Synthesis of hydrolysis-resistant pyridoxal 5'-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin.


:A set of phosphonic acid derivatives (1-4) of pyridoxal 5'-phosphate (PLP) was synthesized and characterized biochemically using purified murine pyridoxal phosphatase (PDXP), also known as chronophin. The most promising compound 1 displayed primarily competitive PDXP inhibitory activity with an IC50 value of 79μM, which was in the range of the Km of the physiological substrate PLP. We also report the X-ray crystal structure of PDXP bound to compound 3, which we solved to 2.75Å resolution (PDB code 5AES). The co-crystal structure proves that compound 3 binds in the same orientation as PLP, and confirms the mode of inhibition to be competitive. Thus, we identify compound 1 as a PDXP phosphatase inhibitor. Our results suggest a strategy to design new, potent and selective PDXP inhibitors, which may be useful to increase the sensitivity of tumor cells to treatment with cytotoxic agents.


Bioorg Med Chem


Knobloch G,Jabari N,Stadlbauer S,Schindelin H,Köhn M,Gohla A




Has Abstract


2015-06-15 00:00:00














  • Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S' subsite binding.

    abstract::A series of mechanism-based inhibitors designed to interact with the S' subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was investigated. The compounds were found to be time-dependent inhibito...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Li Y,Dou D,He G,Lushington GH,Groutas WC

    更新日期:2009-05-15 00:00:00

  • Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies.

    abstract::In the light of known HDAC inhibitors, 33 carboxylic acid derivatives were tested to understand the structural requirements for HDAC inhibition activity. Several modifications were applied to develop the structure-activity relationships of carboxylic acid HDAC inhibitors. HDAC inhibition activities were investigated i...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Bora-Tatar G,Dayangaç-Erden D,Demir AS,Dalkara S,Yelekçi K,Erdem-Yurter H

    更新日期:2009-07-15 00:00:00

  • Optimization and bioevaluation of Cdc37-derived peptides: An insight into Hsp90-Cdc37 protein-protein interaction modulators.

    abstract::Targeting Hsp90-Cdc37 protein-protein interaction (PPI) is becoming an alternative approach for future anti-cancer drug development. We previously reported the discovery of an eleven-residue peptide (Pep-1) with micromolar activity for the disruption of Hsp90-Cdc37 PPI. Efforts to improve upon the Pep-1 led to the dis...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Wang L,Li L,Fu WT,Jiang ZY,You QD,Xu XL

    更新日期:2017-01-01 00:00:00

  • Synthesis and investigation of inhibition effects of new carbonic anhydrase inhibitors.

    abstract::Three new derivatives of 2-substituted 1,3,4-thiadiazole-5-sulfonamide have been synthesized. These compounds are 2-(3-chloropropionylamino)-1,3,4-thiadiazole-5-sulfonamide (1); 2-(2,2-dichloroacetylamino)-1,3,4-thiadiazole-5-sulfonamide (2); and 2-(3-phenylpropionylamino)-1,3,4-thiadiazole-5-sulfonamide (3). Inhibiti...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Arslan O,Küfrevioĝlu OI,Nalbantoĝlu B

    更新日期:1997-03-01 00:00:00

  • Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway.

    abstract::The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-metha...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cheng H,Chong Y,Hwang I,Tavassoli A,Zhang Y,Wilson IA,Benkovic SJ,Boger DL

    更新日期:2005-05-16 00:00:00

  • Benzodiazepine peptidomimetic inhibitors of farnesyltransferase.

    abstract::A structural survey of protein Zn2+ binding geometries was instigated based upon the functional requirement of Ras farnesyltransferase for Zn2+. The Cys-X-X-Cys motif found in Zn(2+)-binding proteins such as aspartate transcarbamylase was used as a template to devise a bidentate-coordination model for Cys-A1-A2-X pept...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Marsters JC Jr,McDowell RS,Reynolds ME,Oare DA,Somers TC,Stanley MS,Rawson TE,Struble ME,Burdick DJ,Chan KS

    更新日期:1994-09-01 00:00:00

  • Synthetic strategies toward carbocyclic purine-pyrimidine hybrid nucleosides.

    abstract::The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid nucleosides can be viewed as either N-3 ribosylated purines or 5,6-disubstituted pyrimidines, thus recognition by both purine- and pyrimidine-metabol...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sadler JM,Mosley SL,Dorgan KM,Zhou ZS,Seley-Radtke KL

    更新日期:2009-08-01 00:00:00

  • Synthesis of a fluorine-18-labelled derivative of 6-nitroquipazine, as a radioligand for the in vivo serotonin transporter imaging with PET.

