当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Studies of pyrrolo[1,2-alpha]benzimidazolequinone DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation.

Studies of pyrrolo[1,2-alpha]benzimidazolequinone DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation.

Abstract：

:The influence of structure on DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation was studied for the 6-aziridinylpyrrolo[1,2-alpha]benzimidazolequinones (PBIs) and the 6-acetamidopyrrolo[1,2-alpha]benzimidazolequinones (APBIs). The PBIs are reductively activated by DT-diaphorase and alkylate the phosphate backbone of DNA via major groove interactions, while the APBIs are reductively inactivated by this enzyme since only the quinone form inhibits topoisomerase II. Bulk at the 7-position (butyl instead of methyl) significantly decreases k(cat)/K(m) for DT-diaphorase reductase activity for both PBIs and APBIs. As a result, a 7-butyl PBI has little cytotoxicity while the 7-butyl APBI has enhanced cytotoxicity. The type of 3-substituent and the configuration of the 3-position of the PBIs and APBIs influence DT-diaphorase substrate activity to a lesser degree. Bulk at the 7-position (butyl instead of methyl) had an adverse effect on APBI inhibition of topoisomerase II while the configuration of the 3-position had either an adverse or positive effect on inhibition of this enzyme. The configuration of the 3-position, when substituted with a hydrogen bond donor, influences the PBI reductive alkylation of DNA homopolymers. The rationale for this observation is that the R or S stereoisomers will determine if the 3-substituent points in the 3' or 5' direction and thereby influence the hydrogen-bonding interactions. The above findings were used to rationalize the relative cytotoxicity of various PBI and APBI derivatives.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Skibo EB,Gordon S,Bess L,Boruah R,Heileman MJ

doi

10.1021/jm960546p

subject

Has Abstract

pub_date

1997-04-25 00:00:00

pages

1327-39

issue

9

eissn

0022-2623

issn

1520-4804

pii

jm960546p

journal_volume

40

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Diamidine compounds for selective inhibition of protein arginine methyltransferase 1.

    abstract：:Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) has been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targe...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm401884z

    authors： Yan L,Yan C,Qian K,Su H,Kofsky-Wofford SA,Lee WC,Zhao X,Ho MC,Ivanov I,Zheng YG

    更新日期：2014-03-27 00:00:00

  • Cell-based medicinal chemistry optimization of high-throughput screening (HTS) hits for orally active antimalarials. Part 1: challenges in potency and absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK).

    abstract：:Malaria represents a significant health issue, and novel and effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. Antimalarial drug discovery has historically benefited from a whole-cell (phenotypic) screening approach to identify lead molecules. This approach has bee...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/jm400314m

    authors： Chatterjee AK

    更新日期：2013-10-24 00:00:00

  • Optimized method of G-protein-coupled receptor homology modeling: its application to the discovery of novel CXCR7 ligands.

    abstract：:Homology modeling of G-protein-coupled seven-transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand-binding pocket of GPCRs. We have developed an optimize...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm400307y

    authors： Yoshikawa Y,Oishi S,Kubo T,Tanahara N,Fujii N,Furuya T

    更新日期：2013-06-13 00:00:00

  • Preparation and analgesic activity of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines.

    abstract：:Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good l...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00160a022

    authors： Cittern PA,Kapoor VK,Parfitt RT

    更新日期：1986-10-01 00:00:00

  • Thiocamptothecin.

    abstract：:The synthesis and the X-ray structure of 16a-thiocamptothecin (TCPT), the thiopyridone analog of camptothecin (CPT), are accomplished. The crystal contains two structurally identical, yet independent molecules. Both of them are connected to other molecules via two intermolecular hydrogen bonds. S-methylation of TCPT l...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm8001982

    authors： Samorì C,Guerrini A,Varchi G,Zunino F,Beretta GL,Femoni C,Bombardelli E,Fontana G,Battaglia A

    更新日期：2008-05-22 00:00:00

  • Renin inhibitors. Substitution of the leucyl residues of Leu-Leu-Val-Phe-OCH3 with 3-amino-2-hydroxy-5-methylhexanoic acid.

    abstract：:The 2S,3S and 2R,3S diastereoisomers of the hydroxy amino acid 3-amino-2-hydroxy-5-methylhexanoic acid (AHMHA) were synthesized and substituted for the leucyl residues of Leu-Leu-Val-Phe-OCH3 to yield the following analogues: AHMHA-Leu-Val-Phe-OCH3, AHMHA-Val-Phe-OCH3, and Leu-AHMHA-Val-Phe-OCH3. These analogues were ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00347a024

    authors： Johnson RL

    更新日期：1982-05-01 00:00:00

  • Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic.

    abstract：:The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substan...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm960281e

    authors： Hirschmann R,Yao W,Cascieri MA,Strader CD,Maechler L,Cichy-Knight MA,Hynes J Jr,van Rijn RD,Sprengeler PA,Smith AB 3rd

