- Synthesis and activity of four (N,N-dimethylamino)benzamide non-steroidal anti-inflammatory drugs based on thiazole and thiazoline
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Four compounds derived from 2-aminothiazole and 2-amino-2-thiazoline were prepared by coupling the respective bases with the acid chlorides of either 3- or 4-(N,N-dimethylamino)benzoic acid. Products were identified using infrared spectroscopy. 1/su
- Lynch, Daniel E.,Hayer, Ravinder,Beddows, Samantha,Howdle, Joy,Thake, C. Douglas
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Read Online
- Circular dichroism studies of molecular recognition with cyclophane hosts in aqueous media
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Circular dichroism (CD) methods have been employed to study molecular recognition phenomena in water soluble cyclophane hosts such as 1 and 2. The CD method is well suited to these systems and produces results that complement and expand upon previous NMR
- Forman, Jonathan E.,Barrans Jr., Richard E.,Dougherty, Dennis A.
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Read Online
- Ni-Catalyzed Direct Carboxylation of Aryl C?H Bonds in Benzamides with CO2
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The direct carboxylation of inert aryl C?H bond catalyzed by abundant and cheap nickel is still facing challenge. Herein, we report the Ni-catalyzed direct carboxylation of aryl C?H bonds in benzamides under 1 atm of CO2 to afford various methyl carboxylates or phthalimides, dealing with different post-processing. The reaction displays excellent functional group tolerance and affords moderate to high carboxylation yields under mild conditions. Detail mechanistic studies suggest that a Ni(0)?Ni(II)?Ni(I) catalytic cycle may be involved in this reaction. (Figure presented.).
- Pei, Chunzhe,Zong, Jiarui,Li, Bin,Wang, Baiquan
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supporting information
p. 493 - 499
(2021/12/08)
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- AMINE CO-INITIATOR MIXTURE
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The invention relates to a co-initiator comprising the aminobenzoate derivative according to Formula (I) and at least one ancillary amine, wherein the reactivity and solubility of said co-imitator in UV-curable resins is sufficiently high that the co-initiator can be used in UV radiation curing processes. Formula (I) wherein R1 and R2 independently represent methyl or ethyl groups; and j, k, l and m are independently 0 to 20.
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(2021/04/23)
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- Systematic Evaluation of 1,2-Migratory Aptitude in Alkylidene Carbenes
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Alkylidene carbenes undergo rapid inter- and intramolecular reactions and rearrangements, including 1,2-migrations of β-substituents to generate alkynes. Their propensity for substituent migration exerts profound influence over the broader utility of alkylidene carbene intermediates, yet prior efforts to categorize 1,2-migratory aptitude in these elusive species have been hampered by disparate modes of carbene generation, ultrashort carbene lifetimes, mechanistic ambiguities, and the need to individually prepare a series of 13C-labeled precursors. Herein we report on the rearrangement of 13C-alkylidene carbenes generated in situ by the homologation of carbonyl compounds with [13C]-Li-TMS-diazomethane, an approach that obviates the need for isotopically labeled substrates and has expedited a systematic investigation (13C{1H} NMR, DLPNO-CCSD(T)) of migratory aptitudes in an unprecedented range of more than 30 alkylidene carbenes. Hammett analyses of the reactions of 26 differentially substituted benzophenones reveal several counterintuitive features of 1,2-migration in alkylidene carbenes that may prove of utility in the study and synthetic application of unsaturated carbenes more generally.
- Dale, Harvey J. A.,Nottingham, Chris,Poree, Carl,Lloyd-Jones, Guy C.