    abstract::Considerable efforts have been engaged in the design, synthesis and pharmacological characterization of radioligands for imaging the serotonin transporter, based on its implication in several neuropsychiatric diseases, such as depression, anxiety and schizophrenia. In the 5-halo-6-nitroquipazine series, the fluoro der...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Karramkam M,Dollé F,Valette H,Besret L,Bramoullé Y,Hinnen F,Vaufrey F,Franklin C,Bourg S,Coulon C,Ottaviani M,Delaforge M,Loc'h C,Bottlaender M,Crouzel C

    更新日期:2002-08-01 00:00:00

  • An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates.

    abstract::The physiology of the oxytocin receptor has increasingly become a focus of scientific investigation due to its connection with social behavior and psychiatric disorders with impairments in social funciton. Experimental utilization of small molecule and peptide antagonists for the oxytocin receptor has played a role in...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Smith AL,Walum H,Connor-Stroud F,Freeman SM,Inoue K,Parr LA,Goodman MM,Young LJ

    更新日期:2017-01-01 00:00:00

  • Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate.

    abstract::Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Poreddy AR,Neumann WL,Freskos JN,Rajagopalan R,Asmelash B,Gaston KR,Fitch RM,Galen KP,Shieh JJ,Dorshow RB

    更新日期:2012-04-15 00:00:00

  • Biochemical and transcriptional profiling to triage additional activities in a series of IGF-1R/IR inhibitors.

    abstract::Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a l...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ross-Macdonald P,de Silva H,Patel V,Truong A,He A,Neuhaus I,Tilford C,Ji R,Siemers N,Greer A,Carboni J,Gottardis M,Menard K,Lee F,Dodier M,Frennesson D,Sampognaro A,Saulnier M,Trainor G,Vyas D,Zimmermann K,Wittm

    更新日期:2012-03-15 00:00:00

  • X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease.

    abstract::The crystal structure of ABT-378 (lopinavir), bound to the active site of HIV-1 protease is described. A comparison with crystal structures of ritonavir, A-78791, and BILA-2450 shows some analogous features with previous reported compounds. A cyclic urea unit in the P(2) position of ABT-378 is novel and makes two bide...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Stoll V,Qin W,Stewart KD,Jakob C,Park C,Walter K,Simmer RL,Helfrich R,Bussiere D,Kao J,Kempf D,Sham HL,Norbeck DW

    更新日期:2002-08-01 00:00:00

  • New mimics of the acetate function in pheromone-based attraction.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hoskovec M,Hovorka O,Kalinová B,Koutek B,Streinz L,Svatos A,Sebek P,Saman D,Vrkoc J

    更新日期:1996-03-01 00:00:00

  • A strategic approach to the synthesis of ferrocene appended chalcone linked triazole allied organosilatranes: Antibacterial, antifungal, antiparasitic and antioxidant studies.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Singh G,Arora A,Kalra P,Maurya IK,Ruizc CE,Estebanc MA,Sinha S,Goyal K,Sehgal R

    更新日期:2019-01-01 00:00:00

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhang C,Zink DL,Ushio M,Burgess B,Onishi R,Masurekar P,Barrett JF,Singh SB

    更新日期:2008-10-01 00:00:00

  • γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: a study of their activity as glycosidase inhibitors and as immunosuppressive agents.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Markad PR,Sonawane DP,Ghosh S,Chopade BA,Kumbhar N,Louat T,Herman J,Waer M,Herdewijn P,Dhavale DD

    更新日期:2014-11-01 00:00:00

  • Substituted indolin-2-ones as p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors: Molecular docking simulation and structure-activity relationship analysis.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhong Y,Xue M,Zhao X,Yuan J,Liu X,Huang J,Zhao Z,Li H,Xu Y

    更新日期:2013-04-01 00:00:00

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    abstract::Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11-14 and 3-substituted 2,6-dioxopiperidines 16 and 18 were synthesized as tumor necrosis factor-α (TNF-α) synthesis inhibitors. Synthesis involved utilization of a novel conde...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Luo W,Yu QS,Salcedo I,Holloway HW,Lahiri DK,Brossi A,Tweedie D,Greig NH

    更新日期:2011-07-01 00:00:00

  • Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Shi G,Shaw G,Liang YH,Subburaman P,Li Y,Wu Y,Yan H,Ji X

    更新日期:2012-01-01 00:00:00

  • A new metabotropic glutamate receptor agonist with in vivo anti-allodynic activity.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Stanley NJ,Hutchinson MR,Kvist T,Nielsen B,Mathiesen JM,Bräuner-Osborne H,Avery TD,Tiekink ER,Pedersen DS,Irvine RJ,Abell AD,Taylor DK

    更新日期:2010-08-15 00:00:00

  • 3'-Hydroxy-3,4'-dimethoxyflavone blocks tubulin polymerization and is a potent apoptotic inducer in human SK-MEL-1 melanoma cells.

