Abstract：
:Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico density functional theory calculations suggested graviquinone as a kinetic product of pcm-scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Fási L,Di Meo F,Kuo CY,Stojkovic Buric S,Martins A,Kúsz N,Béni Z,Dékány M,Balogh GT,Pesic M,Wang HC,Trouillas P,Hunyadi Adoi
10.1021/acs.jmedchem.8b01994subject
Has Abstractpub_date
2019-02-14 00:00:00pages
1657-1668issue
3eissn
0022-2623issn
1520-4804journal_volume
62pub_type
杂志文章abstract：:A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030565g
更新日期：2004-04-08 00:00:00
abstract：:Assembly of human immunodeficiency virus (HIV-1) represents an attractive target for antiretroviral therapy which is not exploited by currently available drugs. We established high-throughput screening for assembly inhibitors based on competition of small molecules for the binding of a known dodecapeptide assembly inh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01089
更新日期：2016-01-28 00:00:00
abstract：:The conformation of the sodium salt of mycophenolic acid (MPA), a potent inhibitor of inosine monophosphate dehydrogenase (IMPD), derived from 1D DIFNOE and 2D ROESY experiments in water and molecular dynamics (MD) is described. The hexenoic acid side chain conformation consistent with the NMR data was similar to that...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950600m
更新日期：1996-03-15 00:00:00
abstract：:From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800876b
更新日期：2008-12-25 00:00:00
abstract：:The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a nu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.9b01318
更新日期：2020-03-12 00:00:00
abstract：:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00324
更新日期：2017-06-22 00:00:00
abstract：:Conformational restriction of previously disclosed acyclic (diphenylethyl)diphenylacetamides led to the discovery of several potent inhibitors of acyl CoA:cholesterol acyltransferase (ACAT). cis-[2-(4-Hydroxyphenyl)-1-indanyl]diphenylacetamide (4a) was the most potent ACAT inhibitor identified (IC50 = 0.04 microM in a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950833d
更新日期：1996-04-12 00:00:00
abstract：:We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximatel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061224g
更新日期：2007-02-22 00:00:00
abstract：:The synthesis of cis and trans isomers of N,N-N-trimethyl-2-phenoxycyclohexylammonium bromide, cis-N,N,-N-trimethyl-2(2',6'-xylyloxy)cyclohexylammonium bromide, and N,N-dimethyl-3-phenoxypiperidinium bromide is described. Their structures and conformations were determined by NMR and uv absorption spectroscopy, the min...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00227a022
更新日期：1976-05-01 00:00:00
abstract：:The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200808v
更新日期：2011-10-27 00:00:00
abstract：:A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01731
更新日期：2018-02-22 00:00:00
abstract：:To improve the biological profile of 20(S)-camptothecin, a novel class of 20-O-linked camptothecin glycoconjugates has been designed for preferential cellular uptake into tumor cells by an active transport mechanism. Such conjugates have been optimized for enhanced solubility, stabilization of the camptothecin lactone...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010893l
更新日期：2001-11-22 00:00:00
abstract：:A series of analogues of the fungal peptaibol type metabolite ampullosporin A containing modifications in the C and N terminus as well as alpha-aminoisobutyric acid (Aib) substitutions in different positions of the peptide were synthesized by solid phase synthesis using the 9-fluorenylmethyloxycarbonyl strategy. Depen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0208018
更新日期：2002-06-20 00:00:00
abstract：:In an effort to explore structural features affecting receptor recognition in a series of conformationally restricted tetrapeptides related to the cyclic, delta opioid receptor-selective analogue, [formula: see text] electronic, lipophilic, and steric effects at the Phe3 residue were assessed by substitution at differ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00087a006
更新日期：1992-05-01 00:00:00
abstract：:Lipophilicity/bioavailibility of Mn(III) N-alkylpyridylporphyrin-based superoxide dismutase (SOD) mimics has a major impact on their in vivo ability to suppress oxidative stress. Meta isomers are less potent SOD mimics than ortho analogues but are 10-fold more lipophilic and more planar. Enhanced lipophilicity contrib...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900576g