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supporting information
p. 2097 - 2107
(2021/02/01)
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- Biocatalytic Strategy for the Highly Stereoselective Synthesis of CHF2-Containing Trisubstituted Cyclopropanes
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The difluoromethyl (CHF2) group has attracted significant attention in drug discovery and development efforts, owing to its ability to serve as fluorinated bioisostere of methyl, hydroxyl, and thiol groups. Herein, we report an efficient biocat
- Carminati, Daniela M.,Decaens, Jonathan,Couve-Bonnaire, Samuel,Jubault, Philippe,Fasan, Rudi
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supporting information
p. 7072 - 7076
(2021/02/27)
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- Design, synthesis, biological evaluation and pharmacophore model analysis of novel tetrahydropyrrolo[3,4-c]pyrazol derivatives as potential TRKs inhibitors
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The tropomyosin receptor kinases TRKs are responsible for different tumor types which caused by NTRK gene fusion, and have been identified as a successful target for anticancer therapeutics. Herein, we report a potent and selectivity TRKs inhibitor 19m through rational drug design strategy from a micromolar potency hit 17a. Compound 19m significantly inhibits the proliferation of TRK-dependent cell lines (Km-12), while it has no inhibitory effect on TRK-independent cell lines (A549 and THLE-2). Furthermore, kinases selectivity profiling showed that in addition to TRKs, compound 19m only displayed relatively strong inhibitory activity on ALK. These data may indicate that compound 19m has a good drug safety. Partial ADME properties were evaluated in vitro and in vivo. Compound 19m exhibited a good AUC values and volume of distribution and low clearance in the pharmacokinetics experiment of rats. Finally, a pharmacophore model guided by experimental results is proposed. We hope this theoretical model can help researchers find type I TRK inhibitors more efficiently.
- Cheng, Maosheng,Liu, Nian,Lv, Ruicheng,Qin, Qiaohua,Sun, Yin,Sun, Yixiang,Wang, Ruifeng,Wang, Xiaoyan,Wu, Tianxiao,Yin, Wenbo,Zhang, Chu,Zhao, Dongmei
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- Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
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An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
- Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
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supporting information
p. 17887 - 17896
(2020/08/19)
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- Microwave-promoted synthesis of highly luminescent s-tetrazine-1,3,4-oxadiazole and s-tetrazine-1,3,4-thiadiazole hybrids
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Two series of new s-tetrazine derivatives containing 1,3,4-oxadiazole and 1,3,4-thiadiazole rings were synthesized from s-tetrazine-3,6-dicarbohydrazide, triethyl orthoesters and aroyl chlorides. Cyclocondensation reactions for both groups of conjugated arrangements proceeded rapidly and efficiently under microwave irradiation. The obtained compounds exhibited luminescence properties and large quantum yield of emitted photons.
- K?dzia, Anna,Kudelko, Agnieszka,?wi?tkowski, Marcin,Kruszyński, Rafa?
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- Nickel-Catalyzed Deaminative Acylation of Activated Aliphatic Amines with Aromatic Amides via C-N Bond Activation
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Deaminative functionalization of aliphatic primary amines has great synthetic utility. Herein, we describe a Ni-catalyzed reductive deaminative cross-electrophile coupling reaction between Katritzky salts and aromatic amides. This work provides examples of the synthesis of various ketones from alkylpyridinium salts, including both primary and secondary alkylamines. Given its mild reaction conditions and high functional group tolerance, this cross-coupling strategy is expected to be useful for late-stage functionalization of complex compounds.
- Yu, Chu-Guo,Matsuo, Yutaka
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supporting information
p. 950 - 955
(2020/02/15)
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- Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents
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Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
- Sijm, Maarten,Siciliano de Araújo, Julianna,Ramos Llorca, Alba,Orrling, Kristina,Stiny, Lydia,Matheeussen, An,Maes, Louis,de Esch, Iwan J. P.,de Nazaré Correia Soeiro, Maria,Sterk, Geert Jan,Leurs, Rob
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supporting information
p. 1662 - 1668
(2019/08/30)
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- Acetic Acid Accelerated Visible-Light Photoredox Catalyzed N-Demethylation of N,N-Dimethylaminophenyl Derivatives
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N,N-Dimethylaminophenyl moiety is a common fragment in medicinal chemistry as several pharmaceuticals bearing this privileged motif are on the market and under clinical evaluation. Oxidative N-demethylation is generally regarded as the major metabolic pathway. However, pharmacokinetics, metabolites studies as well as the further structural modification are precluded by the impracticality of chemical synthesis. Here we report that acetic acid can significantly accelerate visible-light photoredox catalyzed N-demethylation of N,N-dimethylaminophenyl derivatives. This approach is easy for large scale reaction and even for potential industrial manufacture. (Figure presented.).
- Wu, Guolin,Li, Yazhen,Yu, Xuemei,Gao, Yu,Chen, Haijun
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supporting information
p. 687 - 692
(2017/02/23)
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- Rhodium-Catalyzed Decarbonylative Borylation of Aromatic Thioesters for Facile Diversification of Aromatic Carboxylic Acids
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Transformation of aromatic thioesters into arylboronic esters was achieved efficiently using a rhodium catalyst. The broad functional-group tolerance and mild conditions of the method have allowed for the two-step decarboxylative borylation of a wide range of aromatic carboxylic acids, including commercially available drugs.