    abstract::Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. A series of flavonols and their 3-methyl ether derivatives were synthesized and assessed for cytotoxicity. It was found that 3'-hydroxy-3,4'-dimethoxyflavone (flavonoid 7a) displayed strong cytotoxicity agains...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Estévez-Sarmiento F,Said M,Brouard I,León F,García C,Quintana J,Estévez F

    更新日期:2017-11-01 00:00:00

  • Design, synthesis and preliminary biological evaluation of indoline-2,3-dione derivatives as novel HDAC inhibitors.

    abstract::Histone deacetylases (HDACs) are zinc-dependent or NAD(+) dependent enzymes and play a critical role in the process of tumor development. Herein a series of indoline-2,3-dione derivatives have been designed and synthesized as potential HDACs inhibitors. The preliminary biological evaluation showed that most compounds ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Jin K,Li S,Li X,Zhang J,Xu W,Li X

    更新日期:2015-08-01 00:00:00

  • Design, synthesis and biological evaluation of aryl-substituted sialyl Lewis X mimetics prepared via cross-metathesis of C-fucopeptides.

    abstract::Several aryl substituted C-fucopeptides have been developed as sialyl Lewis X mimetics. Although the compounds have a much simpler structure compared to SLe(x), up to 3-times higher binding affinity toward E-selectin and > 1000 times toward P-selectin was observed. Furthermore, a convenient strategy for generating a n...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Huwe CM,Woltering TJ,Jiricek J,Weitz-Schmidt G,Wong CH

    更新日期:1999-05-01 00:00:00

  • A trans-platinum(II) complex induces apoptosis in cancer stem cells of breast cancer.

    abstract::Recent accumulating evidence has supported the notion that tumors have hierarchically organized heterogeneous cell populations and a small subpopulation of cells, termed cancer stem cells (CSCs), are responsible for tumor initiation, maintenance as well as drug resistance. Therefore, targeting the CSCs along with the ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Aztopal N,Karakas D,Cevatemre B,Ari F,Icsel C,Daidone MG,Ulukaya E

    更新日期:2017-01-01 00:00:00

  • 3-Phenylalkyl-2H-chromenes and -chromans as novel rhinovirus infection inhibitors.

    abstract::Following our studies on structure-activity relationships of anti-rhinovirus chromene and chroman derivatives, we designed and synthesized new series of 3-phenylalkyl-2H-chromenes and -chromans bearing differently sized, aliphatic linker chains between the two cycles. The cytotoxicity and the antiviral activity of the...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Conti C,Proietti Monaco L,Desideri N

    更新日期:2017-04-01 00:00:00

  • Synthesis and antitumor activity of 20-O-linked nitrogen-based camptothecin ester derivatives.

    abstract::A series of nitrogen-based 20S-hydroxyl camptothecin ester derivatives were prepared. 3-Aminopropionate of camptothecin was found more cytotoxic in vitro on several human tumor cell lines than 3-amidopropionate of camptothecin. Ester 16 showed best antitumor activity in vivo and in vitro in all esters we prepared. ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Wang CY,Pan XD,Liu HY,Fu ZD,Wei XY,Yang LX

    更新日期:2004-07-01 00:00:00

  • 2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion.

    abstract::A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyraz...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sayer JR,Walldén K,Pesnot T,Campbell F,Gane PJ,Simone M,Koss H,Buelens F,Boyle TP,Selwood DL,Waksman G,Tabor AB

    更新日期:2014-11-15 00:00:00

  • 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives as a new class of potent inhibitors of Interleukin-8-induced neutrophil chemotaxis.

    abstract::A series of 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives was synthesized. The compounds demonstrated to be novel, potent and selective inhibitors of Interleukin-8-induced human neutrophil chemotaxis. A SAR study was performed by varying the carbonyl function at position 5 and...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cesarini S,Spallarossa A,Ranise A,Bruno O,Arduino N,Bertolotto M,Dallegri F,Tognolini M,Gobbetti T,Barocelli E

    更新日期:2009-05-15 00:00:00

  • Beta-hairpin and beta-sheet formation in designed linear peptides.

    abstract::Recent knowledge about the determinants of beta-sheet formation and stability has notably been improved by the structural analysis of model peptides with beta-hairpin structure in aqueous solution. Several experimental studies have shown that the turn region residues can not only determine the stability, but also the ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ramírez-Alvarado M,Kortemme T,Blanco FJ,Serrano L

    更新日期:1999-01-01 00:00:00

  • Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid

    abstract::Here we report the new drug design and synthesis of a series of 6,14-endoethenomorphinan-7-carboxamide derivatives as a putative epsilon opioid receptor agonist. One of these compounds, 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821), ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Fujii H,Narita M,Mizoguchi H,Murachi M,Tanaka T,Kawai K,Tseng LF,Nagase H

    更新日期:2004-08-01 00:00:00