- Construction of dye-stapled Quenchbodies by photochemical crosslinking to antibody nucleotide-binding sites
-
We successfully converted an antibody single-chain variable fragment and a full-sized antibody to Quenchbodies, which are a type of powerful fluorescent immunosensor, through ultraviolet-based photochemical crosslinking of an indole-3-butyric acid-conjugated fluorescent dye to the nucleotide-binding sites near the antigen-binding sites.
- Jeong, Hee-Jin,Matsumoto, Kenji,Itayama, Shuya,Kodama, Kozue,Abe, Ryoji,Dong, Jinhua,Shindo, Mitsuru,Ueda, Hiroshi
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Read Online
- 7-Nitrobenzofurazan (NBD) derivatives of 5′-N-ethylcarboxamidoadenosine (NECA) as new fluorescent probes for human A3 adenosine receptors
-
New fluorescent ligands for adenosine receptors (ARs), obtained by the insertion, in the N6 position of NECA, of NBD-moieties with linear alkyl spacers of increasing length, proved to possess a high affinity and selectivity for the A3 subtype expressed in CHO cells. In fluorescence microscopy assays, compound 2d, the most active and selective for human A3-AR, permitted visualization and localization of this human receptor subtype, showing its potential suitability for internalization and trafficking studies in living cells.
- Macchia, Marco,Salvetti, Francesca,Bertini, Simone,Di Bussolo, Valeria,Gattuso, Lisa,Gesi, Marco,Hamdan, Mahmoud,Klotz, Karl-Norbert,Laragione, Teresina,Lucacchini, Antonio,Minutolo, Filippo,Nencetti, Susanna,Papi, Chiara,Tuscano, Daniela,Martini, Claudia
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Read Online
- Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma
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Traditional EZH2 inhibitors are developed to suppress the enzymatic methylation activity, and they may have therapeutic limitations due to the nonenzymatic functions of EZH2 in cancer development. Here, we report proteolysis-target chimera (PROTAC)-based EZH2 degraders to target the whole EZH2 in lymphoma. Two series of EZH2 degraders were designed and synthesized to hijack E3 ligase systems containing either von Hippel-Lindau (VHL) or cereblon (CRBN), and some VHL-based compounds were able to mediate EZH2 degradation. Two best degraders, YM181 and YM281, induced robust cell viability inhibition in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas, outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat) that was only effective against DLBCL. The EZH2 degraders displayed promising antitumor activities in lymphoma xenografts and patient-derived primary lymphoma cells. Our study demonstrates that EZH2 degraders have better therapeutic activity than EZH2 inhibitors, which may provide a potential anticancer strategy to treat lymphoma.
- Tu, Yalin,Sun, Yameng,Qiao, Shuang,Luo, Yao,Liu, Panpan,Jiang, Zhong-Xing,Hu, Yumin,Wang, Zifeng,Huang, Peng,Wen, Shijun
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p. 10167 - 10184
(2021/07/26)
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- JNK Inhibitor. Pharmaceutical compositions and uses thereof
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Provided herein are compounds represented by the following formula (I), racemates, stereoisomers, tautomers, isotopically labels, solvates, polymorphs, nitrogen oxides or pharmaceutically acceptable salts thereof, which can be used as JNK inhibitors. A method for preparing a compound represented by formula (I), a pharmaceutical composition comprising a compound represented by formula (I), and (I), for the preparation of a medicament for the treatment of a disease treatable by inhibition JNK activity.
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Paragraph 0119-0122
(2021/11/27)
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- Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs
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The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.
- Cui, Xin,Deng, Yun,Fu, Dingqiang,Li, Guangxun,Qin, Fengming,Tang, Zhuo,Xu, Yan,Yao, Shaohua,Yuan, Yi
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supporting information
(2021/10/12)
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- Genetically Engineered Polypeptide Adhesive Coacervates for Surgical Applications
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Adhesive hydrogels have been developed for wound healing applications. However, their adhesive performance is impaired dramatically due to their high swelling on wet tissues. To tackle this challenge, we fabricated a new type of non-swelling protein adhesive for underwater and in vivo applications. In this soft material, the electrostatic complexation between supercharged polypeptides with oppositely charged surfactants containing 3,4-dihydroxylphenylalanine or azobenzene moieties plays an important role for the formation of ultra-strong adhesive coacervates. Remarkably, the adhesion capability is superior to commercial cyanoacrylate when tested in ambient conditions. Moreover, the adhesion is stronger than other reported protein-based adhesives in underwater environment. The ex vivo and in vivo experiments demonstrate the persistent adhesive performance and outstanding behaviors for wound sealing and healing.
