- X-ray Structure and Molecular Docking Guided Discovery of Novel Chitinase Inhibitors with a Scaffold of Dipyridopyrimidine-3-carboxamide
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Chitinases are the glycosyl hydrolase for catalyzing the degradation of chitin and play an indispensable role in bacterial pathogenesis, fungal cell wall remodeling, and insect molting. Thus, chitinases are attractive targets for therapeutic drugs and pes
- Yuan, Pengtao,Jiang, Xi,Wang, Siyu,Shao, Xusheng,Yang, Qing,Qian, Xuhong
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Read Online
- Synthesis and biological evaluation of flavone-8-acrylamide derivatives as potential multi-target-directed anti Alzheimer agents and investigation of binding mechanism with acetylcholinesterase
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In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a─q)were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of Aβ aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate anti-oxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the Aβ aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 × 104, 2.22 × 104, 1.18 × 104, 9.8 × 103 and 3.2 × 104 M?1 and free energy change as ?5.83, ?5.91, ?5.51, ?5.41 and ?6.12 kcal M?1 at 25 °C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i.
- Shaik, Jeelan Basha,Yeggoni, Daniel Pushparaju,Kandrakonda, Yelamanda Rao,Penumala, Mohan,Zinka, Raveendra Babu,Kotapati, Kasi Viswanath,Darla, Mark Manidhar,Ampasala, Dinakara Rao,Subramanyam, Rajagopal,Amooru, Damu Gangaiah
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Read Online
- A CO2-Catalyzed Transamidation Reaction
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Transamidation reactions are often mediated by reactive substrates in the presence of overstoichiometric activating reagents and/or transition metal catalysts. Here we report the use of CO2as a traceless catalyst: in the presence of catalytic amounts of CO2, transamidation reactions were accelerated with primary, secondary, and tertiary amide donors. Various amine nucleophiles including amino acid derivatives were tolerated, showcasing the utility of transamidation in peptide modification and polymer degradation (e.g., Nylon-6,6). In particular,N,O-dimethylhydroxyl amides (Weinreb amides) displayed a distinct reactivity in the CO2-catalyzed transamidation versus a N2atmosphere. Comparative Hammett studies and kinetic analysis were conducted to elucidate the catalytic activation mechanism of molecular CO2, which was supported by DFT calculations. We attributed the positive effect of CO2in the transamidation reaction to the stabilization of tetrahedral intermediates by covalent binding to the electrophilic CO2
- Yang, Yang,Liu, Jian,Kamounah, Fadhil S.,Ciancaleoni, Gianluca,Lee, Ji-Woong
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p. 16867 - 16881
(2021/11/18)
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- Non-alkylator anti-glioblastoma agents induced cell cycle G2/M arrest and apoptosis: Design, in silico physicochemical and SAR studies of 2-aminoquinoline-3-carboxamides
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Malignant gliomas are the most common brain tumors, with generally dismal prognosis, early clinical deterioration and high mortality. Recently, 2-aminoquinoline scaffold derivatives have shown pronounced activity in central nervous system disorders. We herein reported a series of 2-aminoquinoline-3-carboxamides as novel non-alkylator anti-glioblastoma agents. The synthesized compounds showed comparable activity to cisplatin against glioblastoma cell line U87 MG in vitro. Among them, we found that 6a displayed good inhibitory activity against A172 and U118 MG glioblastoma cell lines and induced cell cycle arrest in the G2/M phase and apoptosis in U87 MG by flow cytometry analysis. Additionally, 6a displayed low cytotoxicity to several normal human cell lines. In silico study showed 6a had promising physicochemical properties and was predicted to cross the blood–brain barrier. Moreover, preliminary structure–activity relationships are also investigated, shedding light on further modifications towards more potent agents on this series of compounds. Our results suggest this compound has a promising potential as an anti-glioblastoma agent with a differential effect between tumor and non-malignant cells.