- Ochiai, Hidenori,Uetake, Yuta,Niwa, Takashi,Hosoya, Takamitsu
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supporting information
p. 2482 - 2486
(2017/02/23)
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- Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor
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Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC50: 7?nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35)?=?0.00) among 468 kinases/mutants at the concentration of 1?μM. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited BTK Y223 auto-phosphorylation (EC50: 30?nM), arrested cell cycle in G0/G1 phase and induced apoptosis in U2932 and Pfeiffer cells. We believe these features would make 9 a good pharmacological tool to study the BTK related pathology.
- Liang, Qianmao,Chen, Yongfei,Yu, Kailin,Chen, Cheng,Zhang, Shouxiang,Wang, Aoli,Wang, Wei,Wu, Hong,Liu, Xiaochuan,Wang, Beilei,Wang, Li,Hu, Zhenquan,Wang, Wenchao,Ren, Tao,Zhang, Shanchun,Liu, Qingsong,Yun, Cai-Hong,Liu, Jing
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p. 107 - 125
(2017/03/21)
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- THREE-DIMENSIONAL INKJET PRINTING USING DICYCLOPENTADIENE COMPOUNDS POLYMERIZABLE BY RING-OPENING METATHESIS POLYMERIZATION
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Methods for fabricating three-dimensional objects by 3D-inkjet printing technology, which utilize dicyclopentadiene (DCPD)-based curable materials that polymerize via ring-opening metathesis polymerization (ROMP) for fabricating the object, are provided.
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Page/Page column 126
(2017/05/10)
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- General C-H Arylation Strategy for the Synthesis of Tunable Visible Light-Emitting Benzo[a]imidazo[2,1,5-c,d]indolizine Fluorophores
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Herein we report the discovery of the benzo[a]imidazo[2,1,5-c,d]indolizine motif displaying tunable emission covering most of the visible spectrum. The polycyclic core is obtained from readily available amides via a chemoselective process involving Tf2O-mediated amide cyclodehydration, followed by intramolecular C-H arylation. Additionally, these fluorescent heterocycles are easily functionalized using electrophilic reagents, enabling divergent access to varied substitution. The effects of said substitution on the compounds' photophysical properties were rationalized by density functional theory calculations. For some compounds, emission wavelengths are directly correlated to the substituent's Hammett constants. Easily introduced nonconjugated reactive functional groups allow the labeling of biomolecules without modification of emissive properties. This work provides a straightforward platform for the synthesis of new moderately bright fluorescent dyes remarkable for their chemical stability, predictability, and unusually high excitation-emission differential.
- Lévesque, éric,Bechara, William S.,Constantineau-Forget, Léa,Pelletier, Guillaume,Rachel, Natalie M.,Pelletier, Joelle N.,Charette, André B.
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p. 5046 - 5067
(2017/05/24)
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- DICYCLOPENTADIENE DERIVATIVES AND POLYMERS THEREOF
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Dicyclopentadiene (DCPD) derivatives of following general formula (I); their preparation and use thereof, especially as monomers in polymerization reactions, such as olefin polymerization or ring-opening metathesis polymerization (ROMP).
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Page/Page column 48
(2017/05/10)
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- Iron-catalyzed C-H/N-H activation by triazole guidance: Versatile alkyne annulation
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Iron-catalyzed C-H/N-H functionalizations were achieved by the aid of modular triazole amides. The alkyne annulation allowed for the expedient synthesis of valuable isoquinolone scaffolds with high levels of chemo-, site- and regio-selectivities.
- Cera,Haven,Ackermann
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supporting information
p. 6460 - 6463
(2017/07/10)
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- MnCl2-Catalyzed C?H Alkylations with Alkyl Halides
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C?H alkylations with challenging β-hydrogen-containing alkyl halides were accomplished with sustainable MnCl2 as the catalyst under phosphine-ligand-free conditions. The proximity-induced benzamide C?H activation occurred with ample substrate s
- Liu, Weiping,Cera, Gianpiero,Oliveira, Jo?o C. A.,Shen, Zhigao,Ackermann, Lutz
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supporting information
p. 11524 - 11528
(2017/08/30)
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- Ruthenium-Catalyzed Difluoroalkylation of 8-Aminoquinoline Amides at the C5-Position
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A ruthenium-catalyzed highly selective difluoromethylation of 8-aminoquinoline amides at the C5 position has been developed. It tolerates a broad range of functional groups, providing the corresponding difluoromethylated products in moderate to good yields. Preliminary experimental results indicate that the tricoordinate ruthenium intermediate is the key factor in achieving the C5-position selectivity.