- Herrmann, Andreas,Li, Bo,Li, Jingjing,Liu, Kai,Ma, Chao,Sun, Jing,Wang, Zili,Xiao, Lingling,Zhang, Hongjie,Zhao, Kelu,Zhou, Yu
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supporting information
p. 23687 - 23694
(2021/10/08)
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- Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
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The present invention relates to a degraducer for inducing the decomposition of target protein, a producing method thereof, and a pharmaceutical composition for preventing or treating target protein-related diseases by containing the degraducer as an active ingredient. A novel compound represented by chemical formula 1, ULB-L-PTM, by the present invention, as a degraducer compound inducing the decomposition of target protein using cereblon E3 ubiquitin ligase, is able to significantly achieve a target protein degradation-inducing activity with an excellent binding activity of a cereblon E3 ubiquitin ligase binder thereby, being able to achieve an excellent protein degradation activity by targeting protein or polypeptide related to various diseases. The bromodomain-containing pharmaceutical composition for preventing or treating protein-related diseases or conditions contains the novel compound represented by chemical formula 1 as an active ingredient and has a useful effect of providing a health functional food composition for prevention or improvement.(AA) Example 22 (nM, 24h)COPYRIGHT KIPO 2020
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Paragraph 0852; 0854-0856
(2020/05/01)
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- Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands?
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New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S-methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.
- Pockes, Steffen,Wifling, David,Buschauer, Armin,Elz, Sigurd
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p. 285 - 297
(2019/04/04)
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- REGULATING CHIMERIC ANTIGEN RECEPTORS
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This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.
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Page/Page column 390
(2018/09/08)
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- Fluorescent Benzothiazinone Analogues Efficiently and Selectively Label Dpre1 in Mycobacteria and Actinobacteria
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Benzothiazinones (BTZ) are highly potent bactericidal inhibitors of mycobacteria and the lead compound, BTZ043, and the optimized drug candidate, PBTZ169, have potential for the treatment of tuberculosis. Here, we exploited the tractability of the BTZ scaffold by attaching a range of fluorophores to the 2-substituent of the BTZ ring via short linkers. We show by means of fluorescence imaging that the most advanced derivative, JN108, is capable of efficiently labeling its target, the essential flavoenzyme DprE1, both in cell-free extracts and after purification as well as in growing cells of different actinobacterial species. DprE1 displays a polar localization in Mycobacterium tuberculosis, M. marinum, M. smegmatis, and Nocardia farcinica but not in Corynebacterium glutamicum. Finally, mutation of the cysteine residue in DprE1 in these species, to which BTZ covalently binds, abolishes completely the interaction with JN108, thereby highlighting the specificity of this fluorescent probe.
- Sommer, Raphael,Neres, Joao,Piton, Jérémie,Dhar, Neeraj,Van Der Sar, Astrid,Mukherjee, Raju,Laroche, Thierry,Dyson, Paul J.,McKinney, John D.,Bitter, Wilbert,Makarov, Vadim,Cole, Stewart T.
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p. 3184 - 3192
(2018/11/03)
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- METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES
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The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.
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Paragraph 0720-0722
(2016/07/27)
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- Dynamic self-inclusion behavior of pillar[5]arene-based pseudo[1]rotaxanes
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It was found that spontaneous isomerization takes place between three isomers of a pillar[5]arene (P5)-based pseudo[1]rotaxane. The isomerization process could be monitored by 1H NMR spectra in polar solvent and the geometric configurations of the three isomers were further evaluated by theoretical calculations. In the threaded forms, the alkyl side chain might be preorganized by intramolecular N-H...O bonds between the urea group of the side chain and the methoxy group of the P5 and further stabilized by multiple interactions, including H-bonding, C-H...π interactions, and the steric effect of the N-Boc moiety. These cooperative interactions greatly enhance the stability of the threaded form in polar solvent, and endow it with very special self-inclusion behavior. The Royal Society of Chemistry.
