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Berlin Brandenburg

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  • 1
    Language: English
    In: Journal of medicinal chemistry, 25 May 2017, Vol.60(10), pp.4474-4495
    Description: Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transport proteins remains a major problem in the chemotherapeutic treatment of cancer and might be overcome by inhibition of the transporter. Because of the lack of understanding, the complex mechanisms involved in the transport process, in particular for breast cancer resistance protein (BCRP/ABCG2), there is a persistent need for studies of inhibitors of ABCG2. In this study, we investigated a systematic series of 4-substituted-2-pyridylquinazolines in terms of their inhibitory potency as well as selectivity toward ABCG2. For comparison, the quinazoline scaffold was reduced to the significantly smaller 4-methylpyrimidine basic structure. Furthermore, the cytotoxicity and the ability to reverse MDR was tested with the chemotherapeutic agents SN-38 and mitoxantrone (MX). Interaction of the compounds with ABCG2 was investigated by a colorimetric ATPase assay. Enzyme kinetic studies were carried out with Hoechst 33342 as fluorescent dye and substrate of ABCG2 to elucidate the compounds binding modes.
    Keywords: ATP Binding Cassette Transporter, Subfamily G, Member 2 -- Antagonists & Inhibitors ; Pyrimidines -- Chemistry ; Quinazolines -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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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: Journal of medicinal chemistry, 26 April 2018, Vol.61(8), pp.3389-3408
    Description: Multidrug resistance (MDR) occurring during cancer chemotherapy is a major obstacle for effectiveness and response to therapy and is often caused by ATP-binding cassette (ABC) efflux transporters. Belonging to the family of ABC transporters, breast cancer resistance protein is getting more and more in the spotlight of research. As a strategy to overcome MDR, inhibitors of ABC transporters were synthesized, which could be applied in combination with cytostatic drugs. For this purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized. The investigations confirmed three key characteristics of good inhibitors: a low intrinsic cytotoxicity and a high potency and selectivity toward ABCG2. For selected compounds the interaction with ABCG2 was elucidated and their effect on ATPase activity and conformation sensitive 5D3 antibody binding was investigated. Their ability to reverse MDR in coadministration with the active metabolite of irinotecan and mitoxantron was confirmed.
    Keywords: ATP Binding Cassette Transporter, Subfamily G, Member 2 -- Antagonists & Inhibitors ; Antineoplastic Agents -- Pharmacology ; Neoplasm Proteins -- Antagonists & Inhibitors ; Pyridines -- Pharmacology ; Pyrimidines -- Pharmacology
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 4
    Language: English
    In: Journal of medicinal chemistry, 13 September 2018, Vol.61(17), pp.7952-7976
    Description: Several members of the ABC transporter superfamily play a decisive role in the development of multidrug resistance (MDR) in cancer. One of these MDR associated efflux transporters is ABCG2. One way to overcome this MDR is the coadministration of potent inhibitors of ABCG2. In this study, we identified novel inhibitors containing a 2,4,6-substituted quinazoline scaffold. Introduction of a 6-nitro function led to extraordinarily potent compounds that were highly selective for ABCG2 and also able to reverse the MDR toward the chemotherapeutic drugs SN-38 and mitoxantrone. The binding of substrate Hoechst 33342 and the two potent inhibitors 31 and 41 which differ in their mechanism of inhibition was rationalized using the recently published cryo-EM structures of ABCG2. For a better understanding of the interaction between the inhibitors and ABCG2, additional investigations regarding the ATPase activity, the interaction with Hoechst 33342, and with the conformational sensitive 5D3 antibody were carried out.
    Keywords: ATP Binding Cassette Transporter, Subfamily G, Member 2 -- Antagonists & Inhibitors ; Antineoplastic Agents -- Chemistry ; Drug Resistance, Multiple -- Drug Effects ; Drug Resistance, Neoplasm -- Drug Effects ; Neoplasm Proteins -- Antagonists & Inhibitors ; Neoplasms -- Drug Therapy ; Quinazolines -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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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: European Journal of Medicinal Chemistry, 20 October 2017, Vol.139, pp.587-611
    Description: Expression of ABCG2, a member of the ABC transporter superfamily, has been correlated to the clinical outcome of multiple cancers and is often associated with the occurrence of multidrug resistance (MDR) in chemotherapy. Inhibition of the transport protein by potent and selective inhibitors might be a way to treat cancer more efficiently and improve the therapy of cancer patients. Recently we reported the synthesis of new inhibitors based on a quinazoline scaffold. In the present study more structural variations were explored. Compounds with 3,4-dimethoxy groups and or nitro substituents were found to be highly potent inhibitors of ABCG2. The most potent compound was more than five-fold more potent than Ko143, one of the best inhibitors of ABCG2. To determine the new compounds selectivity toward ABCG2 their inhibitory effects on ABCB1 and ABCC1 were also investigated identifying selective as well as broadspectrum inhibitors. Furthermore, intrinsic cytotoxicity and efficacy regarding the reversal of multidrug resistance toward SN-38 and mitoxantrone were explored. The most potent compounds were able to reverse the resistance toward the cytostatic agents with EC values below 20 nM. Additionally, the type of interaction between inhibitors and the ABCG2 substrate Hoechst 33342 was investigated yielding competitive and non-competitive interactions suggesting different modes of binding. Finally the effect of the derivatives on vanadate-sensitive ATPase activity of ABCG2 was determined. According to the different effects on ATPase activity we conclude the existence of different binding sites. This study provides the structural requirements for high potency inhibition and elucidates the interaction with ABCG2 setting the basis for further studies.
