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Berlin Brandenburg

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  • 1
    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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  • 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, 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, 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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  • 7
    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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  • 8
    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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  • 9
    In: Medical Journal of Australia, July 2011, Vol.195(2), pp.69-73
    Description: To determine the Australian native ant species associated with ant sting anaphylaxis, geographical distribution of allergic reactions, and feasibility of diagnostic venom‐specific IgE (sIgE) testing. Descriptive clinical, entomological and immunological study of Australians with a history of ant sting anaphylaxis, recruited in 2006–2007 through media exposure and referrals from allergy practices and emergency physicians nationwide. We interviewed participants, collected entomological specimens, prepared reference venom extracts, and conducted serum sIgE testing against ant venom panels relevant to the species found in each geographical region. Reaction causation attributed using a combination of ant identification and sIgE testing. 376 participants reported 735 systemic reactions. Of 299 participants for whom a cause was determined, 265 (89%; 95% CI, 84%–92%) had reacted clinically to species and 34 (11%; 95% CI, 8%–16%) to green‐head ant (). Of those with reactions to species, 176 reacted to jack jumper ant ( species complex), 18 to other jumper ants (15 to , three to ) and 56 to a variety of bulldog ants, with some participants reacting to more than one type of bulldog ant. Variable serological cross‐reactivity between bulldog ant species was observed, and sera from patients with bulldog ant allergy were all positive to one or more venoms extracted from , and . Four main groups of Australian ants cause anaphylaxis. Serum sIgE testing enhances the accuracy of diagnosis and is a prerequisite for administering species‐specific venom immunotherapy.
    Keywords: Emergency Medicine ; Immune System Diseases
    ISSN: 0025-729X
    E-ISSN: 1326-5377
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  • 10
    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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