- Guan, Yangfan,Liu, Pingying,Deng, Chao,Ni, Mengfei,Xiong, Shuhan,Lin, Chen,Hu, Xiao-Yu,Ma, Jing,Wang, Leyong
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p. 1079 - 1089
(2014/02/14)
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- Efficient phosphodiester cleaving nanozymes resulting from multivalency and local medium polarity control
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The self-organization of Zn(II) complexes on the surface of 1.6-nm diameter gold nanoparticles (nanozymes) allows the spontaneous formation of multiple bimetallic catalytic sites capable to promote the cleavage of a RNA model substrate. We show that by tu
- Diez-Castellnou, Marta,Mancin, Fabrizio,Scrimin, Paolo
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supporting information
p. 1158 - 1161
(2014/02/14)
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- Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure
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Using rimonabant, a potent inverse agonist for cannabinoid receptor type 1 (CB1R), as parent ligand, a series of novel univalent and bivalent ligands were designed by variation of spacer length and its chemical structure. The ligands synthesized were evaluated for affinity and selectivity by radioligand displacement and a functional steady-state GTPase assay. The results showed the nature of the spacer influences the biological readout. Albeit all compounds show significantly lower affinities than rimonabant, this fact could be used to demonstrate that affinities and selectivity are influenced by the chemical structure and length of the spacer and might be helpful for designing bivalent probes for other GPCR receptors.
- Huang, Guozheng,Pemp, Daniela,Stadtmueller, Patricia,Nimczick, Martin,Heilmann, Joerg,Decker, Michael
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supporting information
p. 4209 - 4214
(2014/09/29)
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- Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase i (Tdp1)-topoisomerase i (Top1) inhibitors
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Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC 50 = 1.52 ± 0.05 μM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1-Tdp1 inhibitors.
- Nguyen, Trung Xuan,Morrell, Andrew,Conda-Sheridan, Martin,Marchand, Christophe,Agama, Keli,Bermingam, Alun,Stephen, Andrew G.,Chergui, Adel,Naumova, Alena,Fisher, Robert,O'Keefe, Barry R.,Pommier, Yves,Cushman, Mark
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scheme or table
p. 4457 - 4478
(2012/08/07)
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- Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: Investigating the hypothesis of shared structure-activity relationships
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The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are 'composites' of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (>6 carbons) possess lower anti-top1 activity than their smaller counterparts (2-4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a 'universal' top1 inhibitor SAR.
- Cinelli, Maris A.,Cordero, Brenda,Dexheimer, Thomas S.,Pommier, Yves,Cushman, Mark
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experimental part
p. 7145 - 7155
(2010/03/01)
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- A new thermo- and photo-driven [2]rotaxane
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A new rotaxane with functional chromophores porphyrin and fluorene as stoppers has been synthesized. It displays dual fluorescent character. The macrocycle ring can shuttle between the fumaramide part and the succinimide part on the dumbbell. Heating and UV light irradiating on the rotaxane lead to the reversible E/Z conversion, driving the ring to shuttle between the two stations. The optical properties of porphyrin and fluorene stoppers of the thread do not change so much while the ring shuttles because the macrocycle does not interact with the two stoppers. However, the active group, propargyloxyl, is introduced onto the two sides of the ring so that the rotaxane has the potential to be functionalized by further decoration.
