Mode of action of 4-hydroxyphenylpyruvate dioxygenase inhibition by triketone-type inhibitors.


:A series of 2-(2-nitrobenzoyl)cyclohexane-1,3-dione analogues (1-9) were designed, synthesized, and evaluated for inhibition of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), a key enzyme involved in the catabolism of tyrosine which catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. The correlations between the results of enzyme inhibition, ferric chloride tests, and the conformational analysis suggested that the tight binding between triketone-type inhibitors and 4-HPPD is likely due to chelation of the enzyme-bound ferric iron with the enol tautomer of 1,3-diketone moiety of the triketones. The presence of a 2-carbonyl group in the triketone is an essential structural feature for potent 4-HPPD inhibition. Modification of the 3-carbonyl group of triketone moiety to other functionality will reduce the overall planarity and thus prevent keto-enol tautomerization, resulting in a decrease or lack of inhibition activity.


J Med Chem


Wu CS,Huang JL,Sun YS,Yang DY





Has Abstract


2002-05-23 00:00:00














  • Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors.

    abstract::Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identif...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Charrier JD,Miller A,Kay DP,Brenchley G,Twin HC,Collier PN,Ramaya S,Keily SB,Durrant SJ,Knegtel RM,Tanner AJ,Brown K,Curnock AP,Jimenez JM

    更新日期:2011-04-14 00:00:00

  • Ru(II) Compounds: Next-Generation Anticancer Metallotherapeutics?

    abstract::Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically imaging, and therapeutics applications. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Thota S,Rodrigues DA,Crans DC,Barreiro EJ

    更新日期:2018-07-26 00:00:00

  • Role of the glycopeptide framework in the antibacterial activity of hydrophobic derivatives of glycopeptide antibiotics.

    abstract::The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Printsevskaya SS,Pavlov AY,Olsufyeva EN,Mirchink EP,Preobrazhenskaya MN

    更新日期:2003-03-27 00:00:00

  • Synthesis and antitumor activity of 4- and 5-substituted derivatives of isoquinoline-1-carboxaldehyde thiosemicarbazone.

    abstract::Various substituted isoquinoline-1-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia. Condensation of 4-bromo-1-methylisoquinoline (4) with ammonium hydroxide, methylamine, ethylamine, and N-acetylethylenediamine gave the...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Liu MC,Lin TS,Penketh P,Sartorelli AC

    更新日期:1995-10-13 00:00:00

  • Discovery of potent, orally bioavailable phthalazinone bradykinin B1 receptor antagonists.

    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

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    authors: Biswas K,Peterkin TA,Bryan MC,Arik L,Lehto SG,Sun H,Hsieh FY,Xu C,Fremeau RT,Allen JR

    更新日期:2011-10-27 00:00:00

  • Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.

    abstract::This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase i...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Mazur M,Olczak J,Olejniczak S,Koralewski R,Czestkowski W,Jedrzejczak A,Golab J,Dzwonek K,Dymek B,Sklepkiewicz PL,Zagozdzon A,Noonan T,Mahboubi K,Conway B,Sheeler R,Beckett P,Hungerford WM,Podjarny A,Mitschler A,Cous

    更新日期:2018-02-08 00:00:00

  • Synthesis and Cytostatic and Antiviral Profiling of Thieno-Fused 7-Deazapurine Ribonucleosides.

    abstract::Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Tichý M,Smoleń S,Tloušt'ová E,Pohl R,Oždian T,Hejtmánková K,Lišková B,Gurská S,Džubák P,Hajdúch M,Hocek M

    更新日期:2017-03-23 00:00:00

  • Derivatives of the triazoloquinazoline adenosine antagonist (CGS15943) are selective for the human A3 receptor subtype.

    abstract::The adenosine antagonist 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) binds to human A3 receptors with high affinity (Ki = 14 nM), while it lacks affinity at rat A3 receptors. Acylated derivatives of the 5-amino group and other modifications were prepared in an effort to provide A3 subtype...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kim YC,Ji XD,Jacobson KA

    更新日期:1996-10-11 00:00:00

  • Selective antiproliferative activity of hydroxynaphthyl-beta-D-xylosides.

    abstract::The antiproliferative activity of the 14 isomeric monoxylosylated dihydroxynaphthalenes has been tested in vitro toward normal HFL-1 and 3T3 A31 cells as well as transformed T24 and 3T3 SV40 cells. The antiproliferative effect toward HFL-1 cells was correlated with the polarity of the compounds. However, in the case o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Jacobsson M,Ellervik U,Belting M,Mani K

    更新日期:2006-03-23 00:00:00

  • Anhydrolide macrolides. 1. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl 11,12-carbamate erythromycin A analogues.