更新日期：2009-12-10 00:00:00
abstract：:A series of 3-(alkoxymethyl)-alpha-(N-substituted aminomethyl)-4-hydroxybenzyl alcohols was synthesized as potential bronchodilators. The ability to prevent effects against histamine-induced bronchoconstriction in guinea pigs was studied to determine their bronchodilating activity. Introduction of a methoxymethyl grou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00189a012
更新日期：1979-03-01 00:00:00
abstract：:The synthesis of a new class of multisubstrate adduct inhibitors of polyamine biosynthesis has been investigated. The first target compound, designed to inhibit spermidine synthase, was obtained and proved to be a very potent inhibitor of that enzyme. Two synthetic routes to effect the coupling of the polyamine spermi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00014a023
更新日期：1995-07-07 00:00:00
abstract：:HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal struc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049137g
更新日期：2005-02-24 00:00:00
abstract：:The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the A...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00148a024
更新日期：1985-10-01 00:00:00
abstract：:A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]cloni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00375a017
更新日期：1984-09-01 00:00:00
abstract：:A series of 3',5'-diesters of a 2,2'-anhydro-1-(beta-D-arabinofuranosyl)cytosine salt bearing functional substituents on the ester side chains (4--16) have been synthesized. The synthesis of these diesters involved the reaction between cytidine and the corresponding acid anhydride or acid chloride in the presence of b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00192a007
更新日期：1979-06-01 00:00:00
abstract：:There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01831
更新日期：2017-05-11 00:00:00
abstract：:Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4008906
更新日期：2013-09-26 00:00:00
abstract：:The synthesis of a series of 2-, 3-, and 4-substituted benzylamine derivatives is described. These compounds were studied for their effect on experimental cardiac arrhythmias. Many of the derivatives, but in particular 2-(p-methoxyphenylethynyl)benzylamine (3d), alpha,alpha-dimethyl-4y(phenylethynyl)benzylamine (7a), ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00236a006
更新日期：1975-02-01 00:00:00
abstract：:In previous reports illustrating the effects of conformational restriction of the N-terminal region of human pancreatic growth hormone releasing factor, we demonstrated that D-amino acid substitutions in either of positions 1, 2, or 3 resulted in greatly increased growth hormone releasing activity both in vivo and in ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a006
更新日期：1985-02-01 00:00:00
abstract：:Two isomeric 6-endo- and 6-exo-(3',4'-dihydroxyphenyl) derivatives (1 and 2) of 2-azabicyclo[2.2.2]octane were synthesized as semirigid analogues of dopamine (DA) to help evaluate the preferred conformation of dopamine at the uptake site of the presynaptic nerve terminal and at the DA receptor. Against the uptake of 0...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00345a004
更新日期：1982-03-01 00:00:00
abstract：:(R)-(-)- and (S)-(+)-alpha-methyl-beta-4-(fluorophenyl)-N-methyl-N- propynylethylamine [R)-(-)- and (S)-(+)-4-fluorodeprenyl) were synthesized via the reaction of 4-fluorobenzaldehyde with nitroethane followed by reduction with lithium aluminum hydride to produce racemic 4-fluoroamphetamine, which was resolved by recr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00169a034
更新日期：1990-07-01 00:00:00
abstract：:In the treatment of cardiovascular diseases, it could be of therapeutic interest to associate the hypotensive effects resulting from the inhibition of angiotensin II formation, ensured by endothelial angiotensin-converting enzyme (ACE), with the diuretic and natriuretic responses due to the protection of the endogenou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00034a005
更新日期：1994-04-15 00:00:00
abstract：:Multiple recent studies have focused on unraveling the content of the medicinal chemist's toolbox. Here, we present an investigation of chemical reactions and molecules retrieved from U.S. patents over the past 40 years (1976-2015). We used a sophisticated text-mining pipeline to extract 1.15 million unique whole reac...
journal_title：Journal of medicinal chemistry
pub_type： 历史文章,杂志文章
doi：10.1021/acs.jmedchem.6b00153
更新日期：2016-05-12 00:00:00
abstract：:Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990418b
更新日期：1999-12-16 00:00:00
