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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of organic chemistry, 21 January 2011, Vol.76(2), pp.512-22
    Description: We report the details of the total synthesis of natural and non-natural jatropha-5,12-dienes. The successful tactic for the assembly of the strained trans-bicyclo[10.3.0]pentadecane scaffold employed a B-alkyl Suzuki-Miyaura cross-coupling for the formation of the C5/C6 double bond and a ring-closing metathesis for the construction of the C12/C13 double bond. The key step of the synthesis of the cyclopentane fragment, an uncatalyzed intramolecular carbonyl-ene reaction, was studied computationally by DFT calculations. The members of the ensemble of synthetic natural and non-natural jatrophanes were subsequently examined as modulators for the ABCB1, ABCG2, and ABCC1 efflux proteins, which are associated with multidrug resistance in cancer chemotherapy.
    Keywords: Antineoplastic Agents -- Chemical Synthesis ; Biological Products -- Chemical Synthesis ; Cross-Linking Reagents -- Chemistry ; Cyclopentanes -- Chemistry ; Diterpenes -- Chemical Synthesis ; Drug Resistance, Multiple -- Drug Effects ; Euphorbia -- Chemistry ; Lung Neoplasms -- Drug Therapy ; Plant Extracts -- Chemical Synthesis
    ISSN: 00223263
    E-ISSN: 1520-6904
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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    In: Journal of the American Geriatrics Society, September 2013, Vol.61(9), pp.1508-1514
    Description: Byline: Emily Reeve, Michael D. Wiese, Ivanka Hendrix, Michael S. Roberts, Sepehr Shakib Keywords: elderly; polypharmacy; deprescribing; potentially inappropriate medications; discontinuation Objectives To capture people's attitudes, beliefs, and experiences regarding the number of medications they are taking and their feelings about stopping medications. Design Administration of a validated questionnaire. Setting Multidisciplinary ambulatory consulting service at the Royal Adelaide Hospital. Participants Participants were individuals aged 18 and older (median 71.5) taking at least one regular prescription medication; 100 participants completed all items of the questionnaire, 65 of whom were aged 65 and older. Measurements Participants were administered the 15-item Patients' Attitudes Towards Deprescribing (PATD) questionnaire. Results Participants were taking an average of 10 different prescription and nonprescription (including complementary), regular and as-needed medications. More than 60% felt that they were taking a "large number" of medications, and 92% stated that they would be willing to stop one or more of their current medications if possible. Number of regular medications, age, and number of medical conditions were not found to be correlated with willingness to stop a medication. The findings were similar in older and younger participants. Conclusion This study has shown that a cohort of mostly older adults were largely accepting of a trial of cessation of medication(s) that their prescriber deemed to be no longer required. Because few factors were associated with willingness to cease medications, all patients should be individually evaluated for deprescribing. CAPTION(S): Figure S1. Distribution of propensity score for Intervention and Control participants. Table S1. List of Exclusionary Comorbidities, ICD-9 Codes, and CPT Codes. Table S2. Control county selection criteria. Table S3. ICD-9-CM diagnosis codes for disease classification of participants. Table S4. Regression specifications. Table S1. Comparison of frailty components for Men in the Cardiovascular Health Study (CHS) and Men in the Osteoporotic Fractures in Men (MrOS) Study.
Table S2. Association between Cystatin C and frailty status among 1,257 Subjects with eGFRCr 〉60 ml/min/1.73 m2. Table S1. Adjusted* odds ratios (95% CI) from logistic regression analyses for cognitive impairment (lowest 10% performance within ethnic group) on individual cognitive tests per 10 mmHg increment in each listed blood pressure measurement.
    Keywords: Elderly ; Polypharmacy ; Deprescribing ; Potentially Inappropriate Medications ; Discontinuation
    ISSN: 0002-8614
    E-ISSN: 1532-5415
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  • 6
    Language: English
    In: Journal of medicinal chemistry, 09 June 2016, Vol.59(11), pp.5449-61
    Description: Chemotherapeutic treatment of cancer often fails due to overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCG2, triggering active efflux of various structurally unrelated drugs. This so-called multidrug resistance (MDR) may be reversed by selective, potent, and nontoxic inhibitors of ABCG2. As only a few potent inhibitors are known, new compounds based on a 4-substituted-2-phenylquinazoline scaffold were investigated. Substitution with hydroxy, cyano, nitro, acetamido, and fluoro led to high inhibitory activities toward ABCG2. The ability to reverse MDR of the most active compounds was confirmed in a MTT efficacy assay. Moreover, a negligibly low intrinsic cytotoxicity was found resulting in a high therapeutic ratio. Investigations of the inhibitory activity toward ABCB1 and ABCC1 yielded a high selectivity toward ABCG2 for the quinazoline compounds. Quinoline-based analogues showed lower inhibitory activity and selectivity. The study yielded a variety of promising compounds, some with superior properties compared to those of the standard inhibitor Ko143.