- Chen, Changpeng,Zeng, Runsheng,Zhang, Jingyu,Zhao, Yingsheng
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supporting information
p. 6947 - 6950
(2017/12/26)
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- Nickel-catalyzed thiolation of unactivated aryl C-H bonds: Efficient access to diverse aryl sulfides
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A nickel-catalyzed thiolation of unactivated C(sp2)-H bonds with disulfides employing the PIP directing group was described. This process uses a catalytic nickel catalyst and no metallic oxidants or cocatalysts are required. The reaction tolera
- Yan, Sheng-Yi,Liu, Yue-Jin,Liu, Bin,Liu, Yan-Hua,Shi, Bing-Feng
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supporting information
p. 4069 - 4072
(2015/03/30)
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- Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors
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A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.
- Deberardinis, Albert M.,Madden, Daniel J.,Banerjee, Upasana,Sail, Vibhavari,Raccuia, Daniel S.,De Carlo, Daniel,Lemieux, Steven M.,Meares, Adam,Hadden, M. Kyle
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p. 3724 - 3736
(2014/05/20)
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- Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia
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A series of 6-acylureido derivatives containing a 3-(pyrrol-2- ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2- one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-1-yl)ethyl)-5-((6-(3-(2- fluoro-4-methoxybenzoyl)ureido)-2-oxoindolin-3-ylidene)methyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML.
- Jagtap, Ajit Dhananjay,Chang, Pei-Teh,Liu, Jia-Rong,Wang, Hsiao-Chun,Kondekar, Nagendra B.,Shen, Li-Jiuan,Tseng, Hsiang-Wen,Chen, Grace Shiahuy,Chern, Ji-Wang
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supporting information
p. 268 - 288
(2014/08/18)
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- BICYCLIC HETEROCYCLIC COMPOUND
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[Problem] To provide a compound useful as an active ingredient of a pharmaceutical composition for treating 11β-hydroxysteroid dehydrogenase type 1-related diseases such as dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance and the like. [Means for Solution] A bicyclic heterocyclic compound (the bicyclic heterocycle is formed when a cyclohexane ring is fused with a 5- to 6-membered monocyclic heterocycle that has only a nitrogen atom as a hetero atom) substituted with an acylamino group such as a (hetero)aroylamino group or the like or a pharmaceutically acceptable salt thereof was found to have an excellent selective inhibitory action against 11β-HSD1. Accordingly, the bicyclic heterocyclic compound of the present invention can be used for treating dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance, and the like.
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Paragraph 0237
(2014/09/16)
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- Effect of ester on rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes
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We systematically examined the effect of different esters on the rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes with a concomitant 1,2-acyloxy migration. Significant rate acceleration was observed for benzoate substrates bearing an electron-donating substituent. The cycloaddition can now be conducted under much more practical conditions for most terminal alkynes. The Royal Society of Chemistry 2013.
- Schienebeck, Casi M.,Robichaux, Patrick J.,Li, Xiaoxun,Chen, Lianqing,Tang, Weiping
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supporting information
p. 2616 - 2618
(2013/04/23)
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- Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2
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Resveratrol (3,5,4′-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation.
- St. John, Sarah E.,Jensen, Katherine C.,Kang, Soosung,Chen, Yafang,Calamini, Barbara,Mesecar, Andrew D.,Lipton, Mark A.
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p. 6022 - 6037
(2013/09/23)
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- ULTRAVIOLET ABSORBING POLY (ORGANIC OXIDIZED SILICON) PARTICLES HAVING IMPROVED ULTRAVIOLET STABILITY, AND METHOD FOR PREPARING SAME
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The present invention relates to a method for preparing poly(organic oxidized silicon) particles having UV-absorbing groups, including reacting an organoalkoxysilane precursor having a UV-absorbing group selected from a group consisting of organotrialkoxy
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Paragraph 0090
(2013/05/09)
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- INDOLIN-2-ONE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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A novel class of indoline-2-one derivatives are disclosed. These compounds are protein kinase inhibitors which are useful for treating hyperproliferative diseases such as cancer.
