当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Nitro seco analogues of the duocarmycins containing sulfonate leaving groups as hypoxia-activated prodrugs for cancer therapy.

Nitro seco analogues of the duocarmycins containing sulfonate leaving groups as hypoxia-activated prodrugs for cancer therapy.

Abstract：

:The synthesis of 19 (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate prodrugs containing sulfonate leaving groups and 7-substituted electron-withdrawing groups is reported. These were designed to undergo hypoxia-selective metabolism to form potent DNA minor groove-alkylating agents. Analogues 17 and 24, containing the benzyl sulfonate leaving group and a neutral DNA minor groove-binding side chain, displayed hypoxic cytotoxicity ratios (HCRs) of >1000 in HT29 human cancer cells in vitro in an antiproliferative assay. Four analogues maintained large HCRs across a panel of eight human cancer cell lines. In a clonogenic assay, 19 showed an HCR of 4090 in HT29 cells. Ten soluble phosphate preprodrugs were also prepared and evaluated in vivo, alone and in combination with radiation in SiHa human tumor xenografts at a nontoxic dose. Compounds 34 and 39 displayed hypoxic log(10) cell kills (LCKs) of 1.78 and 2.71, respectively, equivalent or superior activity to previously reported chloride or bromide analogues, thus showing outstanding promise as hypoxia-activated prodrugs.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Stevenson RJ,Denny WA,Tercel M,Pruijn FB,Ashoorzadeh A

doi

10.1021/jm201717y

subject

Has Abstract

pub_date

2012-03-22 00:00:00

pages

2780-802

issue

6

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Optimal charges in lead progression: a structure-based neuraminidase case study.

    abstract：:Collective experience in structure-based lead progression has found electrostatic interactions to be more difficult to optimize than shape-based ones. A major reason for this is that the net electrostatic contribution observed includes a significant nonintuitive desolvation component in addition to the more intuitive ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm051105l

    authors： Armstrong KA,Tidor B,Cheng AC

    更新日期：2006-04-20 00:00:00

  • Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPARγ-Targeted Antidiabetics.

    abstract：:Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARγ is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARγ with robust antidiabetic properties, which are confounded with signi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b01727

    authors： Frkic RL,He Y,Rodriguez BB,Chang MR,Kuruvilla D,Ciesla A,Abell AD,Kamenecka TM,Griffin PR,Bruning JB

    更新日期：2017-06-08 00:00:00

  • Synthesis, in vitro pharmacology, and molecular modeling of syn-huprines as acetylcholinesterase inhibitors.

    abstract：:Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioiso...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm010949b

    authors： Camps P,Gómez E,Muñoz-Torrero D,Badia A,Vivas NM,Barril X,Orozco M,Luque FJ

    更新日期：2001-12-20 00:00:00

  • Optimization of the central heterocycle of alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase.

    abstract：:The synthesis and evaluation of a refined series of alpha-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explore...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800136b

    authors： Garfunkle J,Ezzili C,Rayl TJ,Hochstatter DG,Hwang I,Boger DL

    更新日期：2008-08-14 00:00:00

  • Effect of structural change on acute toxicity and antiinflammatory activity in a series of imidazothiazoles and thiazolobenzimidazoles.

    abstract：:The effect of structural change on the biological activity of a series of imidazothiazoles and thiazolobenzimidazoles is described. It was found that compounds with polar substituents at the 2 or 3 position of the ring system are less acutely toxic while maintaining antiinflammatory activity. Other structural changes,...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00137a022

    authors： Powers LJ,Fogt SW,Ariyan ZS,Rippin DJ,Heilman RD,Matthews RJ

    更新日期：1981-05-01 00:00:00

  • Nontoxic Metal-Cyclam Complexes, a New Class of Compounds with Potency against Drug-Resistant Mycobacterium tuberculosis.

    abstract：:Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tubercu...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00432

    authors： Yu M,Nagalingam G,Ellis S,Martinez E,Sintchenko V,Spain M,Rutledge PJ,Todd MH,Triccas JA