- Gu, Xiangyu,Liu, Jianwen,Ni, Xintong,Qi, Yingxue,Qian, Xuhong,Shao, Xusheng,Xu, Xiaoyong,Yuan, Pengtao
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supporting information
(2021/09/22)
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- Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones
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The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.
- Wen, Li-Rong,Wang, Ning-Ning,Du, Wu-Bo,Ma, Qiang,Zhang, Lin-Bao,Li, Ming
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supporting information
p. 2895 - 2900
(2021/04/14)
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- Synthesis and Docking Study of Novel Pyranocoumarin Derivatives
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Abstract: A new series of fused tricyclic coumarin derivatives were designed, synthesized by a simple and convenient method, starting from 4-hydroxycoumarin and virtually screened by molecular docking on the target protein 3FRZ (PDB ID: 3FRZ), a HCV RNA-dependent RNA polymerase, for potency against hepatitis C virus (HCV). Efficient binding to the target protein was found for most of the synthesized compounds.
- Karteek, S. Durga,Reddy, A. Gopi,Tej, M. Bhuvan,Rao, M. V. Basaveswara
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p. 272 - 282
(2021/04/02)
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- Structure-activity relationship of spop inhibitors against kidney cancer
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Speckle-type POZ protein (SPOP) is overexpressed in the nucleus and misallocated in the cytoplasm in almost all the clear-cell renal cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously, we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could be suppressed by 6b that inhibits SPOP-mediated protein interactions. Herein, we have established a structure-activity relationship for 6b analogues as SPOP inhibitors. Compound 6lc suppresses the viability and inhibits the colony formation of ccRCC cell lines driven by cytoplasmic SPOP, superior to 6b. Compound 6lc binds to the SPOP protein in vitro and disrupts SPOP binding to phosphatase-and-tensin homologue (PTEN) in HEK293T cells, which causes the observable phenomena: a decline in the ubiquitination of PTEN, elevated levels of both PTEN and dual-specificity phosphatase 7, and decreased levels of phosphorylated AKT and ERK when ccRCC cell lines are exposed to 6lc in a dose-response manner. Taken together, compound 6lc is a potent candidate against kidney tumorigenesis.
- Dong, Ze,Wang, Zhen,Guo, Zhong-Qiang,Gong, Shouzhe,Zhang, Tao,Liu, Jiang,Luo, Cheng,Jiang, Hualiang,Yang, Cai-Guang
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p. 4849 - 4866
(2020/06/08)
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- Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2-b]pyrazole-7-carboxamides
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The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC50 = 0.183 μM).
- Demjén, András,Alf?ldi, Róbert,Angyal, Anikó,Gyuris, Márió,Hackler, László,Szebeni, Gábor J.,W?lfling, János,Puskás, László G.,Kanizsai, Iván
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- New Flavone-Cyanoacetamide Hybrids with a Combination of Cholinergic, Antioxidant, Modulation of β-Amyloid Aggregation, and Neuroprotection Properties as Innovative Multifunctional Therapeutic Candidates for Alzheimer's Disease and Unraveling Their Mechanism of Action with Acetylcholinesterase
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In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC50 of 0.271 ± 0.012 to 1.006 ± 0.075 μM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Aβ aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.
- Basha, Shaik Jeelan,Mohan, Penumala,Yeggoni, Daniel Pushparaju,Babu, Zinka Raveendra,Kumar, Palaka Bhagath,Rao, Ampasala Dinakara,Subramanyam, Rajagopal,Damu, Amooru Gangaiah
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p. 2206 - 2223
(2018/05/23)
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- Acetic acid as a catalyst for the N-acylation of amines using esters as the acyl source
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We report a cheap and simple method for the acetylation of a variety of amines using catalytic acetic acid and either ethyl acetate or butyl acetate as the acyl source. Catalyst loadings as low as 10 mol% afforded acetamide products in excellent yields at temperatures ranging from 80-120 °C. The methodology can also be successfully applied for the synthesis of a broad range of other amides, including the formation of formamides at 20 °C.
- Sanz Sharley, Daniel D.,Williams, Jonathan M. J.