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Paragraph 0161
(2013/11/05)
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- Design and synthesis of 4-(4-benzoylaminophenoxy)phenol derivatives as androgen receptor antagonists
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We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 μM), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 μM), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 μM). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.
- Yamada, Ayumi,Fujii, Shinya,Mori, Shuichi,Kagechika, Hiroyuki
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supporting information
p. 937 - 941
(2013/10/22)
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- Analogues of fenarimol are potent inhibitors of trypanosoma cruzi and are efficacious in a murine model of chagas disease
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We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC50s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
- Keenan, Martine,Abbott, Michael J.,Alexander, Paul W.,Armstrong, Tanya,Best, Wayne M.,Berven, Bradley,Botero, Adriana,Chaplin, Jason H.,Charman, Susan A.,Chatelain, Eric,Von Geldern, Thomas W.,Kerfoot, Maria,Khong, Andrea,Nguyen, Tien,McManus, Joshua D.,Morizzi, Julia,Ryan, Eileen,Scandale, Ivan,Thompson, R. Andrew,Wang, Sen Z.,White, Karen L.
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supporting information; experimental part
p. 4189 - 4204
(2012/07/27)
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- A highly selective chemosensor for copper ion based on ICT fluorescence
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Simple structural compounds 1 to 3 were synthesized. The presence of Cu2+ resulted in the fluorescence and absorption spectra change of 1 and 2, which indicated that 1 and 2 showed a highly selective response to Cu2+ over other metal ions. However, 3 showed no selectivity for metal ions, which means that the compound could bind with several metal ions, such as, Ni2+, Zn2+, Cd2+, Hg2+, Pb2+, Fe3+, Mg2+, Ca2+, and Co 2+, except Cu2+ and Ag+. The different spectral responses were attributed to the difference in binding sites for 1 and 3.
- Wu, Fang Ying,Cao, Sheng Gen,Xie, Cai Xia
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scheme or table
p. 607 - 610
(2012/07/01)
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- Enantioselective Diels-Alder reaction of α-(acylthio)acroleins: A new entry to sulfur-containing chiral quaternary carbons
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A catalytic and enantioselective Diels-Alder reaction of α-(carbamoylthio)acroleins induced by an organoammonium salt of chiral triamine is described. α-(Carbamoylthio)acroleins are designed and synthesized as new sulfur-containing dienophiles for the fir
- Sakakura, Akira,Yamada, Hiroki,Ishihara, Kazuaki
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supporting information; experimental part
p. 2972 - 2975
(2012/07/28)
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- Nickel(0)-catalyzed cyclization of N -benzoylaminals for isoindolinone synthesis
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A nickel(0) catalyst effectively mediates the cyclization of N-benzoyl aminals in the presence of a stoichiometric Lewis acid. This method enables preparation of a variety of isoindolinones with substitution on the benzoyl fragment and C-3 carbon. This reaction likely proceeds via an α-amidoalkylnickel(II) intermediate, which then may cyclize via either an electrophilic aromatic substitution or an insertion pathway.
- Shacklady-Mcatee, Danielle M.,Dasgupta, Srimoyee,Watson, Mary P.
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supporting information; experimental part
p. 3490 - 3493
(2011/09/12)
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- Synthesis and evaluation of 5-fluoro-2-aryloxazolo[5,4- b ]pyridines as β-amyloid PET ligands and identification of MK-3328
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5-Fluoro-2-aryloxazolo[5,4-b]pyridines were synthesized and investigated as potential 18F containing β-amyloid PET ligands. In competition binding assays using human AD brain homogenates, compounds 14b, 16b, and 17b were identified as having favorable potency versus human β-amyloid plaque and were radiolabeled for further evaluation in in vitro binding and in vivo PET imaging experiments. These studies led to the identification of 17b (MK-3328) as a candidate PET ligand for the clinical assessment of β-amyloid plaque load.
- Harrison, Scott T.,Mulhearn, James,Wolkenberg, Scott E.,Miller, Patricia J.,O'Malley, Stacey S.,Zeng, Zhizhen,Williams Jr., David L.,Hostetler, Eric D.,Sanabria-Bohorquez, Sandra,Gammage, Linda,Fan, Hong,Sur, Cyrille,Culberson, J. Christopher,Hargreaves, Richard J.,Cook, Jacquelynn J.,Hartman, George D.,Barrow, James C.
