Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates.

abstract：:Genetic mutations in the phosphatase PTPN11 (SHP2) are associated with childhood leukemias. These mutations cause hyperactivation of SHP2 due to the disruption of the autoinhibitory conformation. By targeting the activation-associated protein conformational change, we have identified an SHP2 inhibitor ( E)-1-(1-(5-(3-...

journal_title：Journal of medicinal chemistry

authors： Wu X,Xu G,Li X,Xu W,Li Q,Liu W,Kirby KA,Loh ML,Li J,Sarafianos SG,Qu CK

更新日期：2019-02-14 00:00:00

abstract：:Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular prun...

journal_title：Journal of medicinal chemistry

authors： Milite C,Feoli A,Sasaki K,La Pietra V,Balzano AL,Marinelli L,Mai A,Novellino E,Castellano S,Tosco A,Sbardella G

更新日期：2015-03-26 00:00:00

abstract：:Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7)...

journal_title：Journal of medicinal chemistry

authors： Gregson SJ,Masterson LA,Wei B,Pillow TH,Spencer SD,Kang GD,Yu SF,Raab H,Lau J,Li G,Lewis Phillips GD,Gunzner-Toste J,Safina BS,Ohri R,Darwish M,Kozak KR,Dela Cruz-Chuh J,Polson A,Flygare JA,Howard PW

更新日期：2017-12-14 00:00:00

abstract：:A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orall...

journal_title：Journal of medicinal chemistry

authors： Yang Q,Kang J,Zheng L,Wang XJ,Wan N,Wu J,Qiao Y,Niu P,Wang SQ,Peng Y,Wang Q,Yu W,Chang J

更新日期：2015-05-14 00:00:00

abstract：:Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enz...

journal_title：Journal of medicinal chemistry

authors： Wilson DP,Wan ZK,Xu WX,Kirincich SJ,Follows BC,Joseph-McCarthy D,Foreman K,Moretto A,Wu J,Zhu M,Binnun E,Zhang YL,Tam M,Erbe DV,Tobin J,Xu X,Leung L,Shilling A,Tam SY,Mansour TS,Lee J

更新日期：2007-09-20 00:00:00

abstract：:Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology...

journal_title：Journal of medicinal chemistry

authors： Geist L,Mayer M,Cockcroft XL,Wolkerstorfer B,Kessler D,Engelhardt H,McConnell DB,Konrat R

更新日期：2017-11-09 00:00:00

abstract：:Resistance to chemotherapy and endocrine therapy is a major cause of breast cancer treatment failure. We have synthesized six novel analogues using C8-ceramide as the lead analogue and studied their effect on hormone therapy resistant (MDA-MB-231) and chemoresistant (MCF-7TN-R) breast cancer cells. Pharmacologic inter...

journal_title：Journal of medicinal chemistry

authors： Antoon JW,Liu J,Gestaut MM,Burow ME,Beckman BS,Foroozesh M

更新日期：2009-09-24 00:00:00

abstract：:We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. A...

journal_title：Journal of medicinal chemistry

authors： Sidhu PS,Abdel Aziz MH,Sarkar A,Mehta AY,Zhou Q,Desai UR

更新日期：2013-06-27 00:00:00

abstract：:Seven 3-alkyl-4-aryl-1,5-dihydro-2H-pyrrol-2-ones were prepared as potential inhibitors of cardiac cAMP phosphodiesterase (PDE). The design of these compounds made use of rolipram, a known inhibitor of the brain cAMP PDE isozyme, as a lead structure and was guided by a model which describes the features required for p...

journal_title：Journal of medicinal chemistry

authors： Lampe JW,Chou YL,Hanna RG,Di Meo SV,Erhardt PW,Hagedorn AA 3rd,Ingebretsen WR,Cantor E

更新日期：1993-04-16 00:00:00

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

authors： Chatterjee AK

更新日期：2013-10-24 00:00:00

abstract：:The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline 1, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin1), wh...

journal_title：Journal of medicinal chemistry

authors： Liu Q,Chang JW,Wang J,Kang SA,Thoreen CC,Markhard A,Hur W,Zhang J,Sim T,Sabatini DM,Gray NS

