Abstract:
:Targeting the tumor cell mitochondrion could produce novel anticancer agents. We designed an aryl-urea fatty acid (1 g; 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid) that disrupted the mitochondrion and decreased MDA-MB-231 breast cancer cell viability. To optimize the aryl-ureas the present study evaluated mitochondrial targeting by 1 g analogues containing alkyl chains between 10-17 carbons. Using the dye JC-1, the C12-C17 analogues efficiently disrupted the mitochondrial membrane potential (IC50 s 3.5±1.2 to 7.6±1.1 μM) and impaired ATP production; shorter analogues were less active. 7-Aminoactinomycin D/annexin V staining and flow cytometry showed that these agents activated the killing mechanisms of necrosis and apoptosis to varying extents (7-aminoactinomycin D/annexin V staining ratios 4.3-6.0). Indeed, 1 g and its C17 analogue preferentially activated necrosis and apoptosis, respectively (ratios 2.1 and 16). Taken together, alkyl chain length is a determinant of mitochondrial targeting by aryl-ureas and can be varied to develop analogues that activate apoptosis or necrosis in a regulated fashion.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Murray M,Roseblade A,Chen Y,Bourget K,Rawling Tdoi
10.1002/cmdc.201900577subject
Has Abstractpub_date
2020-01-17 00:00:00pages
247-255issue
2eissn
1860-7179issn
1860-7187journal_volume
15pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::Prodrugs are effective tools in overcoming drawbacks typically associated with drug formulation and delivery. Those employing esterase-triggered functional groups are frequently utilized to mask polar carboxylic acids and phenols, increasing drug-like properties such as lipophilicity. Herein we detail a comprehensive ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300255
更新日期:2013-10-01 00:00:00
abstract::The ferrocenyl diphenol complexes 1,1-bis(4'-hydroxyphenyl)-2-ferrocenyl-but-1-ene (1) and 1,2-bis(4'-hydroxyphenyl)-1-ferrocenyl-but-1-ene [(Z)-2], which differ by the relative position of the two phenolic substituents, display dramatically different antiproliferative activities on cancer cells (1 is far more cytotox...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900430
更新日期:2019-10-04 00:00:00
abstract::In atomic force microscopy (AFM) a sharp cantilever tip is used to scan surfaces at the atomic level. One further application is force spectroscopy, in which force-distance curves between binding partners located on the cantilever and substrate surface are determined. This requires specifically immobilized molecules. ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402165
更新日期:2014-09-01 00:00:00
abstract::(±)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus. Biological studies revealed attenuated activity relative to earlier structures lacking substitution at C6 of the d...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200291
更新日期:2012-11-01 00:00:00
abstract::The concise synthesis and structure-activity relationship (SAR) studies of 3-aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600125
更新日期:2006-10-01 00:00:00
abstract::Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of thei...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800422
更新日期:2009-04-01 00:00:00
abstract::Herbal medicines (HMs) are an important source of drugs. In this study, an efficient strategy integrating ultrafiltration LC-MS, microplate bioassays, and molecular docking was proposed to screen high-potency enzyme inhibitors from HMs. Using this strategy, the structure-activity relationships (SARs) including binding...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600489
更新日期:2016-12-06 00:00:00
abstract::Targeted structural modifications have led to a novel type of buprenorphine-derived opioid receptor ligand displaying an improved selectivity profile for the μ-OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, witho...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000180
更新日期:2020-07-03 00:00:00
abstract::In an approach to design drugs with higher affinity for π-π stacking and electrostatic interactions with targeted biomolecules, complexes of the type [{cis-Pt(A)2 (L)}2 -μ-{trans-1,4-dach}](NO3 )4 ((A)2 =(NH3 )2 or ethylenediamine (en), L=quinoline (quin) or benzothiazole (bztz), dach=trans-1,4-diaminocyclohexane) wer...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402052
更新日期:2014-06-01 00:00:00
abstract::A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evalua...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300105
更新日期:2013-07-01 00:00:00
abstract::Human equilibrative nucleoside transporter 1 (hENT1) is a prototypical nucleoside transporter protein ubiquitously expressed on the cell surface of almost all human tissue. Given the role of hENT1 in the transport of nucleoside drugs, an important class of therapeutics in the treatment of various cancers and viral inf...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402047
更新日期:2014-09-01 00:00:00
abstract::This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 pla...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200700204
更新日期:2008-01-01 00:00:00
abstract::A common issue during drug design and development is the discovery of novel scaffolds for protein targets. On the one hand the chemical space of purchasable compounds is rather limited; on the other hand artificially generated molecules suffer from a grave lack of accessibility in practice. Therefore, we generated a n...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700689
