- 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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- 4CzIPN catalyzed photochemical oxidation of benzylic alcohols
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A green photoredox oxidation of benzylic primary and secondary alcohols to aldehydes and ketones with air as an oxidant was reported. The oxidation shows broad substrate scope and excellent selectivity over benzylic alcohols to the aliphatic alcohols. Further mechanistic studies revealed a quinuclidine mediated HAT process, and blue LEDs promoted 4CzlPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) photoredox cycle were involved in our oxidation.
- Zhang, Heng,Guo, Tianyun,Wu, Mingzhong,Huo, Xing,Tang, Shouchu,Wang, Xiaolei,Liu, Jian
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supporting information
(2021/02/20)
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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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- 2-phenylchroman-4-one derivatives and antiviral composition comprising the same
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The present invention relates to a 2-phenylchroman-4-one derivative or a pharmaceutically acceptable salt thereof, a method for manufacturing the same, and a therapeutic agent for MERS containing the same as an active component. A compound containing the
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Paragraph 0067; 0152-0156
(2020/09/10)
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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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supporting information
p. 1403 - 1417
(2019/08/01)
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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 Reduction of Sterically Demanding N,N-Diisopropylamides to Aldehydes
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A sequential one-pot process for chemoselectively reducing sterically demanding N,N-diisopropylamides to aldehydes has been developed. In this reaction, amides are activated with EtOTf to form imidates, which are reduced with LiAlH(OR)3 [R = t-Bu, Et] to give aldehydes by hydrolysis of the resulting hemiaminals. The non-nucleophilic base 2,6-DTBMP remarkably improves reaction efficiency. The combination of EtOTf/2,6-DTBMP and LiAlH(O-t-Bu)3 was found to be optimal for reducing alkyl, alkenyl, alkynyl, and 2-monosubstituted aryl N,N-diisopropylamides. In contrast, EtOTf and LiAlH(OEt)3 in the absence of base were found to be optimal for reducing extremely sterically demanding 2,6-disubstituted N,N-diisopropylbenzamides. The reaction tolerates various reducible functional groups, including aldehyde and ketone. 1H NMR studies confirmed the formation of imidates stable in water. The synthetic usefulness of this methodology was demonstrated with N,N-diisopropylamide-directed ortho-metalation and C-H bond activation.
- Xiao, Peihong,Tang, Zhixing,Wang, Kai,Chen, Hua,Guo, Qianyou,Chu, Yang,Gao, Lu,Song, Zhenlei
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p. 1687 - 1700
(2018/02/23)
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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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- Fluorescent probe used for detecting carboxylesterase and preparation method and application thereof
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The invention belongs to the technical field of analysis and detection, and discloses a fluorescent probe used for detecting carboxylesterase and a preparation method and an application thereof. The fluorescent probe is 2-{2-[4-(4'-benzyl acetate benzyloxy-formamido)-styryl]-4H-benzopyran-4-yl}-malononitrile, and has a structural formula in a formula (I). and the fluorescent probe is used for detecting carboxylesterase. Compared with the current detection technique of fluorescence, the fluorescent probe has high selective response for carboxylesterase, strong anti-interference performance, and effective and visual detection mode, low investment cost, and simple synthesis route and method, and is suitable for enlarge production and practical application.
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Paragraph 0066; 0068; 0078; 0085
(2017/08/28)
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- Simple and Efficient Ruthenium-Catalyzed Oxidation of Primary Alcohols with Molecular Oxygen
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Oxidative transformations utilizing molecular oxygen (O2) as the stoichiometric oxidant are of paramount importance in organic synthesis from ecological and economical perspectives. Alcohol oxidation reactions that employ O2are scarce in homogeneous catalysis and the efficacy of such systems has been constrained by limited substrate scope (most involve secondary alcohol oxidation) or practical factors, such as the need for an excess of base or an additive. Catalytic systems employing O2as the “primary” oxidant, in the absence of any additive, are rare. A solution to this longstanding issue is offered by the development of an efficient ruthenium-catalyzed oxidation protocol, which enables smooth oxidation of a wide variety of primary, as well as secondary benzylic, allylic, heterocyclic, and aliphatic, alcohols with molecular oxygen as the primary oxidant and without any base or hydrogen- or electron-transfer agents. Most importantly, a high degree of selectivity during alcohol oxidation has been predicted for complex settings. Preliminary mechanistic studies including18O labeling established the in situ formation of an oxo–ruthenium intermediate as the active catalytic species in the cycle and involvement of a two-electron hydride transfer in the rate-limiting step.
- Ray, Ritwika,Chandra, Shubhadeep,Maiti, Debabrata,Lahiri, Goutam Kumar
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supporting information
p. 8814 - 8822
(2016/07/06)
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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 34
(2015/12/18)
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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 45
(2015/03/13)
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- Palladium-catalyzed synthesis of N-aryl carbamates
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An efficient synthesis of aryl carbamates was achieved by introducing alcohols into the reaction of palladium-catalyzed cross-coupling of ArX (X = Cl, OTf) with sodium cyanate. The use of aryl triflates as electrophilic components in this transformation a
- Vinogradova, Ekaterina V.,Park, Nathaniel H.,Fors, Brett P.,Buchwald, Stephen L.