    abstract::A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-s...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Elliott RL,Pireh D,Griesgraber G,Nilius AM,Ewing PJ,Bui MH,Raney PM,Flamm RK,Kim K,Henry RF,Chu DT,Plattner JJ,Or YS

    更新日期:1998-05-07 00:00:00

  • Resolution, absolute stereochemistry, and pharmacology of the S-(+)- and R-(-)-isomers of the apparent partial AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid [(R,S)-APPA].

    abstract::(R,S)-2-Amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid ((R,S)-APPA) is the only partial agonist at the (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors so far described. In light of the pharmacological interest in partial agonists, we have now a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ebert B,Lenz S,Brehm L,Bregnedal P,Hansen JJ,Frederiksen K,Bøgesø KP,Krogsgaard-Larsen P

    更新日期:1994-04-01 00:00:00

  • Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity.

    abstract::We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Marti L,Abella A,De La Cruz X,García-Vicente S,Unzeta M,Carpéné C,Palacín M,Testar X,Orozco M,Zorzano A

    更新日期:2004-09-23 00:00:00

  • Synthesis and biological evaluation of N1-(anthracen-9-ylmethyl)triamines as molecular recognition elements for the polyamine transporter.

    abstract::An efficient modular synthesis of N(1)-substituted triamines containing different tether lengths between nitrogen centers was developed. A series of N(1)-(9-anthracenylmethyl)triamines were evaluated for biological activity in L1210 (murine leukemia), alpha-difluoromethylornithine (DFMO)-treated L1210, Chinese hamster...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Wang C,Delcros JG,Biggerstaff J,Phanstiel O 4th

    更新日期:2003-06-19 00:00:00

  • Synthesis and CLOGP correlation of imidooxy anticonvulsants.

    abstract::Continuing structure-activity studies on the anticonvulsant activity of analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective index (TD50/ED50) of > 4.5 are reported. An in-depth analysis of this moiety was studied employing the Topliss...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Farrar VA,Ciechanowicz-Rutkowska M,Grochowski J,Serda P,Pilati T,Filippini G,Hinko CN,el-Assadi A,Moore JA,Edafiogho IO

    更新日期:1993-11-12 00:00:00

  • Mapping the turkey erythrocyte beta receptor: a distance geometry approach.

    abstract::Extensions and refinements of the receptor mapping method as originally developed by Crippen are presented. In a set of newly developed algorithms measures are taken to reduce the number of required energy parameters to a statistically acceptable degree. The most important measure is the incorporation of lipophilicity...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Linschoten MR,Bultsma T,IJzerman AP,Timmerman H

    更新日期:1986-02-01 00:00:00

  • Discovery and optimization of a novel series of Dyrk1B kinase inhibitors to explore a MEK resistance hypothesis.

    abstract::Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response. ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kettle JG,Ballard P,Bardelle C,Cockerill M,Colclough N,Critchlow SE,Debreczeni J,Fairley G,Fillery S,Graham MA,Goodwin L,Guichard S,Hudson K,Ward RA,Whittaker D

    更新日期:2015-03-26 00:00:00

  • Anticonvulsant activity of some 4-aminobenzamides.

    abstract::A series of 4- aminobenzamides of some simple primary and secondary amines were prepared and evaluated for anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and pentylenetetrazole ( metrazole ) and in the rotorod assay for neurologic deficit. For those N-alkyl amides te...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Clark CR,Wells MJ,Sansom RT,Norris GN,Dockens RC,Ravis WR

    更新日期:1984-06-01 00:00:00

  • Structure-activity relationships of the antimalarial agent artemisinin. 2. Effect of heteroatom substitution at O-11: synthesis and bioassay of N-alkyl-11-aza-9-desmethylartemisinins.

    abstract::A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Avery MA,Bonk JD,Chong WK,Mehrotra S,Miller R,Milhous W,Goins DK,Venkatesan S,Wyandt C,Khan I

    更新日期:1995-12-22 00:00:00

  • Discovery of new inhibitors of Cdc25B dual specificity phosphatases by structure-based virtual screening.

    abstract::Cell division cycle 25 (Cdc25) proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent attractive drug targets for anticancer therapies. To discover more potent and diverse inhibitors of Cdc25 biological activity, virtual screening was performed by docking 2.1 m...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lavecchia A,Di Giovanni C,Pesapane A,Montuori N,Ragno P,Martucci NM,Masullo M,De Vendittis E,Novellino E

    更新日期:2012-05-10 00:00:00

  • Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from alpha-(N)-acyl heteroaromatics.

