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  • 1
    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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  • 2
    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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  • 3
    Language: English
    In: Chemistry – A European Journal, 09 July 2012, Vol.18(28), pp.8827-8834
    Description: A marine‐derived fungus of the genus was isolated from the sponge cf. Chemical investigation of the bioactive fungal extract led to the isolation of the novel phthalimidine derivatives marilines A (), A (), B (), and C (). The absolute configurations of the enantiomeric compounds and were assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. The skeleton of marilines is most unusual, and its biosynthesis is suggested to require uncommon biochemical reactions in fungal secondary metabolism. Both enantiomers, marilines A () and A (), inhibited human leukocyte elastase (HLE) with an IC value of 0.86 μ. : Marilines A and A isolated from the marine‐derived fungus sp. are potent inhibitors of human leukocyte elastase (HLE) with an IC value of 0.86 μ for both enantiomers. The unusual structures of these compounds suggest uncommon biochemical reactions in fungal secondary metabolism. The absolute configurations of the enantiomeric compounds were assigned by a combination of spectroscopic and quantum chemical methods.
    Keywords: Cd Spectroscopy ; Human Leukocyte Elastase ; Marine Fungus ; Phthalimidine ; Stachylidium
    ISSN: 0947-6539
    E-ISSN: 1521-3765
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  • 4
    Language: English
    In: BBA - Biomembranes, January 2017, Vol.1859(1), pp.69-79
    Description: Multidrug resistance (MDR) is the main cause of diminished success in cancer chemotherapy. ABC transport proteins are considered to be one important factor of MDR. Besides P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2), Multidrug Resistance-associated Protein 1 (MRP1, ABCC1) is associated with non-response to chemotherapy in different cancers. While considerable effort was spent in overcoming MDR during the last two decades, almost nothing is known with respect to activators of transport proteins. In this work we present certain pyrrolo[3,2- ]pyrimidine derivatives with variations at positions 4 and 5 and purine analogs with variations at position 6 as novel activators of MRP1-mediated transport of the MRP1 substrate calcein AM and the anticancer drug daunorubicin in low nanomolar concentration range. Two different MRP1 overexpressing cell lines were used, the doxorubicin-selected human lung cancer cell line H69 AR and the transfected Madin-Darby Canine Kidney cell line MDCK II MRP1. No effect was observed in the sensitive counterparts H69 and MDCK II wild type (wt). Derivatives with higher molecular weight possessed also inhibitory properties at low micromolar concentrations, although most compounds were rather poor MRP1 inhibitors. Purine analogs derived from potent MRP1 inhibitors of the pyrrolopyrimidine class showed equal activating, but no inhibiting effects at all. All tested compounds were non-toxic and had only minor impact on P-gp or BCRP, showing no inhibition or activation.
    Keywords: ABC Transporter ; Mrp1 ; Abcc1 ; Transport Activation ; Activator ; Flux Ratio ; Chemistry
    ISSN: 0005-2736
    E-ISSN: 1879-2642
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  • 5
    Language: English
    In: Sci Rep, 2018, Vol.8(1), pp.3000-3000
    Description: The ability of whole cells to catalyse multistep reactions, often yielding synthetically demanding compounds later used by industrial biotech or pharma, makes them an indispensable tool of synthetic chemistry. The complex reaction network employed by cellular catalysts and the still only moderate predictive power of modelling approaches leaves this tool challenging to engineer. Frequently, large libraries of semi-rationally generated variants are sampled in high-throughput mode in order to then identify improved catalysts. We present a method for space- and time-efficient processing of very large libraries (10) of recombinant cellular catalysts, in which the phenotypic characterisation and the isolation of positive variants for the entire library is done within one minute in a single, highly parallelized operation. Specifically, product formation in nanolitre-sized cultivation vessels is sensed and translated into the formation of catalase as a reporter protein. Exposure to hydrogen peroxide leads to oxygen gas formation and thus to a density shift of the cultivation vessel. Exploiting Archimedes’ principle, this density shift and the resulting upward buoyancy force can be used for batch-wise library sampling. We demonstrate the potential of the method for both, screening and selection protocols, and envision a wide applicability of the system for biosensor-based assays.
    Keywords: Article;
    ISSN: 2045-2322
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  • 6
    Language: English
    In: Biomedical optics express, 01 July 2015, Vol.6(7), pp.2398-411
    Description: Loss of articular cartilage surface integrity is considered the earliest sign of osteoarthritis; however, its reliable detection has not been established by clinical routine diagnostics. This study comprehensively assesses a set of 11 algorithm-based 2-D Optical Coherence Tomography roughness parameters and investigates their clinical impact. Histology and manual irregularity quantification of 105 human cartilage samples with variable degeneration served as reference. The majority of parameters revealed a close-to-linear correlation with the entire spectrum of degeneration. Surface integrity should therefore be assessed by a combination of parameters to improve current diagnostic accuracy in the determination of cartilage degeneration.
    Keywords: (170.1610) Clinical Applications ; (170.3880) Medical and Biological Imaging ; (170.4500) Optical Coherence Tomography ; (170.6935) Tissue Characterization
    ISSN: 2156-7085
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  • 7
  • 8
    Language: English
    Keywords: Metabolic Engineering ; Riboswitches ; High-Throughput Screening
    Source: DataCite
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