- Iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabled aldehyde C-H methylation
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A practical and general iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabling aldehyde C-H methylation for the synthesis of methyl ketones has been developed. This mild, operationally simple method uses ambient air as the sole oxidant and tolerates sensitive functional groups for the late-stage functionalization of complex natural-product-derived and polyfunctionalized molecules.
- Gong, Pei-Xue,Xu, Fangning,Cheng, Lu,Gong, Xu,Zhang, Jie,Gu, Wei-Jin,Han, Wei
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supporting information
p. 5905 - 5908
(2021/06/18)
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- Orthoquinone compound, as well as preparation method and medicinal application thereof
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The invention discloses an active small molecular compound simultaneously targeted to NQO1 and NAMPT, as well as a preparation method and a medicinal application thereof, and particularly relates to an orthoquinone compound or a pharmaceutically acceptable salt, solvate, predrug, ester, raceme and isomer thereof, and a medicine composition comprising the compounds, and applications of these compounds and medicine compositions in preparation of anti-tumor drugs. In the invention, by reasonably jointing an activating substrate tanshinone IIA of the NQO1 and the pharmacophores on the NAMPT inhibitor, the NQO1 substrate/NAMPT inhibitor is obtained, so that the compounds can be reductively activated by the NQO1 and meanwhile can inhibit the activity of the NAMPT, thus consuming the NAD+ and inhibiting biosynthesis of the NAD+ and showing a better tumor inhibiting activity. The orthoquinone compounds or medicine compositions thereof that simultaneously target to the NQO1 and the NAMPT have extensive application prospect and are hopeful to be anti-tumor drugs.
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Paragraph 0263-0264; 0267-0268
(2020/04/17)
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- Synthesis and biological evaluation of 2,2-dimethylbenzopyran derivatives as potent neuroprotection agents
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The development of novel neuroprotection agents is of great significance for the treatment of ischemic stroke. In this study, a series of compounds comprising 2,2-dimethylbenzopyran groups and cinnamic acid groups have been synthesized. Preferential combination principles and bioisostere that improved the neuroprotective effect of the compounds were identified for this series via biological activity assay in vitro. Meanwhile, a functional reversal group of the acrylamide amide resulted in the most active compounds. Among them, BN-07 significantly improved the morphology of neurons and obviously increased cell survival rate of primary neurons induced by oxygen glucose deprivation (OGD), superior to clinically used anti-ischemic stroke drug edaravone (Eda). Overall, our findings may provide an alternative strategy for the design of novel anti-ischemic stroke agents with more potency than Eda.
- Du, Fangyu,Zhou, Qifan,Fu, Xiaoxiao,Shi, Yajie,Chen, Yuanguang,Fang, Wuhong,Yang, Jingyu,Chen, Guoliang
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p. 2498 - 2508
(2019/02/01)
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- 2,2-dimethylbenzopyran derivative and preparation method and use thereof
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The invention belongs to the technical field of medicines, and discloses a 2,2-dimethylbenzopyran derivative and a preparation method and use of the 2,2-dimethylbenzopyran derivative. The derivative and pharmaceutically acceptable salt of the derivative have the structural formulae shown in the description, wherein Ar, Ar, X, Y and R1 are as described in the claims and the description. The preparation methods of the derivative and the pharmaceutically acceptable salt of the derivative comprise the following steps: the formula (I) is obtained by mainly taking acetaminophen as a raw material, and subjected to the reactions of Williamson ether formation, cyclization, hydrolysis, amide formation and the like; the formula II is obtained by mainly taking p-hydroxybenzaldehyde as a raw material, and subjected to the reactions of the Williamson ether formation, cyclization, Knoevenagel condensation, amide formation and the like. The derivative and the pharmaceutically acceptable salt ofthe derivative disclosed by the invention can be used for preparing neuroprotective agents and have better neuroprotective effects on ischemic stroke.
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Page/Page column 13; 14
(2019/01/16)
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- Semi-synthesis and Structure–Activity Relationship of Neuritogenic Oleanene Derivatives
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(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl (2E)-3-(3,4-dihydroxyphenyl)acrylate (1 a), which possesses significant neuritogenic activity, was isolated from the traditional Chinese medicine (TCM) plant, Desmodium sambuense. To confirm the structure and to assess biological activity, we semi-synthesized 1 a from commercially available oleanolic acid. A series of novel 1 a derivatives was then designed and synthesized for a structure–activity relationship (SAR) study. All synthetic derivatives were characterized by analysis of spectral data, and their neuritogenic activities were evaluated in assays with PC12 cells. The SAR results indicate that the number and position of the hydroxy groups on the phenyl ring and the triterpene moiety, as well as the length of the (saturated or unsaturated) alkyl chain that links the phenyl ring with the triterpene critically influence neuritogenic activity. Among all the tested compounds, 1 e [(3S,4R)-23,28-dihydroxyolean-12-en-3-yl (2E)-3-(3,4,5-trihydroxyphenyl)acrylate] was found to be the most potent, inducing significant neurite outgrowth at 1 μm.
