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Berlin Brandenburg

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  • American Chemical Society (CrossRef)  (25)
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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: 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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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    Language: English
    In: Journal of medicinal chemistry, 14 May 2015, Vol.58(9), pp.3910-21
    Description: The breast cancer resistance protein (BCRP, ABCG2) belongs to the superfamily of ATP binding-cassette (ABC) proteins. In addition to other physiological functions, it transports potentially cell-damaging compounds out of the cell using the energy from ATP hydrolysis. Certain tumors overexpressing BCRP were found to become resistant against various anticancer drugs. In previous work, we found that tariquidar analogues lacking the tetrahydroisoquinoline moiety selectively inhibit BCRP. In the present study, we synthesized 21 derivatives of the third-generation P-gp inhibitor HM30181, which is structurally related to tariquidar. The compounds were tested for their inhibitory activities against BCRP and screened against P-glycoprotein (P-gp, ABCB1) and multidrug resistance protein 1 (MRP1, ABCC1) to confirm the selectivity toward BCRP. The most potent compounds are selective toward BCRP and 2-fold more potent than the reference Ko143. Qualitative structure-activity relationship (SAR) analysis revealed that the presence of a methoxy group in the ortho or para position of at least one phenyl ring is beneficial for inhibitory activity. Furthermore, the cytotoxicity and multidrug resistance (MDR)-reversal ability of selected compounds were investigated. It was shown that they have a low cytotoxicity and the ability to reverse the BCRP-mediated SN-38 resistance.
    Keywords: ATP-Binding Cassette Transporters -- Antagonists & Inhibitors ; Antineoplastic Agents -- Chemistry ; Benzopyrans -- Chemistry ; Isoquinolines -- Chemistry ; Neoplasm Proteins -- Antagonists & Inhibitors ; Tetrazoles -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 8
    Language: English
    In: The Journal of organic chemistry, 06 October 2017, Vol.82(19), pp.10504-10522
    Description: The synthesis of the A-B-cis,B-C-trans-annulated cyclohepta[e]hydrindane core of a gagunin E analogue is reported in detail. The tricarbocyclic scaffold was assembled starting from an easily accessible A ring building block by a (4 + 2)-cycloaddition for annulation of the B ring. A ring-closing metathesis served for construction of the seven-membered C ring. The angular methyl groups were attached by electrophilic cyclopropanation-ring opening. A library based on the most active lead compound was made accessible by esterification of the terpenols with commercially available acids. A transannular etherification reaction gave access to tetracyclic derivatives of the synthetic inhibitors. The members of the compound library of non-natural homoverrucosanoid-derived esters were examined as modulators of the membrane transporter proteins ABCB1 (P-gp), ABCG2 (BCRP), and ABCC1 (MRP1), which are involved in the formation of multidrug resistance (MDR) in cancer chemotherapy.
    Keywords: Antineoplastic Agents -- Pharmacology ; Drug Resistance, Multiple -- Drug Effects ; Esters -- Pharmacology ; Polycyclic Compounds -- Pharmacology
    ISSN: 00223263
    E-ISSN: 1520-6904
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  • 9
    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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  • 10
    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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