- Synthesis and antiallergic activity of N-(pyridin-2-yl)-3-(piperazin-1-yl) propanamides
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A series of 6 new N-(pyridin-2-yl)-3-(piperazin-1-yl)propanamides were synthesized from the corresponding N-pyridinylpropenamides to determine potential antiallergic activity as assayed in vivo by the passive cutaneous anaphylaxis test. The IC50 of compound 12 after oral administration was comparable to that of oxatomide.
- Courant,Leblois,Le Baut,Venco,Panconi
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- Silyl Radical-Mediated Activation of Sulfamoyl Chlorides Enables Direct Access to Aliphatic Sulfonamides from Alkenes
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Single electron reduction is more challenging for sulfamoyl chlorides than sulfonyl chlorides. However, sulfamoyl and sulfonyl chlorides can be easily activated by Cl-atom abstraction by a silyl radical with similar rates. This latter mode of activation was therefore selected to access aliphatic sulfonamides, applying a single-step hydrosulfamoylation using inexpensive olefins, tris(trimethylsilyl)silane, and photocatalyst Eosin Y. This late-stage functionalization protocol generates molecules as complex as sulfonamide-containing cyclobutyl-spirooxindoles for direct use in medicinal chemistry.
- Gouverneur, Véronique,Hell, Sandrine M.,Laudadio, Gabriele,Meyer, Claudio F.,Misale, Antonio,No?l, Timothy,Trabanco, Andrés A.,Willis, Michael C.
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supporting information
p. 720 - 725
(2020/02/20)
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- Disulfide Promoted C?P Bond Cleavage of Phosphoramide: “P” Surrogates to Synthesize Phosphonates and Phosphinates
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A metal-free C?P bond cleavage reaction is described herein. Phosphoramides, a phosphine source, can react with alcohols to produce phosphonate and phosphinate derivatives in the presence of a disulfide. P?H2, P-alkyl, and P,P-dialkyl phosphoramides can be used as substrates to obtain the corresponding pentavalent phosphine products. (Figure presented.).
- Hou, Fei,Du, Xing-Peng,Alduma, Anwar I.,Li, Zhi-Feng,Huo, Cong-De,Wang, Xi-Cun,Wu, Xiao-Feng,Quan, Zheng-Jun
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supporting information
p. 4755 - 4760
(2020/10/06)
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- Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase
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Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor β (PDGFR-β) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.
- Shi, Zhi-Hao,Liu, Feng-Tao,Tian, Hao-Zhong,Zhang, Yan-Min,Li, Nian-Guang,Lu, Tao
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p. 4735 - 4744
(2018/08/21)
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- PYRAZOLOPYRIMIDINE DERIVATIVES, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR USE IN PREVENTING OR TREATING CANCER, AUTOIMMUNE DISEASE AND BRAIN DISEASE CONTAINING THE SAME AS AN ACTIVE INGREDIENT
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The present invention relates to a pyrazolopyrimidine derivative, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient for the prevention or treatment of cancer, autoimmune disease and brain disease. The pyrazolopyrimidine derivative of the present invention exhibits excellent Bruton's tyrosine kinase inhibition activity, so that it can be effectively used as a pharmaceutical composition for the prevention or treatment of cancer, autoimmune disease and Parkinson's disease.
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Paragraph 447-451
(2018/12/02)
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- Synthesis of thermo- and photo-responsive polysiloxanes with tunable phase separation: Via aza-Michael addition
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Two kinds of thermo- and photo-dual-responsive polysiloxanes (DRPSs) with functional pendent groups, N-isopropyl amides and azobenzene (Azo) or salicylideneaniline (SA), were synthesized through a facile, effective, and catalyst-free aza-Michael addition of poly(aminopropylmethyl-siloxane) with N-isopropyl acrylamide and N-azobenzene acrylamide or N-salicylaldehyde acrylamide. The chemical structrures of DRPSs were systematically characterized using FT-IR, H NMR and UV-Vis spectroscopy. The as-prepared DRPSs with lower Azo or SA contents exhibited lower critical solution temperature (LCST)-type phase transition in water, which is reversible and can be controlled by temperature and UV light. The effects of Azo and SA contents on the responsive properties of DRPSs are examined in detail. The LCST decreased with the increasing Azo or SA content. Once the content of Azo or SA reached up to 5.7% or 8.2%, respectively, DRPSs could not be dissolved in water even in an ice bath. Higher values of the LCST were measured after irradiation of the polymer solutions due to the higher polarity of cis-Azo and keto-SA conformation, induced by irradiation. The differences in cloud points between the irradiated and the non-irradiated DRPS aqueous solutions increased up to 3.4 °C and 9.8 °C when combined with 3.8% Azo and 5.8% SA units, respectively.
