Discovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines.


:A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors.


J Med Chem


Schnekenburger M,Goffin E,Lee JY,Jang JY,Mazumder A,Ji S,Rogister B,Bouider N,Lefranc F,Miklos W,Mathieu V,de Tullio P,Kim KW,Dicato M,Berger W,Han BW,Kiss R,Pirotte B,Diederich M




Has Abstract


2017-06-08 00:00:00












  • Structure-activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors.

    abstract::Cholecystokinin (CCK) has been identified as a pronociceptive endogenous peptide which also possesses antiopioid actions. CCK may be upregulated in conditions of chronic pain or during sustained morphine administration resulting in attenuation of opioid-mediated pain relief. These complex interactions between opioids ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Agnes RS,Lee YS,Davis P,Ma SW,Badghisi H,Porreca F,Lai J,Hruby VJ

    更新日期:2006-05-18 00:00:00

  • Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis.

    abstract::The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been develo...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ko K,Kim HJ,Ho PS,Lee SO,Lee JE,Min CR,Kim YC,Yoon JH,Park EJ,Kwon YJ,Yun JH,Yoon DO,Kim JS,Park WS,Oh SS,Song YM,Cho WK,Morikawa K,Lee KJ,Park CH

    更新日期:2018-04-12 00:00:00

  • Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: application to the synthesis of glucocorticoid receptor modulators.

    abstract::The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (G...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Xiao HY,Wu DR,Malley MF,Gougoutas JZ,Habte SF,Cunningham MD,Somerville JE,Dodd JH,Barrish JC,Nadler SG,Dhar TG

    更新日期:2010-02-11 00:00:00

  • Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping.

    abstract::Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopp...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ji H,Li H,Martásek P,Roman LJ,Poulos TL,Silverman RB

    更新日期:2009-02-12 00:00:00

  • Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging.

    abstract::We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Andrés JI,De Angelis M,Alcázar J,Iturrino L,Langlois X,Dedeurwaerdere S,Lenaerts I,Vanhoof G,Celen S,Bormans G

    更新日期:2011-08-25 00:00:00

  • Synthesis and biological evaluations of certain 2-halo-2'-substituted derivatives of 9-beta-D-arabinofuranosyladenine.

    abstract::The synthesis of a series of 2-chloro- or 2-fluoro-9-(2-substituted-2-deoxy-beta-D-arabinofuranosyl)adenines (4g-n) is described. New compounds were prepared from either 2-chloroadenosine or 2-fluoroadenosine by first blocking the 3'- and 5'-hydroxyls as the tetraisopropyldisiloxane derivatives. Activation of O-2' by ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Secrist JA 3rd,Shortnacy AT,Montgomery JA

    更新日期:1988-02-01 00:00:00

  • Metal complexes of mitomycins.

    abstract::The preparation of stable complexes between the N7-[2-(2-pyridyl)ethyl] and N7-(2-piperazinylethyl) derivatives of mitomycin C and metal ions such as Cu(II), Zn(II), and Pt(II) was accomplished. Mitomycin C did not form stable complexes, but it rearranged to a mitosene capable of complex formation. Some of these compl...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Iyengar BS,Takahashi T,Remers WA,Bradner WT

    更新日期:1986-01-01 00:00:00

  • Discovery of Isaindigotone Derivatives as Novel Bloom's Syndrome Protein (BLM) Helicase Inhibitors That Disrupt the BLM/DNA Interactions and Regulate the Homologous Recombination Repair.

    abstract::Homologous recombination repair (HRR), a crucial approach in DNA damage repair, is an attractive target in cancer therapy and drug design. The Bloom syndrome protein (BLM) is a 3'-5' DNA helicase that performs an important role in HRR regulation. However, limited studies about BLM inhibitors and their biological effec...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Yin QK,Wang CX,Wang YQ,Guo QL,Zhang ZL,Ou TM,Huang SL,Li D,Wang HG,Tan JH,Chen SB,Huang ZS

    更新日期:2019-03-28 00:00:00

  • Novel orally active antimalarial thiazoles.

    abstract::An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC(50): 0.08 μM (K1, chloroquine and multidrug resistant strain) and 0.07 μM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Co...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: González Cabrera D,Douelle F,Feng TS,Nchinda AT,Younis Y,White KL,Wu Q,Ryan E,Burrows JN,Waterson D,Witty MJ,Wittlin S,Charman SA,Chibale K