    更新日期：2016-06-23 00:00:00

  • Novel peptidomimetics containing a vinyl ester moiety as highly potent and selective falcipain-2 inhibitors.

    abstract：:This paper describes the synthesis and biological evaluation of a new class of peptidomimetic falcipain-2 inhibitors based on a 1,4-benzodiazepine scaffold combined with various alpha,beta-unsaturated electrophilic functions such as vinyl-ketone, -amide, -ester, and -nitrile. The profile of reactivity of this class of...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900047j

    authors： Ettari R,Micale N,Schirmeister T,Gelhaus C,Leippe M,Nizi E,Di Francesco ME,Grasso S,Zappalà M

    更新日期：2009-04-09 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

  • Conformationally-locked N-glycosides with selective β-glucosidase inhibitory activity: identification of a new non-iminosugar-type pharmacological chaperone for Gaucher disease.

    abstract：:A series of conformationally locked N-glycosides having a cis-1,2-fused pyranose-1,3-oxazoline-2-thione structure and bearing different substituents at the exocyclic sulfur has been prepared. The polyhydroxylated bicyclic system was built in only three steps by treatment of the corresponding readily available 1,2-anhy...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm3006178

    authors： Castilla J,Rísquez R,Cruz D,Higaki K,Nanba E,Ohno K,Suzuki Y,Díaz Y,Ortiz Mellet C,García Fernández JM,Castillón S

    更新日期：2012-08-09 00:00:00

  • Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 1.

    abstract：:The synthesis and testing of potential multisubstrate inhibitors of tyrosine-specific protein kinases are described. One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-[4-(fluorosulfonyl)benzoyl]adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics. The resulting mult...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00117a015

    authors： Kruse CH,Holden KG,Pritchard ML,Feild JA,Rieman DJ,Greig RG,Poste G

    更新日期：1988-09-01 00:00:00

  • Development of potent and selective phosphinic peptide inhibitors of angiotensin-converting enzyme 2.

    abstract：:Angiotensin-converting enzyme 2 (ACE2), a recently identified human homologue of angiotensin-converting enzyme, is a zinc metallocarboxypeptidase which may play a unique role in cardiovascular and renal function. Here we report the discovery of potent and selective inhibitors of ACE2, which have been identified by eva...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm701275z

    authors： Mores A,Matziari M,Beau F,Cuniasse P,Yiotakis A,Dive V

    更新日期：2008-04-10 00:00:00

  • Quadruplex Nucleic Acids as Novel Therapeutic Targets.

    abstract：:Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters, and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b01835

    authors： Neidle S

    更新日期：2016-07-14 00:00:00

  • 2,4-diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists.

    abstract：:Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligo...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0510934

    authors： Serby MD,Zhao H,Szczepankiewicz BG,Kosogof C,Xin Z,Liu B,Liu M,Nelson LT,Kaszubska W,Falls HD,Schaefer V,Bush EN,Shapiro R,Droz BA,Knourek-Segel VE,Fey TA,Brune ME,Beno DW,Turner TM,Collins CA,Jacobson PB,Sham H

    更新日期：2006-04-20 00:00:00

  • Benzothiopyranoindazoles, a new class of chromophore modified anthracenedione anticancer agents. Synthesis and activity against murine leukemias.

    abstract：:The synthesis of the benzothiopyranoindazoles, a new class of chromophore modified anthracenediones related to mitoxantrone, is described. In this structural class the quinone moiety, which is believed to be responsible for the cardiotoxicity of the anthracyclines, has been designed out. The synthesis of the benzothio...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00403a009

    authors： Showalter HD,Angelo MM,Berman EM,Kanter GD,Ortwine DF,Ross-Kesten SG,Sercel AD,Turner WR,Werbel LM,Worth DF

    更新日期：1988-08-01 00:00:00

  • Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3-triazoles.

