- Synthesis of rigid photoswitchable hemithioindigo ω-amino acids
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The synthesis of novel N-Boc- and N-Fmoc protected hemithioindigo-based ω-amino acids is described. An approach to modulate the thermal stability of a hemithioindigo subunit is presented. Placing the amino-group in the stilbene part from the para- to meta
- Schadendorf, Torsten,Hoppmann, Christian,Rück-Braun, Karola
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- NON-ATP/CATALYTIC SITE P38 MITOGEN ACTIVATED PROTEIN KINASE INHIBITORS
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Compounds that inhibit p38a MAPK protein, and methods of using the same, are provided for treating or preventing diseases such as cancer or inflammatory diseases.
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Paragraph 00282
(2021/09/17)
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- Methanesulfinylation of Benzyl Halides with Dimethyl Sulfoxide
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A phenyltrimethylammonium tribromide-mediated nucleophilic substitution/oxygen transformation reaction of benzyl halides with DMSO has been developed. In this transition-metal-free reaction, DMSO acts as not only a solvent but also a "S(O)Me" source, thus providing a convenient method for the efficient and direct synthesis of various benzyl methyl sulfoxides.
- Fu, Duo,Dong, Jun,Du, Hongguang,Xu, Jiaxi
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p. 2752 - 2758
(2020/01/31)
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- NON-ATP/CATALYTIC SITE p38 MITOGEN ACTIVATED PROTEIN KINASE INHIBITORS
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Compounds that inhibit p38α MAPK protein, and methods of using the same, are provided for treating or preventing diseases such as cancer or inflammatory diseases.
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Paragraph 00277
(2020/07/04)
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- Synthesis of Nitrogen-Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells
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Two series of racemic goniothalamin analogues displaying nitrogen-containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against a panel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity. Among them, goniothalamin chloroacrylamide 13 e displayed the lowest IC50 values for both MCF-7 (0.5 μm) and PC3 (0.3 μm) cells, about 26-fold more potent than goniothalamin (1). Besides its higher potency, compound 13 e also displayed much higher selectivity than goniothalamin. In contrast, goniothalamin isobutyramide 13 c was the most potent analogue against Caco-2 cells (IC50=0.8 μm), about 10-fold more potent and 17-fold more selective than 1. These results reveal the potential of compounds 13 c and 13 e for further in vivo studies, representing the first goniothalamin analogues with IC50 values in the low micromolar range and high selectivity against MCF-7, Caco-2, and PC3 cancer cell lines.
- Meirelles, Matheus A.,Braga, Carolyne B.,Ornelas, Catia,Pilli, Ronaldo A.
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p. 1403 - 1417
(2019/08/01)
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- CHROMENOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
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The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula (I); where A1, A2, G, R1, R2, R3, R4, and W are described herein.
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Paragraph 0644
(2019/07/13)
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- Development of a self-immolative linker for tetrazine-triggered release of alcohols in cells
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Bioorthogonal decaging reactions are a promising strategy for prodrug activation because they involve bond cleavage to release a molecule of interest. The trans-cyclooctene (TCO)-tetrazine inverse electron-demand Diels-Alder reaction has been widely applied in vivo for decaging of amine prodrugs, however, the release of alcohol-containing bioactive compounds has been less well studied. Here, we report a TCO-carbamate benzyl ether self-immolative linker for the release of OH-molecules upon reaction with a tetrazine trigger. The benzyl ether linker proved to be highly stable and can rapidly liberate alcohols under physiological conditions upon reaction with tetrazines. The mechanism and decaging yield were systematically examined by fluorescence and HPLC analysis by using a fluorogenic TCO-benzyl ether-coumarin probe and different 3,6-substituted tetrazine derivatives. This study revealed that decaging occurs rapidly (t1/2 = 27 min) and the cycloaddition step happens within seconds (t1/2 = 7 s) with reaction rates of ≈100 M-1 s-1. Importantly, the reaction is compatible with living organisms as demonstrated by the decaging of a prodrug of the antibacterial compound triclosan in the presence of live E. Coli, that resulted in complete cell killing by action of the released "OH-active drug". Overall, this work describes a new linker for masking alcohol functionality that can be rapidly reinstated through tetrazine-triggered decaging.
- Davies, Sarah,Oliveira, Bruno L.,Bernardes, Gon?alo J. L.
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supporting information
p. 5725 - 5730
(2019/06/19)
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- Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers
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A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of p-unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radical-trapping antioxidants; more so than the phenols from which they are derived—or transformed to—despite the fact that they do not possess a labile H-atom for transfer to the peroxyl radicals that propagate autoxidation.
- Romero, Kevin J.,Galliher, Matthew S.,Raycroft, Mark A. R.,Chauvin, Jean-Philippe R.,Bosque, Irene,Pratt, Derek A.,Stephenson, Corey R. J.