- Feng, Kai,Li, Shusheng,Feng, Linglong,Feng, Shengyu
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p. 14498 - 14504
(2017/11/28)
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- PYRIMIDINE DERIVATIVES AS KINASE INHIBITORS AND THEIR THERAPEUTICAL APPLICATIONS
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The present invention provides kinase inhibitors with anti-proliferative activity comprising substituted pyrimidine derivatives and pharmaceutically-acceptable formulations thereof. In addition, the invention provides methods for making novel compounds and methods for using the compounds.
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Paragraph 00388
(2016/09/22)
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- Systematic study of the glutathione (GSH) reactivity of N-arylacrylamides: 1. Effects of aryl substitution
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Success in the design of targeted covalent inhibitors depends in part on a knowledge of the factors influencing electrophile reactivity. In an effort to further develop an understanding of structure-reactivity relationships among N-arylacrylamides, we determined glutathione (GSH) reaction rates for a family of N-arylacrylamides independently substituted at ortho-, meta-, and para-positions with 11 different groups common to inhibitor design. We find that substituent effects on reaction rates show a linear Hammett correlation for ortho-, meta-, and para-substitution. In addition, we note a correlation between 1H and 13C NMR chemical shifts of the acrylamide with GSH reaction rates, suggesting that NMR chemical shifts may be a convenient surrogate measure of relative acrylamide reactivity. Density functional theory calculations reveal a correlation between computed activation parameters and experimentally determined reaction rates, validating the use of such methodology for the screening of synthetic candidates in a prospective fashion.
- Cee, Victor J.,Volak, Laurie P.,Chen, Yuping,Bartberger, Michael D.,Tegley, Chris,Arvedson, Tara,McCarter, John,Tasker, Andrew S.,Fotsch, Christopher
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p. 9171 - 9178
(2015/12/23)
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- Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments
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Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
- J?st, Christian,Nitsche, Christoph,Scholz, Therese,Roux, Lionel,Klein, Christian D.
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supporting information
p. 7590 - 7599
(2014/12/11)
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- A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases
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A novel fragment-based drug discovery approach is reported which irreversibly tethers drug-like fragments to catalytic cysteines. We attached an electrophile to 100 fragments without significant alterations in the reactivity of the electrophile. A mass spectrometry assay discovered three nonpeptidic inhibitors of the cysteine protease papain. The identified compounds display the characteristics of irreversible inhibitors. The irreversible tethering system also displays specificity: the three identified papain inhibitors did not covalently react with UbcH7, USP08, or GST-tagged human rhinovirus 3C protease.
- Kathman, Stefan G.,Xu, Ziyang,Statsyuk, Alexander V.
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supporting information
p. 4969 - 4974
(2014/07/07)
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- Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease
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Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.
- Prime, Michael E.,Andersen, Ole A.,Barker, John J.,Brooks, Mark A.,Cheng, Robert K. Y.,Toogood-Johnson, Ian,Courtney, Stephen M.,Brookfield, Frederick A.,Yarnold, Christopher J.,Marston, Richard W.,Johnson, Peter D.,Johnsen, Siw F.,Palfrey, Jordan J.,Vaidya, Darshan,Erfan, Sayeh,Ichihara, Osamu,Felicetti, Brunella,Palan, Shilpa,Pedret-Dunn, Anna,Schaertl, Sabine,Sternberger, Ina,Ebneth, Andreas,Scheel, Andreas,Winkler, Dirk,Toledo-Sherman, Leticia,Beconi, Maria,MacDonald, Douglas,Mu?oz-Sanjuan, Ignacio,Dominguez, Celia,Wityak, John
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p. 1021 - 1046
(2012/04/10)
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- COMPOUNDS
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A compound of formula (I): compositions and medicaments containing the same as well as processes for the preparation and use of such compounds, compositions and medicaments, particularly in diseases associated with inappropriate Aurora activity.