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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Easmon J,Pürstinger G,Thies KS,Heinisch G,Hofmann J

    更新日期:2006-10-19 00:00:00

  • Synthesis and biological evaluation of 14-alkoxymorphinans. 20. 14-phenylpropoxymetopon: an extremely powerful analgesic.

    abstract::The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors mu, kappa, delta), with 14-phenylpropoxym...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Schütz J,Spetea M,Koch M,Aceto MD,Harris LS,Coop A,Schmidhammer H

    更新日期:2003-09-11 00:00:00

  • Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors.

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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lainchbury M,Matthews TP,McHardy T,Boxall KJ,Walton MI,Eve PD,Hayes A,Valenti MR,de Haven Brandon AK,Box G,Aherne GW,Reader JC,Raynaud FI,Eccles SA,Garrett MD,Collins I

    更新日期:2012-11-26 00:00:00

  • Discovery of coumarin-dihydropyridine hybrids as bone anabolic agents.

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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Sashidhara KV,Kumar M,Khedgikar V,Kushwaha P,Modukuri RK,Kumar A,Gautam J,Singh D,Sridhar B,Trivedi R

    更新日期:2013-01-10 00:00:00

  • Optimization of N-benzoylindazole derivatives as inhibitors of human neutrophil elastase.

    abstract::Human neutrophil elastase (HNE) is an important therapeutic target for treatment of pulmonary diseases. Previously, we identified novel N-benzoylindazole derivatives as potent, competitive, and pseudoirreversible HNE inhibitors. Here, we report further development of these inhibitors with improved potency, protease se...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Crocetti L,Schepetkin IA,Cilibrizzi A,Graziano A,Vergelli C,Giomi D,Khlebnikov AI,Quinn MT,Giovannoni MP

    更新日期:2013-08-08 00:00:00

  • 8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists.

    abstract::This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discove...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Gilligan PJ,He L,Clarke T,Tivitmahaisoon P,Lelas S,Li YW,Heman K,Fitzgerald L,Miller K,Zhang G,Marshall A,Krause C,McElroy J,Ward K,Shen H,Wong H,Grossman S,Nemeth G,Zaczek R,Arneric SP,Hartig P,Robertson DW,T

    更新日期:2009-05-14 00:00:00

  • Synthesis of 1-(2-aminophenyl)isoquinolines and the biological activity of their cis-dichloro platinum(II) complexes.

    abstract::The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)isoquinoline derivatives with different levels of hydrogenation and varying substitution of the phenyl ring is reported. These compou...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: von Nussbaum F,Miller B,Wild S,Hilger CS,Schumann S,Zorbas H,Beck W,Steglich W

    更新日期:1999-09-09 00:00:00

  • Binding of phenylalkylamine derivatives at 5-HT1C and 5-HT2 serotonin receptors: evidence for a lack of selectivity.

    abstract::Certain phenylalkylamine derivatives have been considered to bind selectively at 5-HT2 serotonin receptors. It is now recognized that the most widely used derivatives, i.e., 1-(2,5-dimethoxy-4-X-phenyl)-2-aminopropanes where X = Me (DOM), Br (DOB), and I (DOI) (1-3, respectively) also bind at the more recently identif...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Glennon RA,Raghupathi R,Bartyzel P,Teitler M,Leonhardt S

    更新日期:1992-02-21 00:00:00

  • Design, synthesis, and SAR of potent and selective dipeptide-derived inhibitors for dipeptidyl peptidases.

    abstract::In this paper we report the systematic search for new, potent, and selective DPP II inhibitors. A study of the structure-activity relationship was conducted starting from aminoacyl pyrrolidides as lead compounds. Rational exploration of the P(1) and P(2) building blocks led to the discovery of some very potent DPP II ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Senten K,Van der Veken P,De Meester I,Lambeir AM,Scharpé S,Haemers A,Augustyns K

    更新日期:2003-11-06 00:00:00

  • Sleep-inducing N-alkyl-5-[m-(trifluoromethyl)phenyl]-5-hydroxy-2-pyrrolidinones and N-alkyl-3-(trifluoromethyl)cinnamamides.

    abstract::A series of N-alkyl-3-[m-(trifluoromethyl)phenyl]-5-hydroxy-2-pyrrolidinones and N-alkyl-3-(trifluoromethyl)-cinnamamides were prepared and screened in a series of tests designed to detect potential sleep inducers. The more active members of the series were evaluated for their ability to induce sleep in Cebus monkeys....

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Houlihan WJ,Gogerty JH,Ryan EA,Schmitt G

    更新日期:1985-01-01 00:00:00

  • An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.

    abstract::A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of sat...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Colley HE,Muthana M,Danson SJ,Jackson LV,Brett ML,Harrison J,Coole SF,Mason DP,Jennings LR,Wong M,Tulasi V,Norman D,Lockey PM,Williams L,Dossetter AG,Griffen EJ,Thompson MJ

    更新日期:2015-12-10 00:00:00