistry Letters, 01 September 2008, Vol.18(17), pp.4761-4763
    Description: Structure of compound a novel lead for selective inhibitors of multidrug resistance-associated proteins (MRPs). We present a novel lead for inhibitors of multidrug resistance-associated proteins (MRPs). Compound (4-[(5,6,7,8-tetrahydro-4-oxo-4 -[1]benzothieno[2,3- ][1,3]thiazin-2-yl)amino]benzoic acid) was about six times more potent than the known inhibitor MK571 at MRP1, while at MRP2 its effect was similar to that of MK571. Structural analogs were also evaluated. Among them, compound , sharing the 4-aminobenzoic acid substructure with , also inhibited MRP1. Both derivatives were inactive against P-gp. It can be concluded that their carboxyl group is needed for inhibition of MRPs and accounts for the selectivity of these compounds.
    Keywords: ABC Transporters ; Mrp1 ; Mrp2 ; Inhibitors ; Multidrug Resistance ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
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  • 7
    Language: English
    In: The Journal of Allergy and Clinical Immunology, July 2012, Vol.130(1), pp.162-168
    Description: Venom immunotherapy can be initiated by different schedules, but randomized comparisons have not been performed. We aimed to compare the safety of 2 initiation schedules. Patients of any age with prior immediate generalized reactions to jack jumper ant stings were randomized to venom immunotherapy initiation by a semirush schedule over 10 visits (9 weeks) or an ultrarush schedule over 3 visits (2 weeks). In a concurrent treatment efficacy study, the target maintenance dose was randomized to either 50 μg or 100 μg. The primary outcome was the occurrence of 1 or more objective systemic reactions during venom immunotherapy initiation. Analyses were by intention to treat. We also assessed outcomes in patients who declined randomization. Of 213 eligible patients, 93 were randomized to semirush (44 patients) or ultrarush (49 patients) initiation. Objective systemic reactions were more likely during ultrarush initiation (65% vs 29%;  〈 .001), as were severe reactions (12% vs 0%;  = .029). Times to maximal increases in venom-specific IgG were no different between treatments, whereas the maximal increase in venom-specific IgE occurred earlier with ultrarush treatment. Similar differences between methods were observed in patients who declined randomization. One hundred seventy-eight patients were randomized to maintenance doses of either 50 μg (90 patients) or 100 μg (88 patients). The target maintenance dose had no effect on the primary outcome, but multiple-failure-per-subject analysis found that the 50 μg dose reduced the likelihood of reactions. Ultrarush initiation increases the risk of systemic reactions. A lower maintenance dose reduces the risk of repeated reactions, but the effect on treatment efficacy is unknown.
    Keywords: Insect Sting Allergy ; Anaphylaxis ; Immunotherapy ; Venom Immunotherapy ; Randomized Controlled Trial ; Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 8
    Language: English
    In: European Journal of Cancer, March 2016, Vol.55, pp.122-130
    Description: Metastatic colorectal cancer (mCRC) tumours harbouring a mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a G13D mutation (KRAS G13D) and mutations other than G13D (other MT). Eight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p = 0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p = 0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. This meta-analysis demonstrates no significant difference between G13D and other MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.
    Keywords: Kras G13d Mutation ; Metastatic Colorectal Cancer ; Anti-Egfr Monoclonal Antibodies ; Predictive Biomarkers ; Medicine
    ISSN: 0959-8049
    E-ISSN: 1879-0852
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  • 9
    Language: English
    In: Bioorganic & Medicinal Chemistry, 15 March 2011, Vol.19(6), pp.2090-2102
    Description: Summary of structural features influencing the inhibition of BCRP by flavonoids. Plus-circles indicate the positive contribution of structural elements to anti-BCRP activity. Minus-circles illustrate the negative impact on inhibitory potency. Results are based on data from the 3D QSAR approaches of the present study as well as the findings from 2D QSAR analyses of data taken from literature. Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH for the interaction with BCRP.
    Keywords: Breast Cancer Resistance Protein ; Multidrug Resistance ; Hoechst 33342 Assay ; Flavonoids ; P-Glycoprotein ; Qsar ; Comfa ; Comsia ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 10
    Language: English
    In: Journal of Pharmaceutical and Biomedical Analysis, 2011, Vol.54(2), pp.303-310
    Description: Allergy to (Jack Jumper Ant) venom is common in Australia, affecting ∼2.7% of some communities. Venom immunotherapy is a highly effective treatment, but for the venom to be widely distributed for clinical use, the stability and shelf-life of formulated Jack Jumper Ant venom must be demonstrated. HPLC–UV, ELISA Inhibition, SDS-PAGE and SDS-PAGE Immunoblot were used to assess venom stability under conditions of varying temperature, pH and in the presence of various stabilising agents. Optimal stability occurred between pH 8 and 10, however the presence of benzyl alcohol within this pH range resulted in a cloudy appearance within 3 days, so a pH of 6 was used. Increasing polysorbate 80 concentrations accelerated the degradation of allergenic peptides in 100 μg/mL venom, but improved stability at concentrations of 1 μg/mL or less. Sucrose reduced degradation of allergens Myr p 1 and Myr p 3, whilst glycerol was destabilising. In the presence of 22% sucrose, 1.1 mg/mL Jack Jumper Ant venom was stable at −18 °C and 4 °C for 12 months; following dilution to 100 μg/mL with 0.9% sodium chloride, 10 mM phosphate (pH 6), 0.05% polysorbate 80 and 0.9% benzyl alcohol (giving 2% sucrose), venom was stable for 7 days when stored at 4 °C. Concentrated Jack Jumper Ant venom can be stored in 22% sucrose for 12 months, and after dilution to 100 μg/mL for clinical use, it should be discarded after 7 days.
    Keywords: Myrmecia Pilosula ; Hymenoptera Venom Stability ; Hplc–Uv ; ELISA Inhibition ; SDS-Page Immunoblot ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0731-7085
    E-ISSN: 1873-264X
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