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Page/Page column 56
(2010/11/26)
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- Thiazolidinones, their production and use as pharmaceutical agents
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Thiazolidinones of general formula I in which Q, A, B, X, R1 and R2 have the meanings that are indicated in the description, as well as those of general formula IA in which Q, A, B, X, R1 and R2a have the meanings that are indicated in the description, their production and use as inhibitors of the polo-like kinase (PLK) for treating various diseases as well as intermediate products for the production of thiazolidinones are described.
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- Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6- and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation
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The synthesis is reported of a group of 3,6,9-trisubstituted acridine compounds as telomeric quadruplex-stabilizing ligands with systematic variations at the 3-, 6-, and 9-positions. A new microwave-assisted methodology has been developed for trisubstituted acridine synthesis. Structure-activity relationships are reported using surface plasmon resonance and a fluorescence melting assay to examine quadruplex binding, together with a telomerase inhibition assay. These reveal relationships between G-quadruplex stabilization and telomerase inhibition and optimal 3,6- and 9-substituent side-chain lengths for maximal activity. Qualitative molecular modeling using molecular dynamics simulations has been undertaken on four quadruplex-DNA complexes. Long-term exposure of MCF7 cancer cells to a subset of the most active compounds, at doses lower than the IC50 values, showed that one compound produced a marked decrease in population growth, accompanied by senescence, which is consistent with telomere targeting by this agent.
- Moore, Michael J. B.,Schultes, Christoph M.,Cuesta, Javier,Cuenca, Francisco,Gunaratnam, Mekala,Tanious, Farial A.,Wilson, W. David,Neidle, Stephen
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p. 582 - 599
(2007/10/03)
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- Exploring the scope of the 29G12 antibody catalyzed 1,3-dipolar cycloaddition reaction
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29G12 is a murine monoclonal antibody programmed to catalyze the regio- and enantioselective 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide 1a and N,N-dimethylacrylamide 2a (Toker, J. D.; Wentworth, P., Jr.; Hu, Y.; Houk, K. N.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 3244). Given the unique nature of 29G12 as a protein biocatalyst for this chemical reaction, we have investigated both the substrate specificity and mechanistic parameters of the 29G12-catalyzed process. These studies have shown that while 29G12 is specific for its dipole substrate Ia, the antibody is highly promiscuous with respect to the dipolarophiles it can process. 29G12 accepts a bulky hydrophobic dipolarophile cosubstrate, with rates of product formation up to 70-fold faster than with the original substrate 2a. In all cases, the respective isoxazoline products are produced with exquisite regio- and stereochemical control (78-98% ee). Comparison between the steady-state kinetic parameters from the 29G12-catalyzed reaction of 1a with the most efficient versus the original dipolarophile cosubstrate (2m and 2a, respectively), reveals that while the effective molarities (EM)s are almost identical (EM (2m) 26 M; EM(2a) 23 M), the affinity of 29G12 for the larger dipolarophile 2m is more than 1 order of magnitude higher than for 2a [Km(2m) 0.44 ± 0.04 mM; Km(2a) 5.8 ± 0.4 mM]. Furthermore, when 2m is the cosubstrate, the affinity of 29G12 for its dipole 1a is also greatly improved [Km(1a) 0.82 ± 0.1 mM compared to Km(1a) 3.4 ± 0.4 mM when 2a is the cosubstrate]. An analysis of the temperature dependence of the 29G12-catalyzed reaction between 1a and 2m reveals that catalysis is achieved via a decrease in enthalpy of activation (ΔΔH? 4.4 kcal mol-1) and involves a large increase in the entropy of activation (ΔΔS? 10.4 eu). The improved affinity of 29G12 for the nitrile oxide Ia in the presence of 2m, coupled with the increase in ΔΔS? during the 29G12-catalyzed reaction between 1a and 2m supports the notion of a structural reorganization of the active site to facilitate this antibody-catalyzed reaction.