    更新日期：1996-06-21 00:00:00

  • New neplanocin analogues. 1. Synthesis of 6'-modified neplanocin A derivatives as broad-spectrum antiviral agents.

    abstract：:Novel neplanocin A analogues modified at the 6'-position, i.e., 6'-deoxy analogues (2, 3, 6, 9, 20), 6'-O-methylneplanocin A (15), and 6'-C-methylneplanocin A's (22a and 22b) have been synthesized and evaluated for their antiviral activity in a wide variety of DNA and RNA virus systems. These compounds showed an activ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00080a018

    authors： Shuto S,Obara T,Toriya M,Hosoya M,Snoeck R,Andrei G,Balzarini J,De Clercq E

    更新日期：1992-01-24 00:00:00

  • Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans.

    abstract：:The structure of fenoterol, a beta2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor beta2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained beta2-agonistic activity at micromo...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0704595

    authors： Buonsanti MF,Bertinaria M,Stilo AD,Cena C,Fruttero R,Gasco A

    更新日期：2007-10-04 00:00:00

  • Structure-based design of bacterial nitric oxide synthase inhibitors.

    abstract：:Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge becaus...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501723p

    authors： Holden JK,Kang S,Hollingsworth SA,Li H,Lim N,Chen S,Huang H,Xue F,Tang W,Silverman RB,Poulos TL

    更新日期：2015-01-22 00:00:00

  • Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.

    abstract：:Multifunctional ligands with agonist bioactivities at μ/δ opioid receptors (MOR/DOR) and antagonist bioactivity at the neurokinin-1 receptor (NK1R) have been designed and synthesized. These peptide-based ligands are anticipated to produce better biological profiles (e.g., higher analgesic effect with significantly les...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b01170

    authors： Giri AK,Apostol CR,Wang Y,Forte BL,Largent-Milnes TM,Davis P,Rankin D,Molnar G,Olson KM,Porreca F,Vanderah TW,Hruby VJ

    更新日期：2015-11-12 00:00:00

  • Antitumor agents. 123. Synthesis and human DNA topoisomerase II inhibitory activity of 2'-chloro derivatives of etoposide and 4 beta-(arylamino)-4'-O-demethylpodophyllotoxins.

    abstract：:The 2'-chloro derivatives of etoposide and 4 beta-(arylamino)-4'-O-demethylpodophyllotoxins have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results showed that none of the compoun...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00083a009

    authors： Hu H,Wang ZQ,Liu SY,Cheng YC,Lee KH

    更新日期：1992-03-06 00:00:00

  • Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring alpha,alpha-disubstituted amino acids.

    abstract：:In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a-3d and 4a-4d were synthesized utilizing alpha, alpha-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the phi3 and psi3 torsion angles. Constrained conformations were verified by t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980656r

    authors： Evans MC,Pradhan A,Venkatraman S,Ojala WH,Gleason WB,Mishra RK,Johnson RL

    更新日期：1999-04-22 00:00:00

  • Target specific virtual screening: optimization of an estrogen receptor screening platform.

    abstract：:In this work, we introduce a four-step scoring and filtering procedure, furnishing target specific virtual screening (TS-VS), which serves to minimize false positives resulting from conformational artifacts of the docking process and is optimized to converge on novel chemotypes of estrogen receptor alpha (ERalpha). As...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0700262

    authors： Knox AJ,Meegan MJ,Sobolev V,Frost D,Zisterer DM,Williams DC,Lloyd DG

    更新日期：2007-11-01 00:00:00

  • Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha, 25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation.

    abstract：:Four new hybrid analogues of 1alpha,25-dihydroxyvitamin D3 (1) have been synthesized in a convergent manner by joining A-ring and C, D-ring fragments. Each hybrid analogue, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and in...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980031t

    authors： Posner GH,Lee JK,Wang Q,Peleg S,Burke M,Brem H,Dolan P,Kensler TW

    更新日期：1998-07-30 00:00:00

  • Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2.

    abstract：:Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two diffe...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00461

    authors： Iwatani-Yoshihara M,Ito M,Klein MG,Yamamoto T,Yonemori K,Tanaka T,Miwa M,Morishita D,Endo S,Tjhen R,Qin L,Nakanishi A,Maezaki H,Kawamoto T

    更新日期：2017-07-13 00:00:00

  • Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds.

    abstract：:Cyclin-dependent kinases (cdk) have recently raised considerable interest in view of their essential role in the regulation of the cell division cycle. The structure-activity relationships of cdk inhibition showed that the 1, 3; and 7 positions of the purine ring must remain free, probably for a direct interaction, in...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm960666x

    authors： Havlícek L,Hanus J,Veselý J,Leclerc S,Meijer L,Shaw G,Strnad M

    更新日期：1997-02-14 00:00:00

  • Simultaneous measurement of nineteen binding constants of peptides to vancomycin using affinity capillary electrophoresis-mass spectrometry.

    abstract：:On-line affinity capillary electrophoresis-electrospray ionization-mass spectrometry (ACE-MS) was used for the simultaneous measurement of multiple binding constants of an all-D-tetrapeptide library to the model receptor, vancomycin. Determination of Kd values for the 19 peptides of the form Fmoc-DXYA is demonstrated....

