Abstract:
:The clinical use of N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) has been hindered by its lack of bioavailability. N,N'-bis(2-boronic pinacol ester benzyl)ethylenediamine-N,N'-diacetic acid methyl, ethyl, and isopropyl esters 7 a-c, respectively, and their dimesylate salts 8 a-c, are double prodrugs that mask the two phenolate and two carboxylate donors of HBED as boronic esters and carboxylate esters, respectively. Their activation by chemical hydrolysis and oxidation, their passive diffusivity, and their cytoprotective capabilities have been investigated here. 8 a-c hydrolyzed in minimum essential medium at 37 °C with half-lives of 0.69, 0.81, and 2.28 h, respectively. The intermediate formed, 9 [N,N'-bis(2-boronic acid benzyl)ethylenediamine-N,N'-diacetic acid], then underwent oxidative deboronation by H2 O2 to give HBED (k=1.82 m(-1) min(-1) ). Solubility measurements in mineral oil and in phosphate buffer indicated that 7 a had a better balance between lipid and aqueous solubilities than did HBED. 7 a was also able to passively diffuse across a lipid-like silicone membrane (log flux=-0.36), whereas HBED-HCl was not. 8 c provided better protection to retinal cells than did HBED against a lethal dose of H2 O2 (84 % vs. 28 % protection, respectively, at 44 μm). These results suggest that the double prodrugs have better membrane permeability than does HBED, and therefore could be therapeutically useful for improving the delivery of HBED.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Thiele NA,Sloan KBdoi
10.1002/cmdc.201600197subject
Has Abstractpub_date
2016-08-05 00:00:00pages
1596-9issue
15eissn
1860-7179issn
1860-7187journal_volume
11pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the desi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200054
更新日期:2012-05-01 00:00:00
abstract::An emerging and attractive target for the treatment of Alzheimer's disease is to inhibit the aggregation of beta-amyloid protein (Abeta). We applied the retro-enantio concept to design an N-methylated peptidic inhibitor of the Abeta42 aggregation process. This inhibitor, inrD, as well as the corresponding all-L (inL) ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900191
更新日期:2009-09-01 00:00:00
abstract::A novel type of oligonucleotide has been developed, characterized by the attachment of a lysyl moiety to a 2'-O-aminohexyl linker. A protected lysine building block was tethered to 2'-O-aminohexyluridine, and the product was converted into the corresponding phosphoramidite. Up to six modified nucleosides were incorpor...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200700169
更新日期:2008-01-01 00:00:00
abstract::In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300297
更新日期:2014-03-01 00:00:00
abstract::Herein we describe the synthesis and biological evaluation of a series of novel benzothiazoles based on a diaryl urea scaffold previously reported in some allosteric chemokine receptor 2 (CXCR2) inhibitors. From a library of 41 new compounds, 17 showed significant inhibition of CXCR2, with IC50 values less than 10 μm ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700229
更新日期:2017-07-06 00:00:00
abstract::The design and synthesis of heparin mimetics with high anticancer activity but no anticoagulant activity is an important task in medicinal chemistry. Here, we present the efficient synthesis of five Glc-GlcA-Glc sequenced and one Glc-IdoA-Glc sequenced non-glycosaminoglycan, heparin-related trisaccharides with various...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000917
更新日期:2021-01-12 00:00:00
abstract::Despite bioavailability issues, tea catechins have emerged as promising chemopreventive agents because of their efficacy in various animal models. We synthesized two catechin-derived compounds, 3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin (TMCG) and 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), in an attempt to...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000482
更新日期:2011-03-07 00:00:00
abstract::A strategy that combines virtual screening and structure-guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900454
更新日期:2010-04-06 00:00:00
abstract::The present work describes some recent approaches to novel 3-oxabicyclo[3.2.0]heptane-type nucleosides structurally similar to the potent anti-HIV agent stavudine (d4T). To gain knowledge at the molecular level relevant for further synthetic designs, the lack of activity of these compounds was investigated by computat...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200059
更新日期:2012-06-01 00:00:00
abstract::A diverse group of proteins, the activities of which are precisely orchestrated during mitosis, have emerged as targets for cancer therapeutics; these include the Aurora kinases (AKs), Polo-like kinases (PLKs), and the kinesin spindle protein (KSP). KSP is essential for the proper separation of spindle poles during mi...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201300228
更新日期:2013-11-01 00:00:00
abstract::Antimicrobial peptides (AMPs) are promising candidates to help circumvent antibiotic resistance, which is an increasing clinical problem. Amino-terminal copper and nickel (ATCUN) binding motifs are known to actively form reactive oxygen species (ROS) upon metal binding. The combination of these two peptidic constructs...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402033