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supporting information
p. 1394 - 1397
(2013/04/24)
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- Reductive carbonylation of aryl halides employing a two-chamber reactor: A protocol for the synthesis of aryl aldehydes including 13C- and D-isotope labeling
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A protocol has been developed for conducting the palladium-catalyzed reductive carbonylation of aryl iodides and bromides using 9-methylfluorene-9- carbonyl chloride (COgen) as a source of externally delivered carbon monoxide in a sealed two-chamber system (COware), and potassium formate as the in situ hydride source. The method is tolerant to a wide number of functional groups positioned on the aromatic ring, and it can be exploited for the isotope labeling of the aldehyde group. Hence, reductive carbonylations run with 13COgen provide a facile access to 13C-labeled aromatic aldehydes, whereas with DCO2K, the aldehyde is specifically labeled with deuterium. Two examples of double isotopic labeling are also demonstrated. Finally, the method was applied to the specific carbon-13 labeling of the β-amyloid binding compound, florbetaben.
- Korsager, Signe,Taaning, Rolf H.,Lindhardt, Anders T.,Skrydstrup, Troels
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p. 6112 - 6120
(2013/07/26)
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- Combination of NH2OH·HCl and NaIO4: A new and mild oxidizing agent for selective oxidation of alcohols to carbonyl compounds
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A new method for oxidation of alcohols to carbonyl compounds has been developed using NH2OH·HCl and NaIO4 under mild reaction conditions at room temperature. Application of the method for the synthesis of diiodo compound from α,β-unsaturated carbonyl compound is also described.
- Majee, Adinath,Kundu, Shrishnu Kumar,Santra, Sougata,Hajra, Alakananda
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experimental part
p. 4433 - 4435
(2012/09/25)
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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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- 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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- 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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p. 9044 - 9047
(2008/03/18)
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- Mild and selective hydrozirconation of amides to aldehydes using Cp 2Zr(H)Cl: Scope and mechanistic insight
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An investigation of the use of Cp2Zr(H)Cl (Schwartz's reagent) to reduce a variety of amides to the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of tertiary amides, including Weinreb's amides, can be converted directly to the corresponding aldehydes with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for reduction as well, although the yields were somewhat diminished as compared to the corresponding tertiary amides. Results from NMR experiments suggested the presence of a stable, 18-electron zirconacycle intermediate that presumably affords the aldehyde upon water or silica gel workup. A series of competition experiments revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing and thus more delocalized across the amide bond by resonance. This trend accounts for the observed excellent selectivity for tertiary amides versus esters. Experiments regarding the solvent dependence of the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and alkynes. Addition of p-anisidine to the reaction intermediate resulted in the formation of the corresponding imine mimicking the addition of water that forms the aldehyde.
- Spletstoser, Jared T.,White, Jonathan M.,Tunoori, Ashok Rao,Georg, Gunda I.
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p. 3408 - 3419
(2007/10/03)
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- Cross-linking yield variation of a potent matrix metalloproteinase photoaffinity probe and consequences for functional proteomics
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(Chemical Equation Presented) Probing proteinases: A radioactive photoaffinity probe exhibiting subnanomolar potency towards matrix metalloproteinases (MMPs) has been developed (see structure). High sensitivity in the detection of particular MMPs has been
- David, Arnaud,Steer, David,Bregant, Sarah,Devel, Laurent,Makaritis, Anastasios,Beau, Fabrice,Yiotakis, Athanasios,Dive, Vincent
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p. 3275 - 3277
(2008/03/12)
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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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- Indole nitriles
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Compounds of the formula (I) wherein m, n, R1, R2, R3, R4, R5and R6are 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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- A facile and efficient ZrCl4 catalyzed conversion of aldehydes to geminal-diacetates and dipivalates and their cleavage
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A novel, mild and efficient method has been developed for the preparation of geminal-diacetates and dipivalates in high yields through a reaction of aldehydes with acetic anhydride or pivalic anhydride using Zirconium (IV) chloride as a catalyst under solvent free conditions. Regeneration of aldehydes from the acylals was also achieved using the same catalyst in CH3OH.
- Smitha,Reddy, Ch. Sanjeeva
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p. 9571 - 9576
(2007/10/03)
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- Seleno compounds containing nitrone moiety, their preparation and their therapeutic uses
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The present invention provides novel seleno compounds containing nitrone moiety, a process for preparing the same, the use of the novel compounds as therapeutics for treating and/or preventing various medical dysfunctions and diseases arising from reactiv
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- An efficient biomimetic cleavage of gem-diacetates to aldehydes by β-cyclodextrin under neutral conditions in aqueous medium
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The cleavage of gem-diacetates to aldehydes, a widely used protecting group in organic synthesis, has been achieved for the first time under neutral conditions in aqueous medium using β-cyclodextrin as catalyst. The main advantage of the present methodology is that it can be used with compounds having a variety of functional groups since the cleavage is carriedout under neutral conditions in aqueous medium.
- Arjun Reddy,Rajender Reddy,Bhanumathi,Rama Rao
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p. 273 - 277
(2007/10/03)
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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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