更新日期：2010-10-14 00:00:00

abstract：:The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (1) (R1 = OMe) had previously been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 1 (R1 = OH)....

journal_title：Journal of medicinal chemistry

authors： Howe R,Rao BS,Holloway BR,Stribling D

更新日期：1992-05-15 00:00:00

abstract：:Hydroxyurea, hydroxyguanidine, and some thiosemicarbazones have been shown to have anticancer and antiviral activities. One of their possible sites of action is the enzyme ribonucleotide reductase (RR). Combination of the structural features of these compounds led to the design and synthesis of the Schiff bases of N-h...

journal_title：Journal of medicinal chemistry

authors： T'ang A,Lien EJ,Lai MM

更新日期：1985-08-01 00:00:00

abstract：:In tissue engineering, survival of larger constructs remains challenging due to limited supply of oxygen caused by a lack of early vascularization. Controlled release of oxygen from small organic molecules represents a possible strategy to prevent cell death under anoxic conditions. A comprehensive study of methylated...

journal_title：Journal of medicinal chemistry

authors： Benz S,Nötzli S,Siegel JS,Eberli D,Jessen HJ

更新日期：2013-12-27 00:00:00

abstract：:Partition properties, that is partition coefficients and enthalpies (delta Hp degree) and entropies (delta Sp degree) of partition, have been measured for 50 benzoic acids in the 1-octanol/water system, and their role in QSAR (quantitative structure-activity relationship) analysis examined. The novel hydrophobic param...

journal_title：Journal of medicinal chemistry

authors： Da YZ,Ito K,Fujiwara H

更新日期：1992-09-04 00:00:00

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

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

abstract：:A series of N2-[(acylamino)alkyl]-6,7-dimethoxy-2,4-quinazolinediamines was synthesized as potential alpha 1-adrenoceptor antagonists. When administered to spontaneously hypertensive rats at 10 mg/kg po, a number of propanediamine derivatives showed good antihypertensive activity, whereas the ethanediamine derivatives...

journal_title：Journal of medicinal chemistry

authors： Manoury PM,Binet JL,Dumas AP,Lefèvre-Borg F,Cavero I

更新日期：1986-01-01 00:00:00

abstract：:Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate...

journal_title：Journal of medicinal chemistry

authors： Németh G,Greff Z,Sipos A,Varga Z,Székely R,Sebestyén M,Jászay Z,Béni S,Nemes Z,Pirat JL,Volle JN,Virieux D,Gyuris Á,Kelemenics K,Ay E,Minarovits J,Szathmary S,Kéri G,Orfi L

更新日期：2014-05-22 00:00:00

abstract：:The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to...

journal_title：Journal of medicinal chemistry

authors： Sundén H,Schäfer A,Scheepstra M,Leysen S,Malo M,Ma JN,Burstein ES,Ottmann C,Brunsveld L,Olsson R

更新日期：2016-02-11 00:00:00

abstract：:Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferati...

journal_title：Journal of medicinal chemistry

authors： Peleg S,Petersen KS,Suh BC,Dolan P,Agoston ES,Kensler TW,Posner GH

更新日期：2006-12-14 00:00:00

abstract：:The atypical chemokine receptor 3 (ACKR3)/CXC chemokine receptor 7 (CXCR7) recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and is involved in a number of physiological and pathological processes. Here, we investigated the SAR of the component amino acids in an ACKR3-selective ligand, FC313 [ cyclo(-d-Tyr-l-Arg...

journal_title：Journal of medicinal chemistry

authors： Sekiguchi H,Kuroyanagi T,Rhainds D,Kobayashi K,Kobayashi Y,Ohno H,Heveker N,Akaji K,Fujii N,Oishi S

更新日期：2018-04-26 00:00:00

abstract：:New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are ca...

journal_title：Journal of medicinal chemistry

authors： Jin Y,Roycik MD,Bosco DB,Cao Q,Constantino MH,Schwartz MA,Sang QX

更新日期：2013-06-13 00:00:00

abstract：:The inhibition of chicken liver dihydrofolate reductase by a series of substituted benzylpyrimidines has been investigated. From the inhibition constants a quantitative structure-activity relationship has been formulated. This mathematical model is compared with molecular graphics models constructed from the X-ray cry...