    abstract：:Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of aromatic substituents influenced in vitro antiprotozoal activities o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901178d

    authors： Bakunov SA,Bakunova SM,Wenzler T,Ghebru M,Werbovetz KA,Brun R,Tidwell RR

    更新日期：2010-01-14 00:00:00

  • Relating molecular properties and in vitro assay results to in vivo drug disposition and toxicity outcomes.

    abstract：:A primary goal of lead optimization is to identify compounds with improved absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A number of reports have linked computed molecular properties to desirable in vivo ADMET outcomes, but a significant limitation of these analyses is the failure t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm300684u

    authors： Sutherland JJ,Raymond JW,Stevens JL,Baker TK,Watson DE

    更新日期：2012-07-26 00:00:00

  • Identification and prediction of promiscuous aggregating inhibitors among known drugs.

    abstract：:Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzym...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030191r

    authors： Seidler J,McGovern SL,Doman TN,Shoichet BK

    更新日期：2003-10-09 00:00:00

  • Modeling of purine derivatives transport across cell membranes based on their partition coefficient determination and quantum chemical calculations.

    abstract：:Mercaptopurine (6-MP), thioguanine (6-TG), and azathioprine (AZA) are purine antimetabolites introduced as anticancer or immunosuppressive drugs decades ago. Methylated AZA, called MAZA, is among the investigational drugs. The present study compares MAZA to the widely recognized drugs AZA, 6-MP, and 6-TG with respect ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0495273

    authors： Hoffmann M,Chrzanowska M,Hermann T,Rychlewski J

    更新日期：2005-06-30 00:00:00

  • Semisynthesis and Biological Evaluation of Xanthone Amphiphilics as Selective, Highly Potent Antifungal Agents to Combat Fungal Resistance.

    abstract：:New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangos...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b01348

    authors： Lin S,Sin WLW,Koh JJ,Lim F,Wang L,Cao D,Beuerman RW,Ren L,Liu S

    更新日期：2017-12-28 00:00:00

  • Nintedanib: from discovery to the clinic.

    abstract：:Nintedanib (BIBF1120) is a potent, oral, small-molecule tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor rece...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/jm501562a

    authors： Roth GJ,Binder R,Colbatzky F,Dallinger C,Schlenker-Herceg R,Hilberg F,Wollin SL,Kaiser R

    更新日期：2015-02-12 00:00:00

  • Approaches to protection against nerve agent poisoning. (Naphthylvinyl)pyridine derivatives as potential antidotes.

    abstract：:Analogues of the potent inhibitor of choline acetyltransferase (CAT) (E)-4-(1-naphthylvinyl)pyridine methiodide were synthesized and evaluated for their ability to inhibit CAT and protect against nerve agent intoxication. Several compounds, notably (E)-1-(2-hydroxyethyl)-(1-naphthylvinyl)pyridinium bromide (3), (E)-1-...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00399a022

    authors： Gray AP,Platz RD,Henderson TR,Chang TC,Takahashi K,Dretchen KL

    更新日期：1988-04-01 00:00:00

  • A nonionic inhibitor with high specificity for the UDP-Gal donor binding site of human blood group B galactosyltransferase: design, synthesis, and characterization.

    abstract：:9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione (1) was designed and synthesized as a nonionic inhibitor for the donor binding site of human blood group B galactosyltransferase (GTB). Enzymatic characterization showed 1 to be extremely specific, as the highly homologous human N-acetylgalact...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm300642a

    authors： Schaefer K,Sindhuwinata N,Hackl T,Kötzler MP,Niemeyer FC,Palcic MM,Peters T,Meyer B

    更新日期：2013-03-14 00:00:00

  • Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization.

    abstract：:An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00112a036

    authors： Cushman M,Nagarathnam D,Gopal D,Chakraborti AK,Lin CM,Hamel E

    更新日期：1991-08-01 00:00:00

  • Human growth hormone-releasing hormone hGHRH(1-29)-NH2: systematic structure-activity relationship studies.