- Bian, Linglin,Cao, Shining,Cheng, Lihong,Nakazaki, Atsuo,Nishikawa, Toshio,Qi, Jianhua
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supporting information
p. 1972 - 1977
(2018/09/06)
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- Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury
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Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs.
- Chen, Lingfeng,Jin, Yiyi,Chen, Hongjin,Sun, Chuchu,Fu, Weitao,Zheng, Lulu,Lu, Min,Chen, Pengqin,Chen, Gaozhi,Zhang, Yali,Liu, Zhiguo,Wang, Yi,Song, Zengqiang,Liang, Guang
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p. 361 - 375
(2017/12/07)
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- Synthesis and evaluation of N-heteroaromatic ring-based analogs of piperlongumine as potent anticancer agents
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Piperlongumine (PL) selectively targets a wide spectrum of cancer cells and induces their death by triggering various pathways, including apoptosis, necrosis and autophagy. However, the poor solubility is a serious concern for intensive study and clinical application. We synthesized its analogs 1–9 by replacement of the trimethoxyphenyl of PL with an N-heteroaromatic ring and/or not introduction of 2-Cl. These compounds improved aqueous solubility and displayed potent anticancer activity. The most active compound 9 selectively enhanced ROS levels in colon cancer cells and inhibited the cell proliferation but sparing non-tumor colon cells. Importantly, 9 significantly repressed tumor growth in an HCT-116 xenograft mouse model, suggesting that these N-heteroaromatic ring-based analogs of PL warrant further investigation.
- Zou, Yu,Yan, Chang,Zhang, Huibin,Xu, Jinyi,Zhang, Dayong,Huang, Zhangjian,Zhang, Yihua
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p. 313 - 319
(2017/07/07)
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- Strategic Approach to 8-Azacoumarins
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8-Azacoumarins have emerged as a promising class of compounds but are rarely explored due to challenging access. A novel, general, and practical method is provided for this class of compounds. The key lactonization step employs trans-acrylic acid attached pyridine N-oxides as the starting material, with acetic anhydride as both the activation agent and the solvent. Multiple transformations were involved in this reaction, including conjugate addition, nucleophilic aromatic substitution, and elimination. These studies provide the basis for access to 8-azacoumarins, enabling future work including the discovery and development of novel coumarin-type drugs, fluorescent probes, photolabile protecting groups, and other active molecules.
- Wang, Dong,Wang, Yuxi,Zhao, Junjie,Shen, Meng,Hu, Jianyong,Liu, Zhenlin,Li, Linna,Xue, Furen,Yu, Peng
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supporting information
p. 984 - 987
(2017/03/14)
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- 3-aryl acrylic acid and its derivatives viral anti-plant
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The invention relates to an application of 3-aryl acrylic acid represented by a general formula (I) and a derivative thereof in pesticides, wherein the 3-aryl acrylic acid and the derivative thereof can be adopted as novel anti-plant virus agents, can be provided for well inhibiting tobacco mosaic virus, pepper virus, tomato virus, sweet potato virus, potato virus, melon virus, maize dwarf mosaic virus and the like, and can be provided for effectively preventing and controlling virus diseases of a plurality of crops such as tobacco, pepper, tomato, melon vegetables, grains, vegetables, beans and the like, especially tobacco mosaic diseases. (Wherein Ar and R are defined in an instruction).
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Paragraph 0022; 0023
(2016/11/21)
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- Structural features of pyridylcinnamic acid dimers and their extended hydrogen-bonded aggregations
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The conformational as well as the structure-forming properties of E-3-(x-pyridyl)propenoic acids (x = 2, 3 or 4) have been studied with a combination of computational and spectroscopic methods. IR spectroscopy revealed that in the solid state the zwitterionic species predominate, while NMR measurements showed that dimers, kept together by strong CO?HO hydrogen bonds, were formed in a dipolar aprotic solvent (DMSO). In concentrated solution, extended aggregation occurred through the cooperative effect of (aromatic) C-H?N weak hydrogen bonds. Conformational search was performed at the HF/6-31G(d,p) level of theory. Comparison with experimental values as well as benchmarking calculations at several different levels of theory to probe the performance of the methods, B3LYP/6-31G++(d,p) method was found to be able to provide reasonable geometries as well as quantitative formation energies for the dimers and the tetramers, too.