    更新日期:2011-11-10 00:00:00

  • Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208).

    abstract::Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging m...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: De Marco R,Bedini A,Spampinato S,Cavina L,Pirazzoli E,Gentilucci L

    更新日期:2016-10-13 00:00:00

  • beta-Adrenergic blocking agents. 17. 1-Phenoxy-3-phenoxyalkylamino-2-propanols and 1-alkoxyalkylamino-3-phenoxy-2-propanols.

    abstract::The synthesis is described of a series of derivatives of 1-phenoxy-3-phenoxyalkylamino-2-propanols and 1-alkoxyalkylamino-3-phenoxy-2-propranols. The compounds were investigated for their beta-adrenoceptor blocking properties and many showed a surprising degree of cardioselectivity when tested in vivo in anesthetized ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Smith LH,Tucker H

    更新日期:1977-12-01 00:00:00

  • Discovery of bicycloalkyl urea melanin concentrating hormone receptor antagonists: orally efficacious antiobesity therapeutics.

    abstract::Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: McBriar MD,Guzik H,Xu R,Paruchova J,Li S,Palani A,Clader JW,Greenlee WJ,Hawes BE,Kowalski TJ,O'Neill K,Spar B,Weig B

    更新日期:2005-04-07 00:00:00

  • Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants.

    abstract::The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants of HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. The NNRTIs bind in an allosteric pocket in RT ∼10 Å away from the active site. Earlier analogues of the catechol diether compound series have picomol...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Frey KM,Puleo DE,Spasov KA,Bollini M,Jorgensen WL,Anderson KS

    更新日期:2015-03-26 00:00:00

  • Synthesis and biological activity of new peptide segments of gastrin exhibiting gastrin antagonist property.

    abstract::A series of C-terminal peptide segments of gastrin, i.e., (tert-butyloxycarbonyl)-L-tryptophyl-L-methionyl-L-aspartic acid amide, (tert-butyloxycarbonyl)-glycyl-L-tryptophyl-L-methionyl-L-aspartic acid amide, (tert-butyloxy-carbonyl)-L-tyrosyl-glycyl-L-tryptophyl-L-methionyl-L-asp artic acid amide, and (benzyloxycarbo...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


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    更新日期:1984-12-01 00:00:00

  • Substituted imidazo[2,3-alpha]pyridine-2-carbamate anthelmintics.

    abstract::Anthelmintic efficacies of a series of 6-substituted methyl imidazo[1,2-alpha]pyridine-2-carbamates were compared to similarly substituted benzimidazole-2-carbamates. With only one exception, methyl 6-benzoylimidazo[1,2-alpha]pyridine-2-carbamate, both classes of compounds exhibited similar activity vs. Nematospiroide...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Bochis RJ,Olen LE,Waksmunski FS,Mrozik H,Eskola P,Kulsa P,Wilks G,Taylor JE,Egerton JR,Ostlind DA,Olson G

    更新日期:1981-12-01 00:00:00

  • New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics.

    abstract::Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, c...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Gorham RD Jr,Forest DL,Khoury GA,Smadbeck J,Beecher CN,Healy ED,Tamamis P,Archontis G,Larive CK,Floudas CA,Radeke MJ,Johnson LV,Morikis D

    更新日期:2015-01-22 00:00:00

  • Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.

    abstract::From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable t...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ratni H,Rogers-Evans M,Bissantz C,Grundschober C,Moreau JL,Schuler F,Fischer H,Alvarez Sanchez R,Schnider P

    更新日期:2015-03-12 00:00:00

  • 5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives.

    abstract::Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist. Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dop...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Bermudez J,Fake CS,Joiner GF,Joiner KA,King FD,Miner WD,Sanger GJ

    更新日期:1990-07-01 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


    authors: Lin TS,Liu MC

    更新日期:1985-07-01 00:00:00

  • Design and synthesis of 2-arylbenzimidazoles and evaluation of their inhibitory effect against Chlamydia pneumoniae.

    abstract::Chlamydia pneumoniae is an intracellular bacterium that responds poorly to antibiotic treatment. Insufficient antibiotic usage leads to chronic infection, which is linked to disease processes of asthma, atherosclerosis, and Alzheimer's disease. The Chlamydia research lacks genetic tools exploited by other antimicrobia...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Keurulainen L,Salin O,Siiskonen A,Kern JM,Alvesalo J,Kiuru P,Maass M,Yli-Kauhaluoma J,Vuorela P

