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


:6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their K(d) and IC(50) values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.


Bioorg Med Chem


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




Has Abstract


2012-01-01 00:00:00














  • Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure.

    abstract::Novel chemical entities were prepared via Suzuki and S(N) reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6)...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Jagusch C,Negri M,Hille UE,Hu Q,Bartels M,Jahn-Hoffmann K,Pinto-Bazurco Mendieta MA,Rodenwaldt B,Müller-Vieira U,Schmidt D,Lauterbach T,Recanatini M,Cavalli A,Hartmann RW

    更新日期:2008-02-15 00:00:00

  • Synthesis of 1-D- and 1-L-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside establishes substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase.

    abstract::Mycothiol (MSH, 1-D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyranoside) is the principal low molecular weight thiol in actinomycetes. The enzyme 1-D-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase (AcGI deacetylase) is involved in the biosynthesis of MSH and forms the fre...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Nicholas GM,Eckman LL,Kovác P,Otero-Quintero S,Bewley CA

    更新日期:2003-06-12 00:00:00

  • Iromycins from Streptomyces sp. and from synthesis: new inhibitors of the mitochondrial electron transport chain.

    abstract::Two new alpha-pyridone metabolites, iromycins E and F, were isolated from cultures of strain Streptomyces sp. Dra 17, thus expanding the recently discovered iromycin family. The inhibitory potential on the mitochondrial respiratory chain was examined and revealed that iromycin metabolites block NADH oxidation in beef ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Surup F,Shojaei H,von Zezschwitz P,Kunze B,Grond S

    更新日期:2008-02-15 00:00:00

  • Synthesis and human NKT cell stimulating properties of 3-O-sulfo-alpha/beta-galactosylceramides.

    abstract::Two novel hybrid molecules 3-O-sulfo-alpha/beta-galactosylceramide 3 and 4, which are derived from an immunostimulatory agent alpha-GalCer 1 and self-glycolipid ligand sulfatide 2, were designed and synthesized. Compound 3 was shown to efficiently stimulate human NKT cells to secret IL-4 and IFN-gamma, with activities...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Xing GW,Wu D,Poles MA,Horowitz A,Tsuji M,Ho DD,Wong CH

    更新日期:2005-04-15 00:00:00

  • Structure-activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP).

    abstract::Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Pick A,Müller H,Mayer R,Haenisch B,Pajeva IK,Weigt M,Bönisch H,Müller CE,Wiese M

    更新日期:2011-03-15 00:00:00

  • Synthesis and structure-activity relationships of potent 4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors.

    abstract::Dipeptidyl peptidase IV (DPP-IV) inhibitors are promising antidiabetic drugs, and several drugs are in the developmental stage. We previously reported that the introduction of fluorine to the 4-position of 2-cyanopyrrolidine enhanced the DPP-IV inhibitory effect. In the present report, we examined the structure-activi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Fukushima H,Hiratate A,Takahashi M,Mikami A,Saito-Hori M,Munetomo E,Kitano K,Chonan S,Saito H,Suzuki A,Takaoka Y,Yamamoto K

    更新日期:2008-04-01 00:00:00

  • Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity.

    abstract::PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile comp...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Taygerly JP,McGee LR,Rubenstein SM,Houze JB,Cushing TD,Li Y,Motani A,Chen JL,Frankmoelle W,Ye G,Learned MR,Jaen J,Miao S,Timmermans PB,Thoolen M,Kearney P,Flygare J,Beckmann H,Weiszmann J,Lindstrom M,Walker N,Li

    更新日期:2013-02-15 00:00:00

  • A prenylbisabolane with NF-kappaB inhibiting properties from Cascarilla (Croton eluteria).

    abstract::Investigation of the bark of Croton eluteria Bennett for biologically active compounds has led to the isolation of the new prenylbisabolane 3, whose structure was assessed by spectroscopic methods. The corresponding known enone 4 and the eudesmane sesquiterpene 2 were also obtained. Compound 3 proved active in selecti...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Campagnuolo C,Fattorusso E,Petrucci F,Taglialatela-Scafati O,Appendino G,Marquez N,Muñoz E