- Ji, Feng-Yuan,Zhu, Liang-Liang,Ma, Xiang,Wang, Qiao-Chun,Tian, He
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supporting information; experimental part
p. 597 - 600
(2009/05/27)
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- Synthesis of cyanoformamides from primary amines and carbon dioxide under mild conditions. Synthesis of ceratinamine
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Treatment of primary amines with tetramethylphenylguanidine (PhTMG) and a cyanophosphonate at -10 °C under an atmosphere of carbon dioxide provides cyanoformamides in very high to excellent yields. The reaction proceeds efficiently within a short time. By
- Garcia-Egido, Eduardo,Paz, Jairo,Iglesias, Beatriz,Munoz, Luis
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experimental part
p. 3991 - 3999
(2009/12/06)
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- OXOBENZINDOLIZINOQUINOLINES AND USES THEREOF
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The synthesis of aromathecins, substituted 12H-5,l la-diazadibenzo[b,h]fluoren- 11 -ones is described. Use of these cytotoxic compounds and pharmaceutical compositions containing them for the treatment of cancer is described. Two novel processes for the synthesis of this system and a series of 14-substituted aromathecins as novel cytotoxic, topoisomerase I poisons are described.
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Page/Page column 42
(2009/12/23)
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- Parallel synthesis and cytotoxicity evaluation of a polyamine-quinone conjugates library
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A library of 24 derivatives designed by combining two natural products-derived fragments was prepared and tested to determine their anticancer potential in HT29 colon cancer cells. All library members inhibit cell proliferation as measured by MTT mitochondrial functional assay, with IC 50 values in the 1-100 μM range. Entry 1b caused apoptotic EGFR-mediated intracellular signaling. Thus, polyamino-quinones emerged as readily accessible and easily diversified scaffolds for anticancer lead discovery.
- Bolognesi, Maria Laura,Calonghi, Natalia,Mangano, Chiara,Masotti, Lanfranco,Melchiorre, Carlo
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supporting information; experimental part
p. 5463 - 5467
(2009/07/01)
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- Covalent modification of glassy carbon surface with organic redox probes through diamine linkers using electrochemical and solid-phase synthesis methodologies
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Various mono-Boc-protected diamines have been covalently grafted to glassy carbon electrodes by electrochemical oxidation of the free amine. After deprotection of the Boc group, anthraquinone and nitrobenzene probes were coupled to the linkers using solid-phase coupling reactions. X-Ray photoelectron spectroscopy and cyclic voltammetry were used to monitor the coupling efficiency, effect of linker length on the surface coverage and electron transfer between the attached redox probes and electrode. The anthraquinone surface coverage was found to decrease as the chain length of alkyl diamine linker increased and the electron transfer kinetics were found to be faster for the lower coverages and the longer, more flexible linkers. In the case of nitrobenzene, there was only a slightly change in coverage with increasing linker length. This electrochemical attachment of protected diamine linkers followed by solid-phase coupling provides a very versatile methodology for attaching a wide range of molecular architectures onto glassy carbon surfaces. The Royal Society of Chemistry 2008.
- Ghanem, Mohamed A.,Chretien, Jean-Mathieu,Pinczewska, Aleksandra,Kilburn, Jeremy D.,Bartlett, Philip N.
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experimental part
p. 4917 - 4927
(2010/02/28)
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- Mono-acylation of symmetric diamines in the presence of water
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Simply reacting equal equivalents of symmetric diamines with esters or carbonates in the presence of a suitable amount of water gave mono-acylated products in good to quantitative yields.
- Tang, Wei,Fang, Shiyue
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supporting information; scheme or table
p. 6003 - 6006
(2009/04/11)
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- Investigation of the lactam side chain length necessary for optimal indenoisoquinoline topoisomerase I inhibition and cytotoxicity in human cancer cell cultures
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Indenoisoquinolines with lactam substituents such as ethylamino, propylamino, and butylamino have previously demonstrated potent biological activity, but an optimal length has never been established. In the present study, a series of simplified indenoisoquinoline analogues possessing a linker spacing of 0-12 carbon atoms between the lactam nitrogen and the terminal amino group have been prepared, determining that 2-4-atom lengths are optimal for topoisomerase I inhibition and cytotoxicity. Using these lengths, analogues were prepared with the amino group and portions of the linker replaced by a pyridine ring. A three-carbon spacer within the pyridine series still demonstrated potent topoisomerase I inhibition.
