Abstract:
:Multidrug resistance (MDR) in cancer cells is a crucial aspect to consider for a successful cancer therapy. P-gp/ABCB1, a member of ABC transporters, is involved in the main tumour MDR mechanism, responsible for the efflux of drugs and cytotoxic substances. Herein, we describe a discovery of potent selenium-containing ABCB1 MDR efflux pump modulators with promising anticancer activity. On three groups of selenoethers comprehensive studies in terms of design, synthesis, and biological assays, including an insight into cellular mechanisms of anticancer action as well as an ADMET-screening in vitro were performed, followed by in-depth SAR analysis. Among the investigated new phenylselenoether hybrids, four compounds showed significant cytotoxic and anti-proliferative effects, in particular, in resistant cancer cells. Hydantoin derivatives (5-7) were significantly more effective than the reference inhibitor verapamil (up to 2.6-fold at a 10-fold lower concentration) modulating ABCB1-efflux pump, also possessing a good drug-drug interaction profile. The best compound (6) was further evaluated in human JURKAT T-lymphocytic cancer cells for its impact on cell proliferation rate. Mechanistically, the expression of cyclin D1, an enhancer of the cell cycle, decreases, while p53, an inhibitor of cell proliferation, was up-regulated upon the treatment with compound 6 alone or in combination with the chemotherapeutic agent doxorubicin. In summary, a new chemical space of highly active selenium-containing anticancer agents has been discovered, with a new lead compound 6 that warrants more in-depth biological evaluation and further pharmacomodulation.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Ali W,Spengler G,Kincses A,Nové M,Battistelli C,Latacz G,Starek M,Dąbrowska M,Honkisz-Orzechowska E,Romanelli A,Rasile MM,Szymańska E,Jacob C,Zwergel C,Handzlik Jdoi
10.1016/j.ejmech.2020.112435subject
Has Abstractpub_date
2020-08-15 00:00:00pages
112435eissn
0223-5234issn
1768-3254pii
S0223-5234(20)30406-2journal_volume
200pub_type
杂志文章abstract::The synthesis and anti-tuberculosis activity for three series of 2,4-disubstituted quinolines is reported. The synthesized compounds were evaluated for activity against M. tuberculosis H37Rv strain; most promising compounds from the series exhibited MIC99 values ranged between 3.125 and 6.25 μg/mL. None of the compoun...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.02.034
更新日期:2015-03-26 00:00:00
abstract::Two platinum(II) complexes, [Pt(ClQ)(DMSO)Cl] (ClQ-Pt) and [Pt(BrQ)(DMSO)Cl] (BrQ-Pt), with 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 5,7-dibromo-2-methyl-8-quinolinol (H-BrQ) as ligands, respectively, have been synthesized and characterized. The single-crystal X-ray diffraction characterization as well as other ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.10.051
更新日期:2019-01-01 00:00:00
abstract::The quantitative dependencies of in vitro fungistatic action on the physico-chemical parameters connected with the structure of 2, 4-dihydroxythiobenzanilides were investigated. It was stated that the action of these compounds depends on lipophilicity determined by substitution of the N-aryl moiety and on electron pro...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00136-7
更新日期:2000-04-01 00:00:00
abstract::N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) catalyzes the formation of UDP-GlcNAc, a fundamental precursor in cell wall biosynthesis. GlmU represents an attractive target for new antibacterial agents. In this study, a theoretical three-dimensional (3D) structure of GlmU from Xanthomonas oryzae pv. oryzae ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2012.03.051
更新日期:2012-07-01 00:00:00
abstract::Here, we have synthesized and characterized a novel activatable photosensitizer (PS) 8a in which two well-designed boron dipyrromethene (BODIPY) derivatives are utilized as the photosensitizing fluorophore and quencher respectively, which are connected by a disulfide linker via two successive Cu (І) catalyzed click re...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112203
更新日期:2020-05-01 00:00:00
abstract::Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multist...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.111588
更新日期:2019-11-15 00:00:00
abstract::We describe the synthesis of analogs of XHE-III-74, a selective α4β3γ2 GABAAR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2016.11.045
更新日期:2017-01-27 00:00:00
abstract::Tubulin is a major molecular target for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites on tubulin, usually its β-subunit. Among the antimitotic agents that perturb microtubule dynamics, noscapinoids represent an emerging class ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.07.050
更新日期:2014-09-12 00:00:00
abstract::CB2 receptor belongs to the large family of G-protein coupled receptors (GPCRs) controlling a wide variety of signal transduction. The recent crystallographic determination of human β2 adrenoreceptor and its high sequence similarity with human CB2 receptor (hCB2) prompted us to compute a theoretical model of hCB2 base...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.07.023
更新日期:2011-09-01 00:00:00
abstract::A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds v...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.10.063
更新日期:2019-01-01 00:00:00
abstract::We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM agains...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.06.043
更新日期:2015-08-28 00:00:00
abstract::A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's s...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.04.017
更新日期:2019-07-01 00:00:00
abstract::A series of benzofuran-isatin hybrids 6a-n and 7a-g linked by alkyl linkers were designed and synthesized. Among them, hybrids 6a-l and 7a-g were assessed for their in vitro anti-mycobacterial activities against two multi-drug resistant Mycobacterium tuberculosis (MDR-MTB) strains and the cytotoxicity towards CHO cell...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.111678
更新日期:2019-12-01 00:00:00