    更新日期:2005-07-01 00:00:00

  • Synthesis and biological evaluation of 1,4-dihydropyridine calcium channel modulators having a diazen-1-ium-1,2-diolate nitric oxide donor moiety for the potential treatment of congestive heart failure.

    abstract::A group of racemic 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-nitropyridines possessing nitric oxide donor O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino, or 4-ethylpiperazin-1-yl)diazen-1-ium-1,2-diolate, C-5 ester substituents were synthesized by coupling the respective 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Velázquez C,Knaus EE

    更新日期:2004-07-15 00:00:00

  • Synthesis and biological evaluation of indazolo[4,3-bc][1,5]naphthyridines (10-aza-pyrazolo[3,4,5-kl]acridines): a new class of antitumor agents.

    abstract::A series of potential DNA-binding antitumor agents, 2-[omega-(alkylamino)alkyl]-9-methoxy-5-nitro-2,6-dihydroindazolo[4,3-bc][1,5]naphthyridines (2a-f), 10-aza derivatives of PZA, has been prepared by condensation of 9-chloro-2-methoxy-6-nitro-5,10-dihydrobenzo[b][1,5]naphthyridin-10-one (6) with the appropriate (omeg...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Magnano A,Sparapani S,Lucciarini R,Michela M,Amantini C,Santoni G,Antonini I

    更新日期:2004-11-15 00:00:00

  • Progress towards drug discovery for Friedreich's Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein.

    abstract::Friedreich's Ataxia (FRDA) is an incurable genetic disease caused by an expanded trinucleotide AAG repeat within intronic RNA of the frataxin (FXN) gene. We have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded repeat can activate expression of FXN...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Shen X,Wong J,Prakash TP,Rigo F,Li Y,Napierala M,Corey DR

    更新日期:2020-06-01 00:00:00

  • Biocatalytic combinatorial synthesis.

    abstract::Combinatorial biocatalysis, based on a principle of the combinatorial use of biosynthetic steps rather than the combinatorial use of reagents, offers a complementary approach to combinatorial chemistry, which, used individually or in connection with synthetic organic transformations, provides access to analogues not r...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Krstenansky JL,Khmelnitsky Y

    更新日期:1999-10-01 00:00:00

  • Fragment based drug design and diversity-oriented synthesis of carboxylic acid isosteres.

    abstract::The medicinal chemist toolbox is plenty of (bio)isosteres when looking for a carboxylic acid replacement. However, systematic assessment of acid surrogates is often time consuming and expensive, while prediction of both physicochemical properties (logP and logD) as well as acidity would be desirable at early discovery...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ferri M,Alunno M,Greco FA,Mammoli A,Saluti G,Carotti A,Sardella R,Macchiarulo A,Camaioni E,Liscio P

    更新日期:2020-08-28 00:00:00

  • Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase.

    abstract::A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium falciparum. Brequinar was essentially inactive against PfDHODH (IC(50) 880 microM) w...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Boa AN,Canavan SP,Hirst PR,Ramsey C,Stead AM,McConkey GA

    更新日期:2005-03-15 00:00:00

  • Novel synthetic 2-amino-10-(3,5-dimethoxy)benzyl-9(10H)-acridinone derivatives as potent DNA-binding antiproliferative agents.

    abstract::A series of novel 9(10H)-acridinone derivatives with terminal amino substituents at C2 position on the acridinone ring were synthesized and studied for their antiproliferative activity and underlying mechanisms. These compounds demonstrated promising cytotoxicity to leukemia cells CCRF-CEM, displaying IC(50) values in...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Gao C,Liu F,Luan X,Tan C,Liu H,Xie Y,Jin Y,Jiang Y