    abstract：:Two complete and two partial structure-activity relationship scans of the active fragment of human growth hormone-releasing hormone, [Nle27]-hGHRH(1-29)-NH2, have identified potent agonists in vitro. Single-point replacement of each amino acid by alanine led to the identification of [Ala8]-, [Ala9]-, [Ala15]- (Felix e...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm970618s

    authors： Cervini LA,Donaldson CJ,Koerber SC,Vale WW,Rivier JE

    更新日期：1998-02-26 00:00:00

  • Phosphoramidate ProTides of 2'-C-methylguanosine as highly potent inhibitors of hepatitis C virus. Study of their in vitro and in vivo properties.

    abstract：:Hepatitis C virus infection constitutes a serious health problem in need of more effective therapies. Nucleoside analogues with improved exposure, efficacy, and selectivity are recognized as likely key components of future HCV therapy. 2'-C-Methylguanosine triphosphate has been known as a potent inhibitor of HCV RNA p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm1003792

    authors： McGuigan C,Gilles A,Madela K,Aljarah M,Holl S,Jones S,Vernachio J,Hutchins J,Ames B,Bryant KD,Gorovits E,Ganguly B,Hunley D,Hall A,Kolykhalov A,Liu Y,Muhammad J,Raja N,Walters R,Wang J,Chamberlain S,Henson G

    更新日期：2010-07-08 00:00:00

  • Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

    abstract：:BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanom...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm801509w

    authors： Niculescu-Duvaz D,Gaulon C,Dijkstra HP,Niculescu-Duvaz I,Zambon A,Ménard D,Suijkerbuijk BM,Nourry A,Davies L,Manne H,Friedlos F,Ogilvie L,Hedley D,Whittaker S,Kirk R,Gill A,Taylor RD,Raynaud FI,Moreno-Farre J,Marais

    更新日期：2009-04-23 00:00:00

  • Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.

    abstract：:We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a ba...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01719

    authors： Chong PY,Shotwell JB,Miller J,Price DJ,Maynard A,Voitenleitner C,Mathis A,Williams S,Pouliot JJ,Creech K,Wang F,Fang J,Zhang H,Tai VW,Turner E,Kahler KM,Crosby R,Peat AJ

    更新日期：2019-04-11 00:00:00

  • Discovery of novel protease activated receptors 1 antagonists with potent antithrombotic activity in vivo.

    abstract：:Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900553j

    authors： Perez M,Lamothe M,Maraval C,Mirabel E,Loubat C,Planty B,Horn C,Michaux J,Marrot S,Letienne R,Pignier C,Bocquet A,Nadal-Wollbold F,Cussac D,de Vries L,Le Grand B

    更新日期：2009-10-08 00:00:00

  • Comparative toxicities and analgesic activities of three monomethylated analogues of acetaminophen.

    abstract：:Three monomethylated derivatives of 4'-hydroxyacetanilide (acetaminophen) were prepared in order to compare their cytotoxic potential and analgesic activity with that of acetaminophen. Only 4'-hydroxy-N-methylacetanilide (N-methylacetaminophen) was devoid of cytotoxic effects to hepatic tissue of mice. Results of comp...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00159a029

    authors： Harvison PJ,Forte AJ,Nelson SD

    更新日期：1986-09-01 00:00:00

  • Inactivation of S-adenosyl-L-homocysteine hydrolase and antiviral activity with 5',5',6',6'-tetradehydro-6'-deoxy-6'-halohomoadenosine analogues (4'-haloacetylene analogues derived from adenosine).

    abstract：:Treatment of a protected 9-(5, 6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine derivative with silver nitrate and N-iodosuccinimide (NIS) and deprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Halogenation of 3-O-benzoyl-5,6-dideoxy-1, 2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-halo acetyl...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980163m

    authors： Robins MJ,Wnuk SF,Yang X,Yuan CS,Borchardt RT,Balzarini J,De Clercq E

    更新日期：1998-09-24 00:00:00