- Morrell, Andrew,Placzek, Michael S.,Steffen, Jamin D.,Antony, Smitha,Agama, Keli,Pommier, Yves,Cushman, Mark
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p. 2040 - 2048
(2008/02/01)
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- N-SUBSTITUTED INDENOISOQUINOLINES AND SYNTHESES THEREOF
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N-Substituted indenoisoquinoline compounds, and pharmaceutical formulations of N-substituted indenoisoquinoline compounds are described. Also described are processes for preparing N-substituted indenoisoquinoline compounds. Also described are methods for
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Page/Page column 40
(2008/06/13)
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- Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the μ-opioid receptor and I2-imidazoline binding sites
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Two series of fentanyl-derived hybrid molecules bearing potent I2-imidazoline binding site (IBS) ligands (i.e., guanidine and BU224 moieties) linked with an aliphatic (m = 2, 3, 4, 6, 7, 8, 9 and 12 methylene units) or aromatic spacer were prepared. Their affinities for the μ-opioid receptors and for the I2-IBS were determined through competition binding studies on human postmortem brain membranes. Whereas the BU224 hybrid molecules bound to the μ-opioid receptor and the I2-IBS in the micromolar to low micromolar range, the alkaneguanidine series exhibited remarkable affinities in the nanomolar range for both receptors. [35S]GTPγS functional assays were performed on human postmortem brain membranes with selected ligands from each series (4f and 8g) showing the highest dual affinity for the μ-opioid receptor and I2-IBS affinities. Both compounds displayed agonist properties: at the μ-opioid receptor for the alkaneguanidine derivative 4f (spacer: six methylene units) and at a G-protein coupled receptor (GPCR) which remains to be determined for 8g. The lack of analgesic properties of 4f in vivo (i.e., hot plate and writhing tests in mice), discordant with the good in vitro binding data (Ki μ = 1.04 ± 0.28 nM, Ki I2 = 409 ± 238 nM), may possibly be due to the low intrinsic efficacy of the compound. Alternatively, a low access to the central nervous system for this kind of hybrid molecules cannot be ruled out. Two new compounds reported here (9f and 13), which were not dual acting, are worth mentioning for their outstanding binding affinities; 9f bound to the μ-opioid receptor with a picomolar affinity (Ki = 0.0098 ± 0.0033 nM), whereas 13 presented an I2-IBS affinity (Ki = 18 ± 11 nM) similar to the reference compound BU224.
- Dardonville, Christophe,Fernandez-Fernandez, Cristina,Gibbons, Sarah-Louise,Ryan, Gary J.,Jagerovic, Nadine,Gabilondo, Ane M.,Meana, J. Javier,Callado, Luis F.
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p. 6570 - 6580
(2007/10/03)
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- Synthesis of dimeric acridine derived nucleic acid intercalators
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A series of antiviral compounds consisting of an intercalating acridine derived part, a spacer region and a reactive EDTA-derived conjugate was synthesized in an easy sequence. Suitably monoprotected 1,ω-alkyldiamines gave upon reaction with 6,9-dichloro-2-methoxyacridine (1) followed by deprotection and reaction with EDTA dianhydride the target molecules. In the presence of ascorbate a reduction of the phage-titer of the MS2 phages by > 8 logarithmic decades was achieved.
- Csuk, René,Brezesinski, Thorsten,G?the, Gunnar,Raschke, Christian,Rei?mann, Stefan
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- Fentanyl derivatives bearing aliphatic alkaneguanidinium moieties: A new series of hybrid molecules with significant binding affinity for μ-opioid receptors and I2-imidazoline binding sites
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A new series of fentanyl derivatives [i.e., N-[1-(2-phenethyl)-4-piperidyl] -N-(guanidinoalkyl)propanamide] bearing aliphatic alkaneguanidinium moieties were prepared. Their affinities for the μ opioid receptors and for the I 2-imidazoline binding sites (I2-IBS) were determined on human post-mortem prefrontal cortex membranes. All of these hybrid compounds had significant and/or very high affinity for both receptors in the nanomolar range, meaning an improvement compared to the prototype N-[1-(2-phenethyl)-4- piperidyl]-N-(guanidinopropyl)propanamide previously reported.