- Csankó,Ruusuvuori,Tolnai,Sipos,Berkesi,Pálinkó
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- CYCLOPROPYL AMIDE DERIVATIVES
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The present invention relates to certain cyclopropyl amide compounds, pharmaceutical compositions comprising such compounds, and methods of treating cancer, including leukemias and solid tumors, inflammatory diseases, osteoporosis, atherosclerosis, irritable bowel syndrome, and other diseases and medical conditions, with such compounds and pharmaceutical compositions. The present invention also relates to certain cyclopropyl amide compounds for use in inhibiting nicotinamide phosphoribosyltransferase ("NAMPT").
- -
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Paragraph 0170
(2014/05/24)
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- Fragment-based identification of amides derived from trans-2-(pyridin-3-yl) cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
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Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC 50 = 0.0051 μM, A2780 cell culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.
- Giannetti, Anthony M.,Zheng, Xiaozhang,Skelton, Nicholas J.,Wang, Weiru,Bravo, Brandon J.,Bair, Kenneth W.,Baumeister, Timm,Cheng, Eric,Crocker, Lisa,Feng, Yezhen,Gunzner-Toste, Janet,Ho, Yen-Ching,Hua, Rongbao,Liederer, Bianca M.,Liu, Yongbo,Ma, Xiaolei,O'Brien, Thomas,Oeh, Jason,Sampath, Deepak,Shen, Youming,Wang, Chengcheng,Wang, Leslie,Wu, Hongxing,Xiao, Yang,Yuen, Po-Wai,Zak, Mark,Zhao, Guiling,Zhao, Qiang,Dragovich, Peter S.
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p. 770 - 792
(2014/03/21)
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- Tunable plastic films of a crystalline polymer by single-crystal-to-single- crystal photopolymerization of a diene: Self-templating and shock-absorbing two-dimensional hydrogen-bonding layers
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Film review: Two amide-containing bisolefin monomers undergo solid-state polymerization (see example) through a [2+2] reaction in a single-crystal-to- single-crystal fashion. The transformation was favored by the self-templating and shock-absorbing nature of hydrogen-bonding layers. The pyridine-containing polymers were soluble and useful for making plastic films with considerable tensile strengths. Copyright
- Garai, Mousumi,Santra, Ramkinkar,Biradha, Kumar
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supporting information
p. 5548 - 5551
(2013/06/27)
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- Synthesis and biological evaluation of N-(aminopyridine) benzamide analogues as histone deacetylase inhibitors
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A series of benzamide-based histone deacetylases (HDACs) inhibitors possessing N-(aminopyridine) residue as the zinc binding site of HDAC were synthesized and evaluated. Among these derivatives, compounds with N-(2-amino-4-pyridine) benzamide moiety have been found as the most potent ones. Moreover, introduction of appropriate substituents on the terminal aryl group acting as the surface-recognition domain could significantly improve the antiproliferative activity. In particular, the compound 4k possessed favorable pharmacokinetic characteristics and exhibited potent antitumor activity on xenograft model in mice at well tolerated doses, thus suggesting a good therapeutic index.
- Zhang, Qing-Wei,Li, Jian-Qi
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experimental part
p. 535 - 540
(2012/05/04)
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- Design, synthesis and biological evaluation of novel acrylamide analogues as inhibitors of BCR-ABL kinase
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A series of acrylamide analogues were designed and synthesized from Imatinib and Nilotinib as novel BCR-ABL inhibitors by application of the principle of nonclassical electronic isostere. All new compounds were evaluated for their inhibitory effects on the activity of BCR-ABL kinase and the proliferation of K562 leukemia cancer cells in vitro. The acrylamide analogues in which the substituent in C ring was trifluoromethyl group were identified as highly potent BCR-ABL kinase inhibitors. Compound 13f exhibited an IC 50 value as low as 20.6 nM in ABL kinase inhibition and an IC 50 value of 32.3 nM for antiproliferative activity, about 10.5-fold and 12-fold lower than those of Imatinib respectively. These results suggest that compound 13f is a promising candidate as a novel BCR-ABL kinase inhibitor for further development.
- Li, Shuxin,Yao, Zhenglin,Zhao, Yanjin,Chen, Wei,Wang, Huijia,Kuang, Xianzhao,Zhan, Wenhu,Yao, Shan,Yu, Shanyou,Hu, Wenxiang
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scheme or table
p. 5279 - 5282
(2012/09/07)
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- Synthesis of cinnamic acid derivatives in a water-insoluble ionic liquid
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A number of cinnamic acid derivatives have been synthesised from commercially available aromatic aldehydes and propanedioic acid in a water-insoluble ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate, [bmim]PF6) in high yields in the presence of small catalytic amounts of piperidine. The ionic liquid can be reused at least five times.