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supporting information
p. 2020 - 2023
(2017/02/15)
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- Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents
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A series of fused tricyclic coumarin derivatives bearing iminopyran ring connected to various amido moieties were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. In vitro studies revealed that most of these compounds exhibited high inhibitory activity on acetylcholinesterase (AChE), with IC50 values ranging from 0.003 to 0.357 μM which is 2-220 folds more potent than the positive control, galantamine. Their inhibition selectivity against AChE over butyrylcholinesterase (BuChE) has increased about 194 fold compared with galantamine. The developed compounds also showed potent ABTS radical scavenging activity (IC50 7.98-15.99 μM). Specifically, the most potent AChE inhibitor 6n (IC50 0.003 ± 0.0007 μM) has an excellent antioxidant profile as determined by the ABTS method (IC50 7.98 ± 0.77 μM). Moreover, cell viability studies in SK N SH cells showed that the compounds 6m-q have significant neuroprotective effects against H2O2-induced cell death, and are not neurotoxic at all concentrations except 6n and 6q. The kinetic analysis of compound 6n proved that it is a mixed-type inhibitor for EeAChE (Ki1 0.0103 μM and Ki2 0.0193 μM). Accordingly, the molecular modeling study demonstrated that 6m-q with substituted benzyl amido moiety possessed an optimal docking pose with interactions at catalytic active site (CAS) and peripheral anionic site (PAS) of AChE simultaneously and thereby they might prevent aggregation of Aβ induced by AChE. Furthermore, in silico ADMET prediction studies indicated that these compounds satisfied all the characteristics of CNS acting drugs. Most active inhibitor 6n is permeable to BBB as determined in the in vivo brain AChE activity. To sum up, the multipotent therapuetic profile of these novel tricyclic coumarins makes them promising leads for developing anti-Alzheimer agents.
- Shaik, Jeelan Basha,Palaka, Bhagath Kumar,Penumala, Mohan,Kotapati, Kasi Viswanath,Devineni, Subba Rao,Eadlapalli, Siddhartha,Darla, M. Manidhar,Ampasala, Dinakara Rao,Vadde, Ramakrishna,Amooru, G. Damu
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p. 219 - 232
(2015/11/24)
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- Synthesis, Biological Evaluation, and Molecular Docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease
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Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogs (4a–q) were synthesized and evaluated for their multitarget-directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, and amyloid-β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3-bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC50 value of 13 ± 1.4 nm which is 51-fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed-type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e, 4f, 4g, 4j, and 4k have shown 1.4- to 2.5-fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage-dependent acceleration of Aβ1?42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy.
- Shaik, Jeelan Basha,Palaka, Bhagath Kumar,Penumala, Mohan,Eadlapalli, Siddhartha,Darla Mark, Manidhar,Ampasala, Dinakara Rao,Vadde, Ramakrishna,Amooru Gangaiah, Damu
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- Spacer-Modulated Differentiation between Self-Assembly and Folding Pathways for Bichromophoric Merocyanine Dyes
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We have synthesized a large series of bis(merocyanine) dyes with varying spacer unit and investigated in detail their self-organization behavior by concentration- as well as solvent-dependent UV/Vis spectroscopy. Our in-depth studies have shown that the s
- Zitzler-Kunkel, André,Kirchner, Eva,Bialas, David,Simon, Christian,Würthner, Frank
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p. 14851 - 14861
(2015/10/19)
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- Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1
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Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.
- Hu, Dawei,Miyagi, Namiki,Arai, Yuki,Oguri, Hiroaki,Miura, Takeshi,Nishinaka, Toru,Terada, Tomoyuki,Gouda, Hiroaki,El-Kabbani, Ossama,Xia, Shuang,Toyooka, Naoki,Hara, Akira,Matsunaga, Toshiyuki,Ikari, Akira,Endo, Satoshi
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p. 7487 - 7499
(2015/07/15)
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- Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1
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Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.