journal_title：Journal of medicinal chemistry

authors： Selassie CD,Fang ZX,Li RL,Hansch C,Klein T,Langridge R,Kaufman BT

更新日期：1986-05-01 00:00:00

abstract：:Analogues of luliberin containing an alpha-azaamino acid in position 6, 9, or 10 (I--XIV) have been synthesized by the solution method of peptide synthesis. Two nonaza analogues, [D-Phe6]- and [D-Ser(But)6,des-Gly-NH2(10),Pro-ethylamide9]luliberin, were also synthesized for comparison. The ovulation-inducing activity ...

journal_title：Journal of medicinal chemistry

authors： Dutta AS,Furr BJ,Giles MB,Valcaccia B

更新日期：1978-10-01 00:00:00

abstract：:A novel series of diaminoanthraquinones was discovered initially as protein kinase C inhibitors with IC50s in the 50-100 microM range. They exhibited potent tumor cell growth inhibitory activity in vitro without cross resistance to adriamycin. Further evaluation of two of the most active compounds NSC 639365 (3) and N...

journal_title：Journal of medicinal chemistry

authors： Jiang JB,Johnson MG,Defauw JM,Beine TM,Ballas LM,Janzen WP,Loomis CR,Seldin J,Cofield D,Adams L

更新日期：1992-11-13 00:00:00

abstract：:The inclusion of an azaspiroketal Mannich base in the membrane targeting antitubercular 6-methoxy-1- n-octyl-1 H-indole scaffold resulted in analogs with improved selectivity and submicromolar activity against Mycobacterium tuberculosis H37Rv. The potency enhancing properties of the spiro-fused ring motif was affirmed...

journal_title：Journal of medicinal chemistry

authors： Nyantakyi SA,Li M,Gopal P,Zimmerman M,Dartois V,Gengenbacher M,Dick T,Go ML

更新日期：2018-07-12 00:00:00

abstract：:Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflamm...

journal_title：Journal of medicinal chemistry

authors： Gosmini R,Nguyen VL,Toum J,Simon C,Brusq JM,Krysa G,Mirguet O,Riou-Eymard AM,Boursier EV,Trottet L,Bamborough P,Clark H,Chung CW,Cutler L,Demont EH,Kaur R,Lewis AJ,Schilling MB,Soden PE,Taylor S,Walker AL,Walker

更新日期：2014-10-09 00:00:00

abstract：:Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alph...

journal_title：Journal of medicinal chemistry

authors： Nagarathnam D,Miao SW,Lagu B,Chiu G,Fang J,Murali Dhar TG,Zhang J,Tyagarajan S,Marzabadi MR,Zhang F,Wong WC,Sun W,Tian D,Wetzel JM,Forray C,Chang RS,Broten TP,Ransom RW,Schorn TW,Chen TB,O'Malley S,Kling P,Sch

更新日期：1999-11-18 00:00:00

abstract：:The synthesis of a series of N-phosphonalkyl dipeptides 6 is described. Syntheses were devised that allowed the preparation of single diastereoisomers and the assignment of stereochemistry. The compounds were evaluated in vitro for their ability to inhibit the degradation of radiolabeled collagen by purified human lun...

journal_title：Journal of medicinal chemistry

authors： Bird J,De Mello RC,Harper GP,Hunter DJ,Karran EH,Markwell RE,Miles-Williams AJ,Rahman SS,Ward RW

更新日期：1994-01-07 00:00:00

abstract：:A series of 3,7-disubstituted-2-(3',4'-dihydroxyphenyl)flavones was synthesized as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 positions of the flavone nucleus on radical scavenging and antioxidant properties was explored to improve the antioxidant a...

journal_title：Journal of medicinal chemistry

authors： van Acker FA,Hageman JA,Haenen GR,van Der Vijgh WJ,Bast A,Menge WM

更新日期：2000-10-05 00:00:00