更新日期:2014-08-01 00:00:00
abstract::Tau-tubulin kinase 1 (TTBK1) is a serine/threonine/tyrosine kinase that putatively phosphorylates residues including S422 in tau protein. Hyperphosphorylation of tau protein is the primary cause of tau pathology and neuronal death associated with Alzheimer's disease. A library of 12 truncation variants comprising the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300274
更新日期:2013-11-01 00:00:00
abstract::For (64) Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agents, various chelators are commonly applied. It has not yet been determined which of the most potent chelators--NODA-GA ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2'-(1,4,8,1...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500132
更新日期:2015-07-01 00:00:00
abstract::Despite significant advances made in the last decade in the understanding of molecular mechanisms of sepsis and in the development of clinically relevant therapies, sepsis remains the leading cause of mortality in intensive care units with increasing incidence worldwide. Toll-like receptor 4 (TLR4)-a transmembrane pat...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800505
更新日期:2018-11-06 00:00:00
abstract::Leishmaniasis is a complex disease caused by over 20 Leishmania species that primarily affects populations with poor socioeconomic conditions. Currently available drugs for treating leishmaniasis include amphotericin B, paromomycin, and pentavalent antimonials, which have been associated with several limitations, such...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000862
更新日期:2020-12-17 00:00:00
abstract::We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdraw...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600343
更新日期:2016-10-06 00:00:00
abstract::To ascertain whether increasing hydrophobicity can enhance the activity of second-generation antisense oligonucleotides (ASOs) in muscle, we investigated the antisense properties of 2'-O-(2S-methoxypropyl)-RNA (2S-MOP)-modified ASOs. Synthesis of the 2S-MOP 5-methyl uridine phosphoramidite was accomplished on a multi-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402099
更新日期:2014-09-01 00:00:00
abstract::The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300372
更新日期:2014-03-01 00:00:00
abstract::Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace th...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100255
更新日期:2011-10-04 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::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::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 historical overview of key events that led, 50 years ago, to the foundation of the European Federation for Medicinal Chemistry (EFMC), and the impact this had on promoting and structuring medicinal chemistry as a discipline in Europe. EFMC, together with the growing number of newly established national medicinal che...
journal_title:ChemMedChem
pub_type: 社论
doi:10.1002/cmdc.202000691
更新日期:2020-12-15 00:00:00
abstract::Singling out the truth: A combined application of STD-NMR, molecular docking, and CORCEMA-ST calculations is described as an attractive, easily applicable tool for the identification and validation of the binding site for allosteric ligands, with potential application as an aid in drug discovery research. ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300267
更新日期:2013-10-01 00:00:00
abstract::Drugs may have polypharmacological phenomena, that is, in addition to the desired target, they may also bind to many undesired or unknown physiological targets. As a result, they often exert side effects. In some cases, off-target interactions may lead to drug repositioning or to explaining a drug's mode of action. He...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500123
更新日期:2015-07-01 00:00:00
abstract::A series of new C13-triazole-bridged and C13-ether leucomycin analogues with a reduced aldehyde group were synthesized. Derivatives with the highest antibacterial [MIC values (S. epidermidis, S. pneumoniae): ∼2-4 μg mL(-1) ; 2.55-5.09 μm] and cytotoxic [IC50 values (HeLa, KB, MCF-7, A549, HepG2 cells): ∼1.35-3.70 μm] ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600250
更新日期:2016-09-06 00:00:00
abstract::Herein we report the synthesis, photophysical properties, positron emission tomography (PET) imaging and photodynamic therapy (PDT) efficacy of methyl 3-(1'-m-iodobenzyloxy)ethyl-3-devinyl-verdin 4 (with or without the 124 I isotope). The PET imaging ability and ex vivo biodistribution of [124 I]4 were compared with t...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900352
更新日期:2019-08-20 00:00:00
abstract::Having oxaliplatin as archetype, several platinum complexes with a carbohydrate moiety resembling the cyclohexane-1,2-diamine ligand of oxaliplatin have been prepared. As leaving groups, the anionic ligands iodide, oxalate, and malonate were utilized, and for comparison purposes the chloro complex was employed. All co...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600279
更新日期:2007-04-01 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::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