    Keywords: ATP Binding Cassette Transporter, Subfamily G, Member 2 -- Antagonists & Inhibitors ; Neoplasm Proteins -- Antagonists & Inhibitors ; Quinazolines -- Pharmacology ; Quinolines -- Pharmacology
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 7
    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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  • 8
    Language: English
    In: Journal of medicinal chemistry, 14 July 2016, Vol.59(13), pp.6121-35
    Description: The breast cancer resistance protein (ABCG2) transports chemotherapeutic drugs out of cells, which makes it a major player in mediating multidrug resistance (MDR) of cancer cells. To overcome this mechanism, inhibitors of ABCG2 can be used. Only a few potent and selective ABCG2 inhibitors have been discovered, i.e., fumitremorgin C (FTC), Ko143, and the alkaloid harmine, which contain a tetrahydro-β-carboline or β-carboline backbone, respectively. However, toxicity and or instability prevent their use in vivo. Therefore, there is a need for further potent inhibitors. We synthesized and pharmacologically investigated 37 tetrahydro-β-carboline derivatives. The inhibitory activity of two compounds (51, 52) is comparable to that of Ko143, and they are selective for ABCG2 over ABCB1. Furthermore, they are able to reverse the ABCG2-mediated resistance toward SN-38 and inhibit the ATPase activity. The cytotoxicity data show that their inhibitory effect is substantially higher than their toxicity.
    Keywords: ATP Binding Cassette Transporter, Subfamily G, Member 2 -- Antagonists & Inhibitors ; Carbolines -- Chemistry ; Neoplasm Proteins -- Antagonists & Inhibitors
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 9
    Language: English
    In: Journal of medicinal chemistry, 14 April 2016, Vol.59(7), pp.3018-33
    Description: Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopyrimidines using the doxorubicin selected and MRP1 overexpressing small cell lung cancer cell line H69 AR in a calcein AM and daunorubicin cell accumulation assay. New compounds with high potency and selectivity were identified. Piperazine residues at position 4 bearing large phenylalkyl side chains proved to be beneficial for MRP1 inhibition. Its replacement by an amino group led to decreased activity. Aliphatic and aliphatic-aromatic variations at position 5 and 6 revealed compounds with IC50 values in high nanomolar range. All investigated compounds had low affinity toward P-glycoprotein (P-gp, ABCB1). Pyrrolopyrimidines with small substituents showed moderate inhibition against breast cancer resistance protein (BCRP, ABCG2).
    Keywords: Antineoplastic Agents -- Chemistry ; Drug Resistance, Neoplasm -- Drug Effects ; Multidrug Resistance-Associated Proteins -- Antagonists & Inhibitors
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 10
    Language: English
    In: Journal of medicinal chemistry, 09 November 2017, Vol.60(21), pp.8758-8780
    Description: P-Glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are the three major ABC transport proteins conferring resistance to many structurally diverse anticancer agents, leading to the phenomenon called multidrug resistance (MDR). Much effort has been put into the development of clinically useful compounds to reverse MDR. Broad-spectrum inhibitors of ABC transport proteins can be of great use in cancers that simultaneously coexpress two or three transporters. In this work, we continued our effort to generate new, potent, nontoxic, and multiply effective inhibitors of the three major ABC transporters. The best compound was active in a very low micromolar concentration range against all three transporters and restored sensitivity toward daunorubicin (P-gp and MRP1) and SN-38 (BCRP) in A2780/ADR (P-gp), H69AR (MRP1), and MDCK II BCRP (BCRP) cells. Additionally, the compound is a noncompetitive inhibitor of daunorubicin (MRP1), calcein AM (P-gp), and pheophorbide A (BCRP) transport.
    Keywords: ATP-Binding Cassette Transporters -- Antagonists & Inhibitors ; Drug Resistance, Multiple -- Drug Effects ; Drug Resistance, Neoplasm -- Drug Effects ; Purine Nucleosides -- Therapeutic Use
    ISSN: 00222623
    E-ISSN: 1520-4804
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