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supporting information; experimental part
p. 498 - 502
(2011/09/14)
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- Nickel-catalyzed chelation-assisted transformations involving ortho C-H bond activation: Regioselective oxidative cycloaddition of aromatic amides to alkynes
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Although the pioneering example of ortho metalation involving cleavage of C-H bonds was achieved using a nickel complex (Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544), no examples of catalysis using nickel complexes have been reported. In this work, the Ni-catalyzed transformation of ortho C-H bonds utilizing chelation assistance, such as oxidative cycloaddition of aromatic amides with alkynes, has been achieved.
- Shiota, Hirotaka,Ano, Yusuke,Aihara, Yoshinori,Fukumoto, Yoshiya,Chatani, Naoto
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supporting information; experimental part
p. 14952 - 14955
(2011/11/05)
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- PH-dependent conformational switching in 2,6-benzamidodiphenylacetylenes
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The conformational equilibrium of a pH-dependent switch based on an intramolecularly H-bonded diphenylacetylene can be predictably biased by using electron-donating or -withdrawing groups (see scheme). Furthermore, protonation of the electron-donating dim
- Jones, Ian M.,Lingard, Hannah,Hamilton, Andrew D.
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supporting information; experimental part
p. 12569 - 12571
(2012/02/15)
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- Simple ratiometric fluorophore for the selective detection of mercury through Hg(II)-mediated oxazole formation
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A simple propargylamide-fuctionalized chemodosimeter was prepared for the ratiometric fluorescence detection of mercuric ions in HEPES buffer. The chemodosimeter exhibited Hg2+-induced propargyl amide-tooxazole transformation, with a significan
- Lee, Heejin,Kim, Hae-Jo
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experimental part
p. 3959 - 3962
(2012/03/26)
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- Rapid and efficient synthesis of [18F]fluoronicotinamides, [18F]fluoroisonicotinamides and [18F]fluorobenzamides as potential pet radiopharmaceuticals for melanoma imaging
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In an attempt to simplify nucleophilic radiofluorination reactions to be amenable for automation, a series of [18F]fluoronicotinamides, [ 18F]fluoroisonicotinamides and [18F]fluorobenzamides were synthesized using one-step
- Al Jammaz,Al-Otaibi,Okarvi,Amartey
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experimental part
p. 312 - 317
(2012/06/04)
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- Conformations, conformational preferences, and conformational exchange of N′-substituted N -acylguanidines: Intermolecular interactions hold the key
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Guanidine and acylguanidine groups are crucial structural features of numerous biologically active compounds. Depending on the biological target, acylguanidines may be considered as considerably less basic bioisosteres of guanidines with improved pharmacokinetics and pharmacodynamics, as recently reported for N′-monoalkylated N-acylguanidines as ligands of G-protein-coupled receptors (GPCRs). The molecular basis for enhanced ligand-receptor interactions of acylguanidines is far from being understood. So far, only a few and contradictory results about their conformational preferences have been reported. In this study, the conformations, conformational preferences, and conformational exchange of four unprotonated and seven protonated monoalkylated acylguanidines with up to six anions and with bisphosphonate tweezers are investigated by NMR. Furthermore, the effects of the acceptor properties in acylguanidine salts, of microsolvation by dimethylsulfoxide, and of varying acyl and alkyl substituents are studied. Throughout the whole study, exclusively two out of eight possible acylguanidine conformations were detected, independent of the compound, the anion, or the solvent used. For the first time, it is shown that the strength and number of intermolecular interactions with anions, solvent molecules, or biomimetic receptors decide the conformational preferences and exchange rates. One recently presented and two new crystal structures resemble the conformational preferences observed in solution. Thus, consistent conformational trends are found throughout the structurally diverse compound pool, including two potent GPCR ligands, different anions, and receptors. The presented results may contribute to a better understanding of the mechanism of action at the molecular level and to the prediction and rational design of these biologically active compounds.
- Kleinmaier, Roland,Keller, Max,Igel, Patrick,Buschauer, Armin,Gschwind, Ruth M.