- Hu, Dawei,Miyagi, Namiki,Arai, Yuki,Oguri, Hiroaki,Miura, Takeshi,Nishinaka, Toru,Terada, Tomoyuki,Gouda, Hiroaki,El-Kabbani, Ossama,Xia, Shuang,Toyooka, Naoki,Hara, Akira,Matsunaga, Toshiyuki,Ikari, Akira,Endo, Satoshi
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p. 7487 - 7499
(2015/11/27)
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- Tracing binding modes in hit-to-lead optimization: Chameleon-like poses of aspartic protease inhibitors
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Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and β-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.
- Kuhnert, Maren,K?ster, Helene,Bartholom?us, Ruben,Park, Ah Young,Shahim, Amir,Heine, Andreas,Steuber, Holger,Klebe, Gerhard,Diederich, Wibke E.
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supporting information
p. 2849 - 2853
(2015/03/04)
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- Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments
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Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
- J?st, Christian,Nitsche, Christoph,Scholz, Therese,Roux, Lionel,Klein, Christian D.
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supporting information
p. 7590 - 7599
(2014/12/11)
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- Lanthanum(III) triflate catalyzed direct amidation of esters
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Lanthanum trifluoromethanesulfonate is an effective single-component catalyst for synthesizing a variety of amides directly from esters and amines under mild conditions. Highly selective amidation of esters and amines, as well as catalyst-controlled amidation of esters, demonstrated the effectiveness of the catalyst system.
- Morimoto, Hiroyuki,Fujiwara, Risa,Shimizu, Yuhei,Morisaki, Kazuhiro,Ohshima, Takashi
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supporting information
p. 2018 - 2021
(2014/05/06)
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- KINASE INHIBITORS
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Methods of inhibiting kinases using kinase inhibitors having olefin moieties are disclosed.
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Paragraph 0302; 0303
(2013/03/26)
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- Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach
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Based on a known nanomolar Bcl-2 homology domain 3 (BH3) mimetic 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b] pyrrole-9-carbonitrile (S1, MW: 331), we applied a fragment-based approach to obtain BH3 mimetics with improved affinity and improved solubility in a water-ethanol (9:1) cosolvent. After the deconstruction of 1 (S1), we obtained fragment cyanoacetamide (4), which was determined to be a ligand efficiency (LE) hot part. After a rational optimization through fragment evolution beginning with fragment 4, a smaller Mcl-1 inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g, MW: 288) with a 6-fold increase in affinity compared to 1 was obtained, as predicted by our optimization curve and identified by Mcl-1 protein nuclear magnetic resonance (NMR).
- Zhang, Zhichao,Song, Ting,Li, Xiangqian,Wu, Zhiyong,Feng, Yingang,Xie, Feibo,Liu, Chengwu,Qin, Jianquan,Chen, Hongbo
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supporting information
p. 141 - 149
(2013/03/13)
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- Synthesis of new 8-formyl-4-methyl-7-hydroxy coumarin derivatives
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8-Formyl-4-Methyl-7-Hydroxy Coumarin Derivatives were synthesized via Penchem condensation followed by Duffs reaction. Treatment of this with N,N-di substituted cyano acetamides in the presence of piperdine afforded New 8- Formyl-4-Methyl-7-Hydroxy Coumarin Derivatives (7a-o). Their structures were characterized by IR, 1H and 13C NMR and Mass spectral and elemental analysis data.
- Manidhar,Rao, K. Uma Maheswara,Reddy, N. Bakthavatchala,Sundar, Ch. Syama,Reddy, C. Suresh
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p. 459 - 463
(2012/11/07)
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- Cell-permeable iminocoumarine-based fluorescent dyes for mitochondria
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A class of small molecule fluorophores, 2-iminocoumarin-3-carboxamide derivatives, has been developed by a rapid microwave-assisted process. These fluorescent probes are cell membrane permeable with low cytotoxicity and able to selectively stain organelles in living cells.