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supporting information
p. 17125 - 17129
(2018/12/04)
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- Chemoselective continuous-flow hydrogenation of aldehydes catalyzed by platinum nanoparticles dispersed in an amphiphilic resin
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A chemoselective continuous-flow hydrogenation of aldehydes catalyzed by a dispersion of platinum nanoparticles in an amphiphilic polymer (ARP-Pt) has been developed. Aromatic and aliphatic aldehydes bearing various reducible functional groups, such as keto, ester, or amide groups, readily underwent flow hydrogenation in aqueous solutions within 22 s in a continuous-flow system containing ARP-Pt to give the corresponding primary benzylic or aliphatic alcohols in ≤99% yield with excellent chemoselectivity. Moreover, the long-term continuous-flow hydrogenation of benzaldehyde for 8 days was realized, and the total turnover number of the catalyst reached 997. The flow hydrogenation system provides an efficient and practical method for the chemoselective hydrogenation of aldehydes bearing reducible functional groups.
- Osako, Takao,Torii, Kaoru,Hirata, Shuichi,Uozumi, Yasuhiro
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p. 7371 - 7377
(2017/11/09)
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- Efficient and expeditious chemoselective BOC protection of amines in catalyst and solvent-free media
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A green and eco-friendly route for the almost quantitative BOC protection of a large variety of aliphatic and aromatic amines, amino acids, and amino alcohols is reported in catalyst and solvent-free media under mild reaction conditions. The products were confirmed by 1H, 13C NMR, IR spectroscopy, and in some cases, elemental analysis. This protocol does not require any water quenches, solvent separations, and purification steps, such as recrystallization and column chromatography.
- Viswanadham, Balaga,Mahomed, Abdul S.,Friedrich, Holger B.,Singh, Sooboo
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p. 1355 - 1363
(2017/02/15)
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- DRUG-LINKER CONJUGATE PHARMACEUTICAL COMPOSITIONS
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Compositions are disclosed having a cytotoxic and/or vascular disrupting agent (VDA) payload attached to a linker. The linker can be a cathepsin B protease cleavable linker or a non-cleavable linker that may degrade intracellularly. Methods for making and using the compositions are also provided. The compositions can be provided to a patient in need thereof with the composition coming into contact with a cancer cell to activate or release the cytotoxic and/or vascular disrupting agent payload.
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Paragraph 000218-000221
(2017/05/02)
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- Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential
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In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was c
- Fujimoto, Jun,Hirayama, Takaharu,Hirata, Yasuhiro,Hikichi, Yukiko,Murai, Saomi,Hasegawa, Maki,Hasegawa, Yuka,Yonemori, Kazuko,Hata, Akito,Aoyama, Kazunobu,Cary, Douglas R.
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supporting information
p. 3018 - 3033
(2017/05/24)
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- Optimization and biological evaluation of 2-aminobenzothiazole derivatives as Aurora B kinase inhibitors
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A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G2/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics.
- Lee, Eun,An, Ying,Kwon, Junhee,Kim, Keun Il,Jeon, Raok
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p. 3614 - 3622
(2017/06/13)
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- NOVEL AND SPECIFIC INHIBITORS OF CYTOCHROME P450 26 RETINOIC ACID HYDROLASE
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The present disclosure is generally directed to compositions and methods for treating diseases that are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism.
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Page/Page column 44; 45
(2015/03/13)
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- NOVEL KLK4 INHIBITORS
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The present invention relates to novel compounds and probes which have a common chemical structure necessary to obtain potent inhibitory activity against KLK4 and/or may be used for the detection of KLK4 peptides and their activity. It further relates to the use of these compounds and methods for inhibiting and/or detecting KLK4 activity in vitro and in vivo by making use of said probes or inhibitors. The compounds of the invention differ from prior art compounds at least in the presence of phenyl guanidine (instead of e.g. benzyl guanidine) and/or the presence of a heteroatom in the tail group, their combined presence unexpectedly leading to potent and selective KLK4 inhibitory activity.
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Page/Page column 33; 34
(2015/12/18)
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- Discovery of Nanomolar Dengue and West Nile Virus Protease Inhibitors Containing a 4-Benzyloxyphenylglycine Residue
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The dengue virus (DENV) and West Nile Virus (WNV) NS2B-NS3 proteases are attractive targets for the development of dual-acting therapeutics against these arboviral pathogens. We present the synthesis and extensive biological evaluation of inhibitors that
- Behnam, Mira A. M.,Graf, Dominik,Bartenschlager, Ralf,Zlotos, Darius P.,Klein, Christian D.