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experimental part
p. 11223 - 11233
(2010/10/04)
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- Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway
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Hedgehog (Hh) signaling plays an important role in cell signaling of embryonic development and adult tissue homeostasis. In vertebrates, the hh gene encodes three different unique proteins: sonic hedgehog (Shh), desert hedgehog (Dhh) and indian hedgehog (Ihh). Disruption of the Hh signaling pathway leads to severe disorders in the development of vertebrates whereas aberrant activation of the Hh pathway has been associated with several malignancies including Gorlin syndrome (a disorder predisposing to basal cell carcinoma, medulloblastoma and rhabdomyosarcoma), prostate, pancreatic and breast cancers. In vivo evidence suggests the antagonism of excessive Hh signaling provides a route to unique mechanism-based anti-cancer therapies. Recently the small molecule SANT-2 was identified as a potent antagonist of Hh-signaling pathway. Here, we describe the synthesis, SAR studies as well as biological evaluation of SANT-2 and its analogues. Fifteen SANT-2 derivatives were synthesized and analyzed for their interference with the expression of the Hh target gene Gli1 in a reporter gene assay. By comparison of structure and activity important molecular descriptors for Gli inhibition could be identified. Furthermore we identified derivative TC-132 that was slightly more potent than the parent compound SANT-2. Selected compounds were tested for Hh related teratogenic effects in the small teleost model medaka. Albeit Gli expression has indicated a 16-fold higher Hh-inhibiting activity than observed for the plant alkaloid cyclopamine, none of the tested compounds were able to induce the cyclopamine-specific phenotype in the medaka assay.
- Buettner, Anita,Seifert, Katrin,Cottin, Thomas,Sarli, Vasiliki,Tzagkaroulaki, Lito,Scholz, Stefan,Giannis, Athanassios
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experimental part
p. 4943 - 4954
(2009/12/24)
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- NOVEL SUBSTITUTED AZABENZOXAZOLES
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The present invention relates to novel amyloid binding compounds and methods for measuring effects of the compounds, by measuring changes of amyloid plaque level in living patients. More specifically, the present invention relates to a method of using the
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Page/Page column 30-31
(2010/01/12)
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- Intramolecular hydrogen bonding and anion binding of N-benzamido-N′- benzoylthioureas
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(Chemical Equation Presented) N-(p-Dimethylamino)benzoyl-N′- phenylthiourea as an N-acylthiourea is known to be unable to bind anions due to a strong intramolecular hydrogen bond (IHB). We show here that by inserting an amido group in the N′-phenyl side the newly designed N-benzamido-N′- benzoylthioureas, despite this IHB too, bind strongly to anions with binding constants on the order of 106-107 mol-1 L. Results suggest that potential anion receptors or organocatalysts could be developed on the basis of this framework with a wide structural diversity.
- Liu, Wen-Xia,Jiang, Yun-Bao
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p. 1124 - 1127
(2008/09/18)
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- Mechanistic studies of the copper-catalyzed electrophilic amination of diorganozinc reagents and development of a zinc-free protocol
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Equation Presented An SN2 mechanism for the copper-catalyzed amination of diorganozinc reagents by O-benzoyl-N,N-dialkylhydroxyamines is supported by following stereochemically defined organometallics through the reaction and by employing the endocyclic restriction test. A copper-catalyzed electrophilic amination of organomagnesium compounds is also described in which the use of zinc halides has been eliminated.
- Campbell, Matthew J.,Johnson, Jeffrey S.
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p. 1521 - 1524
(2008/02/02)
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- Sensitive and selective method and device for the detection of trace amounts of a substance
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A piezoelectric crystal element and a sensor utilizing the same are presented for use in a sensor device for identifying at least one foreign material from environment. The crystal element comprises at least one crystal resonator in the form of a inverted mesa structure, which has a membrane-like region and has a certain resonance frequency value. A surface region of the crystal resonator is modified by reactive molecules of a kind capable of interacting with the foreign material to yield a reaction product that effects a change in the resonance frequency of the crystal resonator from said certain resonance frequency value. This change is indicative of the identity and quantity of the foreign material.