    更新日期:2010-11-11 00:00:00

  • The structural basis of camptothecin interactions with human serum albumin: impact on drug stability.

    abstract::The intense intrinsic fluorescence emissions from several clinically relevant camptothecin drugs have been exploited in order to study the structural basis of drug binding to human serum albumin. Both HPLC and time-resolved fluorescence spectroscopic methodologies were employed to characterize the associations of camp...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Burke TG,Mi Z

    更新日期:1994-01-07 00:00:00

  • Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency.

    abstract::A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. E...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Borthwick AD,Liddle J,Davies DE,Exall AM,Hamlett C,Hickey DM,Mason AM,Smith IE,Nerozzi F,Peace S,Pollard D,Sollis SL,Allen MJ,Woollard PM,Pullen MA,Westfall TD,Stanislaus DJ

    更新日期:2012-01-26 00:00:00

  • Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues.

    abstract::Largazole 4a and analogues with modifications at the C7 position, as well as 2,4'-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Souto JA,Vaz E,Lepore I,Pöppler AC,Franci G,Alvarez R,Altucci L,de Lera AR

    更新日期:2010-06-24 00:00:00

  • Renin inhibitors containing psi[CH2O] pseudopeptide inserts.

    abstract::Renin inhibitors 2-4 with the D-Lys renin inhibitory peptide (RIP) sequence, but containing Leu psi[CH2O]Ala (2), Leu psi[CH2O]Val (3), and Leu psi[CH2O]Leu (4) at the P1-P1' site, were of a comparable potency to RIP. N-Terminal Boc-protected inhibitors containing Pro psi[CH2O]Phe in positions P4-P3 were potent inhibi...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: TenBrink RE,Pals DT,Harris DW,Johnson GA

    更新日期:1988-03-01 00:00:00

  • N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity.

    abstract::Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped ve...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Fernandez AM,Van Derpoorten K,Dasnois L,Lebtahi K,Dubois V,Lobl TJ,Gangwar S,Oliyai C,Lewis ER,Shochat D,Trouet A

    更新日期:2001-10-25 00:00:00

  • Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK).

    abstract::As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, in...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Kong X,Pan P,Sun H,Xia H,Wang X,Li Y,Hou T

    更新日期:2019-12-26 00:00:00

  • Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes.

    abstract::In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Biftu T,Sinha-Roy R,Chen P,Qian X,Feng D,Kuethe JT,Scapin G,Gao YD,Yan Y,Krueger D,Bak A,Eiermann G,He J,Cox J,Hicks J,Lyons K,He H,Salituro G,Tong S,Patel S,Doss G,Petrov A,Wu J,Xu SS,Sewall C,Zhang X,

    更新日期:2014-04-24 00:00:00

  • Synthesis of 5-substituted 2'-deoxyuridines.

    abstract::A series of thymidylate synthetase inhibitors was synthesized, some of which were potential irreversible inhibitors. 5-Formyl-2'-deoxyuridine (9) and its dithiolane derivative 11 were prepared by condensation of the bis(trimethylsilyl) derivative of 5-formyluracil dimethyl acetal and the protected chloro sugar followe...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kampf A,Pillar CJ,Woodford WJ,Mertes MP

    更新日期:1976-07-01 00:00:00

  • Synthesis and biological evaluation of analogues of the peptaibol ampullosporin A.

    abstract::A series of analogues of the fungal peptaibol type metabolite ampullosporin A containing modifications in the C and N terminus as well as alpha-aminoisobutyric acid (Aib) substitutions in different positions of the peptide were synthesized by solid phase synthesis using the 9-fluorenylmethyloxycarbonyl strategy. Depen...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Nguyen HH,Imhof D,Kronen M,Schlegel B,Härtl A,Gräfe U,Gera L,Reissmann S

    更新日期:2002-06-20 00:00:00

  • Gramine Derivatives Targeting Ca(2+) Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases.

    abstract::We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer's disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca(2+) channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatase...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lajarín-Cuesta R,Nanclares C,Arranz-Tagarro JA,González-Lafuente L,Arribas RL,Araujo de Brito M,Gandía L,de Los Ríos C

    更新日期:2016-07-14 00:00:00