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supporting information
p. 9354 - 9370
(2015/12/23)
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- Discovery of 1,2,4-thiadiazolidine-3,5-dione analogs that exhibit unusual and selective rapid cell death kinetics against acute myelogenous leukemia cells in culture
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4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was previously identified as an antileukemic agent exhibiting no evident toxicity toward normal hematopoietic cells. An SAR study has been carried out to examine the effect of varying the C-2 and
- Nasim, Shama,Guzman, Monica L.,Jordan, Craig T.,Crooks, Peter A.
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scheme or table
p. 4879 - 4883
(2011/09/16)
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- Aminophenylnitronylnitroxides: Highly networked hydrogen-bond assembly in organic radical materials
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2-(Meta-aminophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-3-oxide- 1-oxyl (mAPN) and 2-(para-aminophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H- imidazole-3-oxide-1-oxyl (pAPN) were synthesized and subjected to magnetostructural analysis. Both form extended hydrogen bonding networks involving both amino NH bonds to radical spin-density bearing nitronylnitroxide NO groups. Their crystallographic assembly motifs and magnetic exchange properties are compared to those of tert-butoxylcarbonyl (BOC) and amide derivatives having only one NH bond. The conversion of pAPN to acid salt derivatives gives a solid that is essentially diamagnetic, although dissolution of the solid shows the radical spin units to be preserved.
- Aboaku, Safo,Paduan-Filho, Armando,Bindilatti, Valdir,Oliveira, Nei Fernandes,Schlueter, John A.,Lahti, Paul M.
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scheme or table
p. 4844 - 4856
(2012/05/20)
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- Amination of aryl iodides using a fluorous-tagged ammonia equivalent
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A fluorous-tagged ammonia equivalent for the Cu-catalyzed amination of aryl iodides is described in which N-Boc-protected anilines are produced in high overall yield and purity. All purification steps are performed using Fluorous SolidPhase Extraction (F-SPE) greatly simplifying and speeding up the isolation of the desired products.
- Nielsen, Simon Dalsgaard,Smith, Garrick,Begtrup, Mikael,Kristensen, Jesper L.
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experimental part
p. 3704 - 3710
(2010/09/05)
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- Schiff bases derived from p-aminobenzyl alcohol as trigger groups for pH-dependent prodrug activation
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A number of novel acid-sensitive Schiff bases derived from p-aminobenzyl alcohol and various benzaldehyde derivatives were synthesized and were subsequently shown to trigger benzyl elimination reactions. The kinetics of acid-catalyzed hydrolysis at pH 5.0 as well as stability at pH 7.4 were studied using fluorogenic model compounds. Two fluoro-substituted Schiff bases showed efficient hydrolysis at pH 5.0 combined with a long-term stability at pH 7.4 and are considered suitable candidates for the development of anticancer prodrugs.
- Müller, Ivonne A.,Kratz, Felix,Jung, Manfred,Warnecke, André
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supporting information; experimental part
p. 4371 - 4374
(2010/09/12)
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- NOVEL CURCUMIN DERIVATIVE
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The present invention provides a novel compound that is structurally similar to curcumin and has a suppressive effect on Aβ aggregation, a degradative effect on Aβ aggregates, an inhibitory effect on β-secretase, and a protective effect on neurons. The novel compound is a compound represented by the following general formula (Ia) or a salt thereof: wherein R1 represents a 4-hydroxy-3-methoxyphenyl group or the like, and R2 represents a 1H-indol-6-yl group or the like.
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Page/Page column 75
(2009/12/07)
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- Aminostyrylbenzofuran derivatives as potent inhibitors for Aβ fibril formation
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The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a-w and their inhibitory activities for Aβ fibril formation were described. All the synthesized compounds were evaluated by thioflavin T (ThT) assay and displayed potent inhibitory activities for Aβ fibril formation. Among them, compounds 1i and 1q exhibited excellent inhibitory activities (IC50 = 0.07 and 0.08 μM, respectively) than those of Curcumin (IC50 = 0.80 μM) and IMSB (IC50 = 8.00 μM) as reference compounds. Both compounds were selected as promising candidates for further biological evaluation.
- Byun, Ji Hun,Kim, HyeYun,Kim, YoungSoo,Mook-Jung, Inhee,Kim, Dong Jin,Lee, Won Koo,Yoo, Kyung Ho
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scheme or table
p. 5591 - 5593
(2009/06/18)
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- TARGETED POLYMERIC PRODRUGS CONTAINING MULTIFUNCTIONAL LINKERS
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The present invention provides single chain antibody-directed polymeric prodrugs containing multifunctional linkers. Methods of making the polymeric delivery systems and methods of treating mammals using the same are also disclosed.
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Page/Page column 72-73
(2008/06/13)
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- ORGANIC COMPOUNDS
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The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.