abstract::Identifying desired interactions with a target receptor is often the first step when designing new active compounds. However, attention should also be focused on contacts with other proteins that result in either selective or polypharmacological compounds. Here, the search for the structural determinants of selectivit...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.04.010
更新日期:2018-05-10 00:00:00
abstract::In this work, marketed drug compounds (or known drug space) were used as a metric to test the principles of eliminating parent structures of the nitrenium ion (aryl-amine/nitro compounds) as well as sulphur and halogen containing molecules from screening compound collections. Molecules containing such moieties and/or ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2009.08.014
更新日期:2009-12-01 00:00:00
abstract::Purple acid phosphatases (PAPs) are binuclear hydrolases that catalyze the hydrolysis of phosphorylated substrates under acidic to neutral conditions. Elevated serum concentrations of PAP are observed in patients suffering from osteoporosis, identifying this enzyme as a potential target for the development of novel th...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.111611
更新日期:2019-11-15 00:00:00
abstract::Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down reg...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2017.12.041
更新日期:2018-02-10 00:00:00
abstract::GSK805 (1) is a potent RORγt inverse agonist, but a drawback of 1 is its low solubility, leading to a limited absorption in high doses. We have explored detailed structure-activity relationship on the amide linker, biaryl and arylsulfonyl moieties of 1 trying to improve solubility while maintaining RORγt activity. As ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112536
更新日期:2020-09-15 00:00:00
abstract::Taking the rising interest in jasmone structure based fragrant compounds into account it has been decided to take up an attempt to synthesize the new heterocyclic derivatives of this 2,3-disubstituted cyclopentenone, which could be characterized by the ability of interaction with the same receptors with which jasmone ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2008.07.028
更新日期:2009-07-01 00:00:00
abstract::A series of novel γ-(triazolyl ethylidene)butenolides (4-23) were prepared from commercially available l-ascorbic acid in good yields. These butenolides on reaction with ethanolic ammonia/amines led to formation of respective 5-hydroxy pyrrolinones (24-33). The two of these pyrrolinones on dehydration with p-toluenesu...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.05.042
更新日期:2014-07-23 00:00:00
abstract::Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a pot...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.12.005
更新日期:2015-01-27 00:00:00
abstract::Among the different classes of antibiotics, oxazolidinone derivatives represent important drugs, since their unique mechanism of action overcomes commonly diffused multidrug-resistant bacteria. Anyway, the structural similarity of these molecules to monoamino oxidase (MAO) inhibitors, like toloxatone and blefoxatone, ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2016.09.007
更新日期:2016-11-29 00:00:00
abstract::The hydroxyl group in ring A of pentacyclic triterpene is essential for antibacterial activity. Pentacyclic triterpenes bearing three hydroxyl groups in ring A were mainly found in plants and displayed significant antibacterial activity. However, no study reported how to obtain this type of compounds by chemical modif...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.01.015
更新日期:2015-05-05 00:00:00
abstract::Novel triterpene derivatives were prepared and evaluated in salsolinol (SAL)- and glutamate (Glu)-induced models of neurodegeneration in neuron-like SH-SY5Y cells. Among the tested compounds, betulin triazole 4 bearing a tetraacetyl-β-d-glucose substituent showed a highly potent neuroprotective effect. Further studies...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2021.113168
更新日期:2021-01-16 00:00:00
abstract::A series of novel 4-thiazolidinone and indolin-2-one hybrid derivatives 5a-5s and 10a-10s have been designed and synthesized and their cytotoxic activities were evaluated in vitro against three human cancer cell lines including HT-29 (human colon cancer), H460 (human lung cancer), MDA-MB-231 (human breast cancer) by M...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.05.017
更新日期:2011-08-01 00:00:00
abstract::In continuation of our effort to improve the physiological stability and the antibacterial activity of curcuminoids against drug-resistant bacteria, a series of novel monocarbonyl curcuminoids were synthesized and screened for antibacterial activity against S. aureus and E. coli strains. These curcuminoids showed pote...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112276
更新日期:2020-06-01 00:00:00
abstract::Based on a contiguous and structurally as well as biologically diverse set of 87 sigma(1) ligands, a 5D-QSAR study was conducted in which a quasi-atomistic receptor surface modeling approach (program package Quasar) was applied. The superposition of the ligands was performed with the tool Pharmacophore Elucidation (MO...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.03.048
更新日期:2010-07-01 00:00:00
abstract::Indoleamine-2,3-dioxygenase 1 (IDO1) catalyses the first and rate limiting step of kynurenine pathway accounting for the major contributor of L-Tryptophan degradation. The Kynurenine metabolites are identified as essential cofactors, antagonists, neurotoxins, immunomodulators, antioxidants as well as carcinogens. The ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2020.113071
更新日期:2021-02-05 00:00:00
abstract::A series of novel N(6)-alkyl(aryl)-2-alkyl(aryl)thioadenosines were synthesized, and their human antiplatelet aggregation activities were evaluated by the stimulation of adenosine 5'-diphosphate (ADP). Some of these compounds showed strong activity, among which compound 5b(11) displayed the highest activity with an IC...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2012.03.047
更新日期:2012-07-01 00:00:00
abstract::Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined thro...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2016.07.016
更新日期:2016-11-10 00:00:00