    Keywords: ABC Transporter ; Inhibitor ; Abcg2 ; Quinazolines ; Bcrp ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0223-5234
    E-ISSN: 1768-3254
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  • 7
    Language: English
    In: The American journal of occupational therapy : official publication of the American Occupational Therapy Association, 2003, Vol.57(1), pp.108-11
    Description: The Purdue Pegboard test often is used in clinical settings to evaluate changes in clients' fine motor dexterity. The purpose of this study was to determine the test-retest reliability and practice effects of the Purdue Pegboard for persons with multiple sclerosis. In addition, this study compared the reliability of one-trial administration to three-trial administration of the four subtests. Thirty-two volunteers from a midwestern community-based maintenance rehabilitation center for persons with multiple sclerosis participated in this study. The participants were administered the four subtests of the Purdue Pegboard, three trials in a row. A second administration was completed 1 week later. Data from 25 participants were analyzed using paired t tests, Pearson product-moment correlations, and intraclass correlation coefficients. The test-retest reliability coefficients ranged from .85 to .90 for one-trial administration and from .92 to .96 for the sum of three trials. No significant practice effects existed except for the sum of three trials of both hands. This study suggests that the one-trial administration of the Purdue Pegboard is a sufficiently reliable assessment to use with persons with multiple sclerosis. Findings further suggest that for a person with multiple sclerosis, any changes in Purdue Pegboard scores using one-trial administration may reflect actual change in that person's dexterity, as no practice effect was demonstrated in this study.
    Keywords: Multiple Sclerosis -- Physiopathology
    ISSN: 0272-9490
    E-ISSN: 19437676
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  • 8
    Language: English
    In: European Journal of Medicinal Chemistry, 01 January 2019, Vol.161, pp.506-525
    Description: Multidrug resistance (MDR) is a major obstacle for effective chemotherapeutic treatment of cancer frequently leading to failure of the therapy. MDR is often associated with the overexpression of ABC transport proteins like ABCB1 or ABCG2 which efflux harmful substances out of cells at the cost of ATP hydrolysis. One way to overcome MDR is to apply potent inhibitors of ABC transporters to restore the sensitivity of the cells toward cytostatic agents. This study focusses on the synthesis and evaluation of novel 2,4-disubstituted quinazoline derivatives regarding the structure-activity-relationship (SAR), their ability to reverse MDR and their mode of interaction with ABCG2. Hence, the inhibitory potency and selectivity toward ABCG2 was determined. Moreover, the intrinsic cytotoxicity and the reversal of MDR were investigated. Interaction type studies with the substrate Hoechst 33342 and conformational analyses of ABCG2 with 5D3 monoclonal antibody were performed for a better understanding of the underlying mechanisms. In our study we could further enhance the inhibitory effect against ABCG2 (compound , IC : 55 nM) and identify the structural features that are crucial for inhibitory potency, the impact on transport activity and binding to the protein.
    Keywords: ABC Transporter ; Inhibitor ; Abcg2 ; Quinazolines ; SAR ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0223-5234
    E-ISSN: 1768-3254
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  • 9
    In: Journal of Occupational and Organizational Psychology, March 2009, Vol.82(1), pp.159-182
    Description: We examined the effects of gender and work‐groups' perceptions of climate for sexual harassment on the relationship between individuals' sexual harassment experiences and job‐related outcomes (namely, job satisfaction, affective organizational commitment, work withdrawal, and job withdrawal). Drawing from a variety of theories, we proposed that a beneficial climate would buffer men from negative outcomes, but would intensify negative outcomes for women. Significant three‐way interactions were found for job satisfaction, affective organizational commitment, and job withdrawal. Results indicated that beneficial work‐group climate perceptions buffered men from decrements in job satisfaction and work withdrawal, but intensified decrements in all three outcomes for women. Implications for research and practice are discussed.
    Keywords: Cross-Sectional Analysis ; Harassment ; Sexual Abuse ; Working Conditions ; Group Dynamics ; Gender Differentiation ; Job Satisfaction ; Organizational Behaviour ; Psychology ; Sociology;
    ISSN: 0963-1798
    E-ISSN: 2044-8325
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  • 10
    Language: English
    In: Research and Practice for Persons with Severe Disabilities, June 2016, Vol.41(2), pp.116-131
    Description: The deinstitutionalization movement that began 50 years ago remains a current issue for professionals and families. Using qualitative phenomenology methodology, we investigated the experience of mandated deinstitutionalization for parents and siblings whose relatives with intellectual and developmental disabilities (IDD) transitioned from institutionalization to community living within the past 1 to 3 years. Findings from the current study align with previous research wherein, over time, most families shift from opposition to satisfaction regarding community living; however, family members’ narratives in the current study reveal there is more to the process of deinstitutionalization than the outcome of satisfaction. Family members, regardless of current opposition or satisfaction, shared six common themes concerning what they desired and valued throughout the deinstitutionalization process: (a) respect our relative’s history, (b) collaborate: make us feel like we are a part of the process, (c) provide quality care, (d) provide consistent care, (e) include my relative in the community, and (f) remember we are family. As the desirable goals of full community inclusion (e.g., education, community living, competitive employment) are implemented through policy and practice, professionals must continue to develop intentional collaborations with, and supports for, families during times of transition in conjunction with services and supports developed for individuals with IDD.
    Keywords: Deinstitutionalization ; Community Living ; Intellectual and Developmental Disabilities ; Family System ; Transition ; Education ; Social Welfare & Social Work ; Occupational Therapy & Rehabilitation
    ISSN: 1540-7969
    E-ISSN: 2169-2408
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