更新日期:2018-03-20 00:00:00
abstract::Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential thera...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000839
更新日期:2020-12-04 00:00:00
abstract::Because only a few studies have investigated the affinity and functional activity of NMDA receptor open channel blockers under the same assay conditions, a comparative study of common open channel blockers is of major interest. The pharmacological activities of MK-801, phencyclidine (PCP), dexoxadrol, etoxadrol, (S)- ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700810
更新日期:2018-03-06 00:00:00
abstract::Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblast...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700629
更新日期:2018-01-22 00:00:00
abstract::A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC50 values in the mic...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900277
更新日期:2019-07-17 00:00:00
abstract::Serine- and metallo-β-lactamases present a threat to the clinical use of nearly all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo-β-lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β-lactamase activity and eff...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300350
更新日期:2013-12-01 00:00:00
abstract::Using the original approach, a series of metallated N-confused porphyrins and metallated porphyrins have been synthesized and characterized. For all the synthesized porphyrins, in vitro studies of cytotoxic activity against K562, U937, HL-60, Jurkat, A549 and HeLa cancer cell lines, the ability to induce apoptosis and...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900633
更新日期:2020-04-03 00:00:00
abstract::A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)(2)BC and corresponding zinc chelate (NC)(2)BC-Zn and palladium chelate (NC)(2)BC-Pd were studied. Direct dilution of a solutio...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200351
更新日期:2012-12-01 00:00:00
abstract::A group of acidic nucleosides were synthesized to develop a new class of ribonuclease A (RNase A) inhibitors. Our recent study on carboxymethylsulfonyl-modified nucleosides revealed some interesting results in RNase A inhibition. This positive outcome triggered an investigation of the role played by secondary sugar hy...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402179
更新日期:2014-09-01 00:00:00
abstract::The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly in...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000456
更新日期:2011-03-07 00:00:00
abstract::Given the worldwide spread of bacterial drug resistance, there is an urgent need to develop new compounds that exhibit potent antibacterial activity and that are unimpaired by this phenomenon. Quaternary ammonium compounds have been used for many years as disinfectants, but recent advances have shown that polycationic...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900151
更新日期:2019-07-03 00:00:00
abstract::Modern organizations conducting drug-discovery programs frequently apply high-throughput screening to generate novel hit structures for the indications of interest. Systematic hit-to-lead processes have been established at most pharmaceutical companies to ensure a smooth conversion of hits into high-quality lead struc...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200500031
更新日期:2006-01-01 00:00:00
abstract::Drug metabolism, toxicity, and their interaction profiles are major issues in the drug-discovery and lead-optimization processes. The cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of marketed drugs. Therefore, the prediction of the binding affinity towards CYP2D6 an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000358
更新日期:2010-12-03 00:00:00
abstract::A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm. Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H-imidazo[4,5-b]pyrazin-2(3H)...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500300
更新日期:2015-11-01 00:00:00
abstract::The renin angiotensin aldosterone system (RAAS) is a hormonal cascade involved in the regulation of blood pressure and electrolyte balance, and represents a common target for the treatment of various diseases including hypertension, heart failure, and diabetes. Herein we present a novel 18 F-labeled derivative of the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800638
更新日期:2018-12-06 00:00:00
abstract::Over the past few years, the number of people diagnosed with type 2 diabetes has increased owing to an unhealthy diet, a limited amount of exercise, and obesity. The search for novel and efficient antidiabetes agents has become an urgent task for scientists. Among the antidiabetes drugs, α-glucosidase inhibitor drugs ...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201700216
更新日期:2017-06-07 00:00:00
abstract::Recently we reported on aryl-fluorosulfates as possible stable and effective electrophiles for the design of lysine covalent, cell permeable antagonists of protein-protein interactions (PPIs). Here we revisit the use of aryl-sulfonyl fluorides as Lys-targeting moieties, incorporating these electrophiles in XIAP (X-lin...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000355
更新日期:2020-11-18 00:00:00
abstract::The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200377
更新日期:2013-01-01 00:00:00