- Dardonville, Christophe,Jagerovic, Nadine,Callado, Luis F.,Meana, J. Javier
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p. 491 - 493
(2007/10/03)
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- Synthesis of pathogen inactivating nucleic acid intercalators
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A series of antiviral compounds consisting of an intercalating acridine derived part, a spacer region and a reactive EDTA-derived conjugate was synthesized in an easy sequence starting from 1,ω-alkyldiamines. As shown in model screenings, in the presence of ascorbic acid the Fe-complexes of these compounds reduced the phage-titer of MS2-phages by several logarithmic decades.
- Csuk, René,Barthel, Alexander,Brezesinski, Thorsten,Raschke, Christian
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p. 975 - 988
(2007/10/03)
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- Defining the Molecular Requirements for the Selective Delivery of Polyamine Conjugates into Cells Containing Active Polyamine Transporters
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Several N1-substituted polyamines containing various spacer units between nitrogen centers were synthesized as their respective HCl salts. The N1-substituents included benzyl, naphthalen-1-ylmethyl, anthracen-9-ylmethyl, and pyren-1-
- Wang, Chaojie,Delcros, Jean-Guy,Cannon, Laura,Konate, Fanta,Carias, Horacio,Biggerstaff, John,Gardner, Richard Andrew,Phanstiel IV, Otto
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p. 5129 - 5138
(2007/10/03)
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- SULFONAMIDE DERIVATIVES OF 3-SUBSTITUTED IMIDAZOL[1,2-D] -1,2,4-THIADIAZOLES AND 3-SUBSTITUTED-[1,2,4] THIADIAZOLO[4,5-A] BENZIMIDAZOLE AS INHIBITORS OF FIBRIN CROSS-LINKING AND TRANSGLUTAMINASES
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A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles sufficient to inhibit the activity
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- Sulfonamide derivatives of 3-substituted imidazo[1,2-D]-1,2,4-thiadiazoles and 3-substituted-[1,2,4]thiadiazolo[4,5-A]benzimidazole as inhibitors of fibrin cross-linking and transglutaminases
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A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles sufficient to inhibit the activity.
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Page/Page column 24
(2008/06/13)
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- Heterocycle derivatives and drugs
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There is provided an excellent novel analgesic having an analgesic effect which is effective widely against a pain including a chronic pain or an allodynia accompanied with herpes zoster by acting on a nociceptin receptor. The present invention relates to a compound represented by the following formula: or a salt thereof. In the formula, X and Y are same or different and each represents a nitrogen atom or CH; R1 represents a hydrogen atom or alkyl and the like; A1 and A2 are same or different and each represents a single bond or a divalent aliphatic hydrocarbon group; Q represents a single bond, cycloalkylene group, phenylene group or divalent heterocyclic group; R2A, R2B, R2C and R2D are same or different and each represents a hydrogen atom, alkyl or phenyl; E represents a ethenylene group or —NRCO— (in which R is hydrogen or alkyl) and the like; R3 represents a phenyl group or a heterocyclic group; R4 and R5 are same or different and each represents a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen, nitro, hydroxy, alkoxycarbonyl, —NR6R7 (in which R6 and R7 are same or different and each represents a hydrogen atom or alkyl) and the like.