    更新日期:2010-11-01 00:00:00

  • Synthesis and biological activity of N(4)-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents.

    abstract::A series of eight N(4)-phenylsubstituted-6-(2,4-dichlorophenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines 8-15 were synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with varied substitutions in the phenyl ring of the 4-anilino moiety. In addition, five N(4)-phenylsubstituted-6-phe...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Gangjee A,Kurup S,Ihnat MA,Thorpe JE,Shenoy SS

    更新日期:2010-05-15 00:00:00

  • Carbonic anhydrase inhibitors: Synthesis, molecular docking, cytotoxic and inhibition of the human carbonic anhydrase isoforms I, II, IX, XII with novel benzenesulfonamides incorporating pyrrole, pyrrolopyrimidine and fused pyrrolopyrimidine moieties.

    abstract::A series of novel pyrroles, pyrrolopyrimidines, pyrazolopyrrolopyrimidine, triazolopyrrolopyrimidines, tetrazolopyrrolopyrimidine, triazinopyrrolopyrimidines and pyrrolopyrimidotriazepines bearing the biologically active benzenesulfonamide moiety were synthesized by using pyrrole-o-amino-carbonitrile as key intermedia...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ghorab MM,Alsaid MS,Ceruso M,Nissan YM,Supuran CT

    更新日期:2014-07-15 00:00:00

  • Design, synthesis and biological activity of 3-pyrazine-2-yl-oxazolidin-2-ones as novel, potent and selective inhibitors of mutant isocitrate dehydrogenase 1.

    abstract::Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) generating carbon dioxide and NADPH/NADH. Evidence suggests that the specific mutations in IDH1 are critical to the growth and reproduction of some tumor cells such as gliomas and acute myeloid leukemia,...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ma T,Zou F,Pusch S,Yang L,Zhu Q,Xu Y,Gu Y,von Deimling A,Zha X

    更新日期:2017-12-15 00:00:00

  • The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells.

    abstract::Alternative splicing of the androgen receptor (AR) is frequently observed in castration resistant prostate cancer (CRPC). One AR isoform, the AR-V7 splice variant, is a constitutively active transcription factor which lacks a ligand binding domain and is therefore undruggable. AR-V7 expression correlates with resistan...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Melnyk JE,Steri V,Nguyen HG,Hann B,Feng FY,Shokat KM

    更新日期:2020-10-15 00:00:00

  • Andrographolide derivative as STAT3 inhibitor that protects acute liver damage in mice.

    abstract::Sustained activation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway contributed to the progression of cancer and liver diseases. STAT3 signaling inhibitor has been extensively investigated for pharmacological use. We synthesized a series of andrographolide derivatives, and ch...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Chen SR,Li F,Ding MY,Wang D,Zhao Q,Wang Y,Zhou GC,Wang Y

    更新日期:2018-10-01 00:00:00

  • Purinergic receptor P2X₇: a novel target for anti-inflammatory therapy.

    abstract::Purinergic receptors, also known as purinoceptors, are ligand gated membrane ion channels involved in many cellular functions. Among all identified purinergic receptors, P2X₇ subform is unique since it induces the caspase activity, cytokine secretion, and apoptosis. The distribution of P2X₇ receptors, and the need of ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Mehta N,Kaur M,Singh M,Chand S,Vyas B,Silakari P,Bahia MS,Silakari O

    更新日期:2014-01-01 00:00:00

  • Inhibitory activity of a ceramide library on interleukin-4 production from activated T cells.

    abstract::Allergic diseases are hypersensitivity disorders associated with the production of specific immunoglobulin E (IgE) to environmental allergens. Interleukin (IL)-4, produced primarily by CD4(+) T cells, is an important stimulus for the switch of the antibody isotype to IgE in both mice and humans. In this study we inves...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Park J,Li Q,Chang YT,Kim TS

    更新日期:2005-04-01 00:00:00

  • Triterpenoids from Momordica balsamina: Reversal of ABCB1-mediated multidrug resistance.