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Page/Page column 103
(2008/12/08)
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- 2-THIOPYRIMIDINONES AS THERAPEUTIC AGENTS
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The present invention provides compounds of Formulas I-VII, or pharmaceutically acceptable derivatives thereof, wherein the compounds are as defined in the specification. These compounds are inhibitors of protein kinases, particularly inhibitors of MEKK p
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Page/Page column 99
(2008/06/13)
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- New mustard-linked 2-aryl-bis-benzimidazoles with anti-proliferative activity
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We describe new methodology for the synthesis of symmetric bis-benzimidazoles carrying 2-aryl moieties, including 2-[4-(3′- aminopropoxy)phenyl] and 2-[4-(3′-aminopropanamido)phenyl] substituents, together with the synthesis of novel hybrid molecules comprising bis-benzimidazoles in ester and amide combination with the N-mustard chlorambucil. The in vitro activities of these compounds against five cancer cell lines are also provided. The Royal Society of Chemistry 2006.
- Le Sann, Christine,Baron, Anne,Mann, John,Van Den Berg, Hendrik,Gunaratnam, Mekala,Neidle, Stephen
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p. 1305 - 1312
(2007/10/03)
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- Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator
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In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A kapp value in the 103 M -1 s-1 range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.
- Joossens,Van Der Veken,Lambeir,Augustyns,Haemers
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p. 2411 - 2413
(2007/10/03)
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- Isoxazole-containing thiourea inhibitors useful for treatment of varicella zoster virus
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This Invention provides a compound of the Formula: wherein X is R1, R2, R3 and R4 are described in the specification and a pharmaceutical composition comprising the compound used for inhibiting replication of a
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- Indole nitriles
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Compounds of the formula (I) wherein m, n, R1, R2, R3, R4, R5 and R6 are as described herein, together with methods for making the compounds and using the compounds for treatment of diseases or conditions mediated by Cathepsin K.
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- Rational design, synthesis and structure-Activity relationships of a cyclic succinate series of TNF-α converting enzyme inhibitors. Part 1: Lead identification
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Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC50=
- Xue, Chu-Biao,He, Xiaohua,Roderick, John,Corbett, Ronald L.,Duan, James J.-W.,Liu, Rui-Qin,Covington, Maryanne B.,Newton, Robert C.,Trzaskos, James M.,Magolda, Ronald L.,Wexler, Ruth R.,Decicco, Carl P.
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p. 4293 - 4297
(2007/10/03)
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- Pyrrolopyrimidines as therapeutic agents
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Chemical compounds having structural formula I and physiologically acceptable salts and metabolites thereof, are inhibitors of serine/threonine and tyrosine kinase activity. Several of the kinases, whose activity is inhibited by these chemical compounds, are involved in immunologic, hyperproliferative, or angiogenic processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis or endothelial cell hyperproliferation is a factor. These compounds can be used to treat cancer and hyper proliferative disorders, rheumatiod arthritis, disorders of the immune system, trasplant refections and imflammatory disorders.
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- Design and synthesis of non-peptidic inhibitors for the Syk C-terminal SH2 domain based on structure-based in-silico screening
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Structure-based in-silico screening was carried out for the Syk C-terminal SH2 domain. Fragments that could interact with the pY or pY+1 pockets were selected by our in-silico screening. After tethering two fragments bound to these pockets, we have designed and synthesized new compounds that show favorable interaction with the pY+3 pocket. One such compound, having a cyclohexylmalonic acid moiety identified as a novel potent phosphotyrosyl mimetic, exhibited an affinity comparable to that of the monophosphorylated ligand peptide.
- Niimi,Orita,Okazawa-Igarashi,Sakashita,Kikuchi,Ball,Ichikawa,Yamagiwa,Sakamoto,Tanaka,Tsukamoto,Fujita
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p. 4737 - 4740
(2007/10/03)
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- Guanidinophenyl-Substituted Enol Lactones as Selective, Mechanism-Based Inhibitors of Trypsin-like Serine Proteases
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We have synthesized four guanidinophenyl-substituted protio enol and iodo enol lactones (3-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone (1), 3-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyranone (2), 4-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone (3), and 4-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyranone (4)) and tested them for inhibitory activity against some trypsin-like enzymes, namely trypsin, urokinase, tissue plasminogen activator (t-PA), plasmin, and thrombin, as well as α-chymotrypsin and human neutrophil elastase (HNE).The β-aryl-substituted protio lactone 3 was a potent alternate substrate inhibitor of trypsin and urokinase.The α-aryl-substituted iodo lactone 2 was a permanent inactivator of urokinase, plasmin, t-PA, thrombin, and α-chymotrypsin, exhibiting a relatively high specificity for the former two enzymes.In general, these compounds showed a preference for inactivating trypsin-like enzymes over α-chymotrypsin and HNE.Also, within the class of trypsin-like enzymes, there was generally good selectivity of inhibition.
- Rai, Roopa,Katzenellenbogen, John A.
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p. 4150 - 4159
(2007/10/02)
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