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- Preparation and biological assessment of hydroxycinnamic acid amides of polyamines
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Many plants contain hydroxycinnamic acid conjugates of polyamines that are remarkably similar in general structure to the acylated polyamines found in spider and wasp toxins. In an effort to determine whether these compounds might play a role in the chemical defense of plants against arthropod pests we synthesized a variety of analogues of the coumaric (4-hydroxycinnamic) acid conjugates of di-, tri-, and tetraamines using common protection and acylation strategies. N1- and N8-coumaroyl spcrmidinc spermidine were tested in feeding trials with insect larvae including the European corn borer (Ostrinia nuhilalis), the tobacco budworm (Heliothis verescens) and the oblique banded leaf roller (Choristoneura rosaceana). Antifeedant assays with the rice weevil Sitophilus oryzae were also performed. Neither the naturally occurring coumaric acid conjugates of polyamines nor their analogues showed notable toxicity towards insects, despite precautions to maintain these easily oxidized materials in the wet diet. However, more direct bioassays of these compounds on glutamate dependent neuroreceptors including the deep abdominal extensor muscles of crayfish, or mammalian NMDA, 62, and AMPA receptors, clearly showed that these compounds were inhibitory. N1-Coumnaoryl spermine, a dodecyl and a cyclohexyl analogue were especially active at NMDA NR1/NR2B receptors. The latter had an IC50 of 300 μM in the crayfish. N1-Coumaroyl spermine had an IC50 in the crayfish preparation of 70-300 μM and against the mammalian NR1/ NR2B receptor of 38 nM. Structure-activity variations show similar trends of length and hydrophobicity as has been seen previously with analogues of spider toxins. We conclude from this work that while the coumaric acid polyamine conjugates are active when directly applied to neuroreceptors, they show no overt toxicity when ingested by insect larvae.
- Fixon-Owoo, Solomon,Levasseur, Frederic,Williams, Keith,Sabado, Thomas N.,Lowe, Mike,Klose, Markus,Mercier, A. Joffre,Fields, Paul,Atkinson, Jeffrey
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p. 315 - 334
(2007/10/03)
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- Space-filling effects in membrane disruption by cationic amphiphiles
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We studied the hemolytic activity towards bovine erythrocytes of novel synthetic steroid-polyamine conjugate consisting of a rigid hydrophobic steroid unit, and a flexible hydrophilic polyamine unit connected by a linker. The steroid structure, polyamine chain length, and the presence of a hydrophobic substituent on the steroid, all influenced the activity. Analysis of the time dependence of hemolysis suggested that these structurally related cationic amphiphiles have different mechanisms of membrane perturbation. Copyright
- Fujiwara, Tomoko,Hirashima, Naohide,Hasegawa, Seiji,Nakanishi, Mamoru,Ohwada, Tomohiko
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p. 1013 - 1024
(2007/10/03)
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- COMB COPOLYMERS WITH THERMOTROPIC AND LYOTROPIC PROPERTIES SYNTHESIS AND STRUCTURAL STUDY
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Comb copolymers with polyacrylamide or polymethacrylamide main chains and lipopeptidic side chains were synthesized in two steps: synthesis of a polymerizable lipopeptide followed by radical polymerization of the lipopeptidic macromonomer.X ray diffraction and DSC studies showed that comb copolymers exhibit both a thermotropic and a lyotropic behaviour.The influence of the nature and the degree of polymerization of the peptidic chains on the type (smectic, nematic or cholesteric) and the domain of stability of the liquid-crystalline structures was established.In the case of smectic structures, the influence of the solvent concentration and the degree of polymerization of the peptidic chains on the distances between the smectic planes was also established.
- Gallot, Bernard,Douy, Andre
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p. 367 - 374
(2007/10/02)
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- 9-Acridinyl and 2-Methoxy-6-chloro-9-acridinyl Derivatives of Aliphatic Di-, Tri-, and Tetraamines. Chemistry, Cytostatic Activity, and Schistosomicidal Activity
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9-acridinyl derivatives of 1,6-hexanediamine, 1,8-octanediamine, bis(3-aminopropyl)amine, N,N'-bis(3-aminopropyl)piperazine, and N-ethyl-1,6-hexanediamine in the form of their hydrochlorides were prepared in high yields and converted into potential hetero bis DNA intercalating diacridines.The corresponding potential homo bis DNA intercalating reagents were prepared by heating the above amines with 9-chloroacridines.The chemical stability of the acridines was examined.Their cytostatic activity against Cloudman melanoma cells, in vitro, has been determined.The strongest cytostatic activity was observed for the acridine derivatives of the tri- and tetraamines.The schistosomicidal activity of selected acridine and diacridine derivatives against Schistosoma mansoni in mice was found to be insignificant.The S. mansoni egg development was apparently suppressed by this treatment.
- Hansen, John B.,Langvad, Eyvind,Frandsen, Flemming,Buchardt, Ole
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p. 1510 - 1514
(2007/10/02)
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