    abstract::The ability as P-glycoprotein (P-gp, ABCB1) modulators of thirty (1-30) triterpenoids of the cucurbitane-type was evaluated on human L5178 mouse T-lymphoma cell line transfected with the human MDR1 gene, through the rhodamine-123 exclusion assay. Compounds (1-26, and 29, 30) were previously obtained from the African m...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ramalhete C,Mulhovo S,Molnar J,Ferreira MU

    更新日期:2016-11-01 00:00:00

  • The search for potent, small molecule NNRTIs: A review.

    abstract::AIDS has become the leading pandemic disease, and is the cause of death worldwide. Presently, HAART treatment, a combination of reverse transcriptase (RT) and protease inhibitors is also unsuccessful due to the virus getting resistant to the drugs because of mutational changes. Two types of RT inhibitors exist namely ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Prajapati DG,Ramajayam R,Yadav MR,Giridhar R

    更新日期:2009-08-15 00:00:00

  • Synthesis and Pin1 inhibitory activity of thiazole derivatives.

    abstract::Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis-trans isomerase (PPIase) which specifically catalyze the conformational conversion of the amide bond of pSer/Thr-Pro motifs in its substrate proteins and is a novel promising anticancer target. A series of new thiazole derivatives were designed and synthes...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhao H,Cui G,Jin J,Chen X,Xu B

    更新日期:2016-11-15 00:00:00

  • Synthesis and C-11 labeling of three potent norepinephrine transporter selective ligands ((R)-nisoxetine, lortalamine, and oxaprotiline) for comparative PET studies in baboons.

    abstract::Three potent antidepressants, (R)-nisoxetine, lortalamine, and oxaprotiline, with high affinity and high selectivity for the norepinephrine transporter (NET) were synthesized and radiolabeled with C-11 via [11C]methylation. The reference compounds and their corresponding normethyl precursors were synthesized via multi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lin KS,Ding YS

    更新日期:2005-08-01 00:00:00

  • Acetyl analogs of combretastatin A-4: synthesis and biological studies.

    abstract::The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Babu B,Lee M,Lee L,Strobel R,Brockway O,Nickols A,Sjoholm R,Tzou S,Chavda S,Desta D,Fraley G,Siegfried A,Pennington W,Hartley RM,Westbrook C,Mooberry SL,Kiakos K,Hartley JA,Lee M

    更新日期:2011-04-01 00:00:00

  • Use of enzyme penicillin acylase in selective amidation/amide hydrolysis to resolve ethyl 3-amino-4-pentynoate isomers.

    abstract::The beta-amino acid, (S)-ethyl-3-amino-4-pentynoate, is a chiral synthon used in the synthesis of xemilofiban hydrochloride, an anti-platelet agent. A biocatalytic approach was developed to resolve (R)- and (S)-enantiomers of ethyl 3-amino-4-pentynoate in enantiomerically pure form employing the enzyme Penicillin acyl...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Topgi RS,Ng JS,Landis B,Wang P,Behling JR

    更新日期:1999-10-01 00:00:00

  • Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation.

    abstract::Amyloid-β (Aβ) and tau protein are two crucial hallmarks in Alzheimer's disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aβ and tau aggregation. I...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lv P,Xia CL,Wang N,Liu ZQ,Huang ZS,Huang SL

    更新日期:2018-09-01 00:00:00

  • Toward protein-cleaving catalytic drugs: artificial protease selective for myoglobin.

    abstract::A protein-cleaving catalyst highly selective for a disease-related protein can be used as a catalytic drug. As the first protein-cleaving catalyst selective for a protein substrate, a catalyst for myoglobin (Mb) was designed by attaching the Cu(II) or Co(III) complex of cyclen to a binding site searched by a combinato...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Jeon JW,Son SJ,Yoo CE,Hong IS,Suh J

    更新日期:2003-07-03 00:00:00