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Page/Page column 8
(2010/11/27)
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- Intramolecular charge transfer dual fluorescent sensors from 4-(dialkylamino)benzanilides with metal binding site within electron acceptor
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Three fluoroionophores (2a-c) were designed as the intramolecular charge transfer (CT) dual fluorescent sensors for metal cations with metal binding site within the electron acceptor. These sensors were derived from 4-dialkylaminobenzanilides (alkyl=methyl, ethyl, and n-butyl) with the amido phenyl ring being an arm of 15-crown-5 thus bearing binding site for alkaline and alkaline earth metal cations. Compounds 2a-c were expected to have two possible CT channels of opposite direction. The absorption and fluorescence spectra of 2a-c and their crown-ether free model molecules 3a-c in a variety of solvents were recorded. Dual fluorescence was observed with 2a-c and was assigned to the LE and the CT states, respectively. In nonpolar or less polar solvents the CT occurring with 2a-c was identified as that occurred with benzanilides (BA) with the amido anilines being the electron donor (the BA-like CT), while in polar solvents such as acetonitrile (ACN), the CT was still mainly the BA-like. In the presence of alkali and alkaline earth metal cations in ACN, the CT dual fluorescence underwent substantial changes so as increased total quantum yield, red-shifted LE band and enhanced CT to LE intensity ratio. Binding of the metal cations at the 15-crown-5 moiety of 2a-c was shown to turn the CT direction that the dialkylamino group in the binding complexes being the electron donor while the benzo-15-crown-5 moiety now being within the electron acceptor. The occurrence of this CT enhances metal cation binding to 15-crown-5 ether in 2a-c, which was confirmed by the observed higher metal binding constants. Compounds 2a-c as the CT dual fluorescent sensors were shown to operate under the mechanism of the metal cation binding induced switching of the CT character from the BA-like to that occurred with 4-(dimethylamino)benzamides (the DMABA-like). Compounds 2a-c therefore represent successful examples for the CT dual fluorescent sensors for cations with the metal binding site within the electron acceptor and can be employed as sensitive ratiometric fluorescent sensors for metal cations of improved sensing performance.
- Liu, Li-Hong,Zhang, Han,Li, Ai-Fang,Xie, Jian-Wei,Jiang, Yun-Bao
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p. 10441 - 10449
(2007/10/03)
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- Novel potent and efficacious nonpeptidic urotensin II receptor agonists
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Six different series of nonpeptidic urotensin II receptor agonists have been synthesized and evaluated for their agonistic activity in a cell-based assay (R-SAT). The compounds are ring-opened analogues of the isochromanone-based agonist AC-7954 with different functionalities constituting the linker between the two aromatic ring moieties. Several of the compounds are highly potent and efficacious, with N-[1-(4-chlorophenyl)-3-(dimethylamino)- propyl]-4-phenylbenzamide oxalate (5d) being the most potent. The pure enantiomers of 5d were obtained from the corresponding diastereomeric amides. It was shown by a combination of X-ray crystallography and chemical correlation that the activity resides in the S-enantiomer of 5d (pEC50 7.49).
- Lehmann, Fredrik,Pettersen, Anna,Currier, Erika A.,Sherbukhin, Vladimir,Olsson, Roger,Hacksell, Uli,Luthman, Kristina
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p. 2232 - 2240
(2007/10/03)
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- CRYSTALLINE CARBAPENEM INTERMEDIATE
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This invention relates to crystals of compounds of formula (I), wherein TBS represents t-butyldimethylsilyl, and Ph represents phenyl, or its salt or solvate. Compounds of formula (I) are synthesis intermediates of 2-substituted-1β-methyl carbapenem compo
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Page/Page column 14-15
(2008/06/13)
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- Oral GLP-1 formulations
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The present invention provides phamaceutical compositions comprising at least one delivery agent and GLP-1. These pharmaceutical compositions facilitate the oral delivery of GLP-1, providing improved (e.g. increased) bioavailability of GLP-1 compared to a
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Page/Page column 19
(2010/11/25)
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- Compounds and compositions for delivering active agents
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Compounds and compositions for the delivery of active agents are provided. Methods of administration and preparation are provided as well.
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Page/Page column 6
(2010/02/12)
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- Infrared and Nuclear Magnetic Resonance Properties of Benzoyl Derivatives of Five-membered Monoheterocycles and Determination of Aromaticity Indices
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Benzophenones, 2-benzoylthiophenes, 2-benzoylpyrroles, and 2-benzoylfurans, which have substituents at m- and p-positions of the benzoyl ring were prepared and their ir and nmr spectra were obtained in 0.1 M chloroform-d solution. The chemical shift values of each series were plotted against the Hammett substituent parameters to give good correlation, with the exception of the ortho-Hs and -Cs. The slopes as well as the differences in chemical shift gave sets of meaningful values for the indices of aromaticy.
- Jeon, Kyu Ok,Jun, Jung Ho,Yu, Ji Sook,Lee, Chang Kiu
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p. 763 - 771
(2007/10/03)
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