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm970578s

    authors： Dunayevskiy YM,Lyubarskaya YV,Chu YH,Vouros P,Karger BL

    更新日期：1998-03-26 00:00:00

  • Tyrosine Kinase 2 (TYK2) Allosteric Inhibitors To Treat Autoimmune Diseases.

    abstract：:TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homologue 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-meth...

    journal_title：Journal of medicinal chemistry

    pub_type： 评论,杂志文章

    doi：10.1021/acs.jmedchem.9b01612

    authors： Chang Y,Xu S,Ding K

    更新日期：2019-10-24 00:00:00

  • Discovery of 5-substituted-6-chlorouracils as efficient inhibitors of human thymidine phosphorylase.

    abstract：:Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm070644i

    authors： Nencka R,Votruba I,Hrebabecký H,Jansa P,Tloust'ová E,Horská K,Masojídková M,Holý A

    更新日期：2007-11-29 00:00:00

  • Phenylalanyl transfer ribonucleic acid synthetase from Escherichia coli B. Potent inhibition by analogues of N-benzyl-2-phenylethylamine.

    abstract：:A potent new class of inhibitors of phenylalanyl-tRNA synthetase from Escherichia coli B is described. N-Benzyl-2-phenylethylamine is a competitive inhibitor with respect to L-phenylalanine and appears to possess the structural features required for near-optimal binding. Hydrophobic substituents at the ortho position ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00233a002

    authors： Anderson RT Jr,Santi DV

    更新日期：1976-11-01 00:00:00

  • Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection.

    abstract：:Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as report...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b01249

    authors： Ren J,Zhao Y,Fry EE,Stuart DI

    更新日期：2018-02-08 00:00:00

  • Synthesis of 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-5-benzyluracil and its amino analogue, new potent uridine phosphorylase inhibitors with high water solubility.

    abstract：:Acyclic nucleosides 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-5-benzyluracil (DHPBU) (1) and 1-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]-5-benzyluracil (AHPBU) (2) have been synthesized by direct coupling of bis(trimethylsilyl)-5-benzyluracil with the corresponding chloromethyl ether, followed by removal of the b...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00145a023

    authors： Lin TS,Liu MC

    更新日期：1985-07-01 00:00:00

  • Methyl effects on protein-ligand binding.

    abstract：:The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in dept...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm3003697

    authors： Leung CS,Leung SS,Tirado-Rives J,Jorgensen WL

    更新日期：2012-05-10 00:00:00

  • Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern.

    abstract：:We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmaco...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm020171+

    authors： Nugiel DA,Vidwans A,Etzkorn AM,Rossi KA,Benfield PA,Burton CR,Cox S,Doleniak D,Seitz SP

    更新日期：2002-11-21 00:00:00

  • Camptothecin and minor-groove binder hybrid molecules: synthesis, inhibition of topoisomerase I, and anticancer cytotoxicity in vitro.

    abstract：:The synthesis, characterization, inhibitory activity against topoisomerase I, and biological evaluation of a series of 14 camptothecin derivatives of polypyrrolecarboxamide (lexitropsin) conjugates of two structural classes: (A) camptothecin-NHCO-lexitropsin 44-51 and (B) camptothecin-CONH-lexitropsin 38-43 are descri...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9605804

    authors： Zhao R,al-Said NH,Sternbach DL,Lown JW

    更新日期：1997-01-17 00:00:00

  • Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides.

    abstract：:We recently introduced sulfated pentagalloylglucopyranoside (SPGG) as an allosteric inhibitor of factor XIa (FXIa) (Al-Horani et al., J. Med Chem. 2013, 56, 867-878). To better understand the SPGG-FXIa interaction, we utilized eight SPGG variants and a range of biochemical techniques. The results reveal that SPGG's su...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm500311e

    authors： Al-Horani RA,Desai UR

    更新日期：2014-06-12 00:00:00

  • Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins.

    abstract：:Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogena...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00163a035

    authors： DeGraw JI,Christie PH,Kisliuk RL,Gaumont Y,Sirotnak FM

    更新日期：1990-01-01 00:00:00

  • Antimalarials. Synthesis and antimalarial activity of 1-(4-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine and derivatives.

    abstract：:The preparation and activity against Plasmodium berghei of derivatives of 1-(4-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine are described. Replacement of the cinnamoyl group was accomplished by acylation or alkylation of 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine. Modifications of the 5-phenyl grou...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00246a009

    authors： Herrin TR,Pauvlik JM,Schuber EV,Geiszler AO

    更新日期：1975-12-01 00:00:00

  • Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches.

    abstract：:Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in ac...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00809

    authors： Whitehouse AJ,Thomas SE,Brown KP,Fanourakis A,Chan DS,Libardo MDJ,Mendes V,Boshoff HIM,Floto RA,Abell C,Blundell TL,Coyne AG

    更新日期：2019-08-08 00:00:00