- Zhang, Wensheng,Xu, Wenjing,Liu, Mei,Yan, Yuerong,Sun, Yuezhi,Zhang, Sheli
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experimental part
p. 723 - 725
(2012/03/09)
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- Competitive formation of β-amino acids, propenoic, and ylidenemalonic acids by the Rodionov reaction from malonic acid, aldehydes, and ammonium acetate in alcoholic medium
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The Rodionov reaction of 49 available aliphatic and aromatic aldehydes with malonic acid and ammonium acetate in alcoholic medium, resulting in formation of β-amino acids, propenoic, and ylidenemalonic acids, was studied. Certain regioselectivity regularities of the reaction were revealed. Among the variety of ketones studied, cyclohexanone is the only whose reaction yields a β-amino acid. Unusual dehydrofluorination of 6-chloro-2-fluorocinnamic acid under the Rodionov reaction was discovered. 2005 Pleiades Publishing, Inc.
- Lebedev,Lebedeva,Sheludyakov,Kovaleva,Ustinova,Kozhevnikov
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p. 1113 - 1124
(2007/10/03)
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- KOH-promoted reaction of C,O,O-tris(trimethylsilyl) ketene acetal with aldehydes: Practical and easy access to (E)-α,β-ethylenic carboxylic acids
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The use of a catalytic amount of KOH has been found to be very efficient in promoting reaction of silylketene acetal 1 with aldehydes 2 to afford the corresponding (E)-α,β-ethylenic carboxylic acids 3 under very mild conditions.
- Lensen,Mouelhi,Bellassoued
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p. 1007 - 1011
(2007/10/03)
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- Two-carbon homologation of aldehydes via silyl ketene acetals: A new stereoselective approach to (E)-alkenoic acids
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Aldehydes are converted into (E)-α,β-unsaturated carboxylic acids using C,O,O-tris(trimethylsilyl)ketene acetal 1. This organosilicon reagent is easily generated from trimethylsilyl acetate, LDA, and chlorotrimethylsilane. The effectiveness of the reaction has been explored for a large variety of aldehydes with Lewis acids and fluorides as catalysts.
- Bellassoued, Moncef,Lensen, Nathalie,Bakasse, Mina,Mouelhi, Sinda
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p. 8785 - 8789
(2007/10/03)
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- EFFECT OF SUBSTITUENTS OF THE 1H AND 13C NMR CHEMICAL SHIFTS OF trans-PYRIDINEACRYLIC AND SUBSTITUTED trans-CINNAMIC ACIDS
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The principles of linear free energy relationships were applied to the 1H nmr and 13C nmr chemical shifts induced by substituents in three isomeric trans-pyridineacrylic and substituted trans-cinnamic acids.The data for the carboxy proton chemical shift correlated well with the simple Hammett equation.Taft's dual substituent parameter equation was used for the interpretation of the balance of the inductive and resonance effects through the ethylenic bond for the Cα and Cβ 13C nmr shift.Using the nuclear Overhauser method, the conformation of the carboxylic group in 2-pyridineacrylic acid was determined, and its unexpected behaviour in both 1H nmr chemical shifts and in the previously studied reaction with diazodiphenylmethane was interpreted by the increased electron density in the ?-electronic system favoured by the orbital symmetry of the part of the acid molecule.
- Jovanovic, Bratislav,Misic-Vukovic, Milica,Drmanic, Sasa,Csanadi, Janos
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p. 1495 - 1502
(2007/10/02)
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- Symmetry-Based Inhibitors of HIV Protease. Structure-Activity Studies of Acylated 2,4-Diamino-1,5-diphenyl-3-hydroxypentane and 2,5-Diamino-1,6-diphenylhexane-3,4-diol
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The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described.Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends of the symmetric or pseudosymmetric inhibitors was probed.Aqueous solubility was enhanced >1000-fold while maintaining potent inhibition of purified HIV-1 protease and anti-HIV activity in vitro.Pharmacokinetic studies in rats indicated a substantial difference in the absorption properties of mono-ol-based and diol-based inhibitors.The oral bioavailability of inhibitor 19 in rats was 19percent; however, the Cmax obtained failed to exceed the anti-HIV EC50 in vitro.Substantial plasma levels of potent inhibitors of the diol class were not obtained after oral administration in rats; however, the optimal combination of aqueous solubility and in vitro antiviral activity of several inhibitors support their potential use in intravenous therapy.
- Kempf, Dale J.,Codacovi, Lynnmarie,Wang, Xiu Chun,Kohlbrenner, William E.,Wideburg, Norman E.,et al.
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p. 320 - 330
(2007/10/02)
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