- Toker, Jonathan D.,Tremblay, Martin R.,Yli-Kauhaluoma, Jari,Wentworth, Anita D.,Zhou, Bin,Wentworth Jr., Paul,Janda, Kim D.
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p. 7810 - 7815
(2007/10/03)
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- Synthesis and capsule formation of upper rim substituted tetra-acrylamido calix[4]arenes
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Upper rim substituted tetraiodo calix[4]arenes are coupled to a variety of acrylamides using the palladium catalysed Heck reaction. Tetra-acrylamido upper rim substituted calix[4]arenes are obtained in good yields with exceptionally high stereoselectivity, to produce the & all-trans isomers. Tetra-acrylamido calix[4]arenes derived from secondary acrylamides are shown to dimerise via eight hydrogen bonds to form dimeric capsules, which are able to include small organic molecules. The Royal Society of Chemistry 2005.
- Kuhnert, Nikolai,Le-Gresley, Adam
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p. 2175 - 2182
(2007/10/03)
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- Substituted triazinyl acrylamide derivatives and methods of use
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The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer and polycystic kidney disease.
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- Diaminopuridine-containing thiourea inhibitors of herpes viruses
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Compounds of the formula STR1 are useful in the treatment of diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.
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- Langmuir-Blodgett film formation by polymeric materials
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Polymeric materials such as: poly(n-octadecyl methacrylate), poly(n-octadecyl methacrylate-co-N-p-nitrophenylmaleimide) and poly(n-octadecyl methacrylate-co-N-p-nitrophenylacrylamide) were synthesized to investigate their ability for monolayer film formation and deposition. It was found that polymerization of n-octadecyl methacrylate yielded the material with improved ability of film formation as compared with the monomer, and the surface pressure-area isotherm showed a distinct solid film phase formation with a high value of film collapse pressure of ca. 56 mN/m. The incorporation of a co-monomer resulted in a shift of the surface pressure isotherm towards higher area values, still with a distinct solid film phase region and high film collapse pressure. The thickness of the poly(n-octadecyl methacrylate) film deposited onto a solid subphase was ca. 3 nm per monolayer (as determined by surface plasmon resonance) and this value corresponded to the length of the monomer molecule.
- Razna,Kucharski,Bryjak
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p. 2312 - 2320
(2007/10/03)
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- Mechanochemical solid-state polymerization. VI. Quantum chemical considerations for structural criteria of mechanically polymerizable vinyl monomers
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To provide the structural criteria for mechanically polymerizable vinyl monomers in metallic vessels, we carried out the MO calculations (AM1 method) of several acrylamide, acrylate and styrene derivatives as model compounds for such reactions. It was found that the nature of LUMO of vinyl monomers is closely related to the capability for initiation of mechanochemical polymerization. The following requisite concerning the nature of LUMO was shown to be a necessary condition for the activity of such reactions: Even if the LUMO energy is lower than 0.166 eV in the AM1 scheme, the LUMO coefficient must be highly localized in the vinyl group, when the monomer does not meet this criterion, the introduction of a saturated group such as an alkyl group to insulate electronically the π-electron system of vinyl group from the rest of the molecules will lead to the mechanically polymerizable monomers.
- Kondo,Murase,Kuzuya
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p. 768 - 773
(2007/10/02)
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- Antianaphylactic and antibronchospastic N-benzhydryldiazacycloalkylalkananilides
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New piperazine derivatives of general formula: wherein:, R is hydrogen or lower alkyl,A is straight or branched lower alkyl and R1 and R2 are respectively hydrogen, amino, alkylamino, dialkylamino mono or di(hydroxyalkyl)amino,morpholino, piperidino, N-alkylpiperazino, 1,3-dithiolan-2-ylidenamino, N--alkylureido, isomers mixture thereof, individual enantiomers and pharmaceutically acceptable acid addition salts thereof. The new compounds exhibit a high antianaphylactic and antibronchospastic activity.
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