- Guo, Diliang,Chen, Tao,Ye, Deju,Xu, Jinyi,Jiang, Hualiang,Chen, Kaixian,Wang, Hui,Liu, Hong
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supporting information; experimental part
p. 2884 - 2887
(2011/07/07)
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- Efficient synthesis of new butenolides by subsequent reactions: Application for the synthesis of original iminolactones, bis-iminolactones and bis-lactones
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We have developed the synthesis of twenty four new iminolactones, bis-iminolactones and bis-lactones by subsequent esterification-condensation or addition-condensation reactions according to two strategies from α-hydroxyketones. The X-ray diffraction data of a bis-iminolactone is described and present an interesting helical column packing.
- Cheikh, Nawel,Bar, Nathalie,Choukchou-Braham, Nourredine,Mostefa-Kara, Bachir,Lohier, Jean-Franois,Sopkova, Jana,Villemin, Didier
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experimental part
p. 1540 - 1551
(2011/04/15)
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- Synthesis and antiviral bioactivities of 2-cyano-3-substitutedamino(phenyl) methylphosphonylacrylates (Acrylamides) containing alkoxyethyl moieties
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An efficient reaction under microwave irradiation has been developed for the synthesis of a series of novel 2-cyano-3-substituted-amino(phenyl) methylphosphonylacrylates (acrylamides) II. The products obtained in shorter reaction time with moderate yields are fully characterized by elemental analysis, IR, 1H, 13C, and 31P NMR spectral data. The role of introducing various substituents and the effect of incorporating a-aminophosphonates with an alkoxyethyl moiety into the parent cyanoacrylate (acrylamide) structure are investigated. Among the studied compounds, both II-17 and II-24 displayed good in vivo curative, protection, and inactivation effects, which were comparable to those of the commercial reference ningnanmycin (inhibitory rates of 58.8, 60.2, 78.9% and 60.0, 58.9, 85.5%, respectively, at 500 mg/L against TMV). To the best of the authors' knowledge, this is the first report on the synthesis and antiviral activity of the title compounds II.
- Yang, Jia-Qiang,Song, Bao-An,Bhadury, Pinaki S.,Chen, Zhuo,Yang, Song,Xue-Jian, Cai,Hu, De-Yu,Xue, Wei
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experimental part
p. 2730 - 2735
(2011/07/31)
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- Green chemistry: A facile synthesis of polyfunctionally substituted thieno[3,4-c]pyridinones and thieno[3,4-d]pyridazinones under neat reaction conditions
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A facile, solvent free, ecofriendly approach for the synthesis of pyridine-2,6-diones 4a-d, pyridazinone derivatives 8a-c and thienoazines 6 and 9 is herein described employing neat reaction conditions under both microwave and ultrasound irradiations. This solventless methodology is environmentally benign as it completely eliminates the use of solvent from the reaction procedure.
- Al-Zaydi, Khadijah M.,Borik, Rita M.,Mekheimer, Ramadan A.,Elnagdi, Mohamed H.
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body text
p. 909 - 915
(2011/10/08)
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- Mild and efficient DBU-catalyzed amidation of cyanoacetates
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A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.
- Price, Kristin E.,Larrivee-Aboussafy, Claude,Lillie, Brett M.,McLaughlin, Robert W.,Mustakis, Jason,Hettenbach, Kevin W.,Hawkins, Joel M.,Vaidyanathan, Rajappa
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supporting information; experimental part
p. 2003 - 2006
(2009/09/30)
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- COMPOSITIONS AND MEHTODS FOR INHIBITION OF HEPATOCYTE GROWTH FACTORY RECEPTOR C-MET SIGNALING
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Derivatives and analogs of inhibitors of receptor tyrosine kinase c-Met, pharmaceutical compositions containing derivatives and analogs of c-Met inhibitors are provided. Methods of making derivatives and analogs of c-Met inhibitors and methods of use thereof are provided.
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Page/Page column 21-22
(2009/10/30)
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- Synthesis and antiviral activities of cyanoacrylate derivatives containing an α-aminophosphonate moiety
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Target compounds 8 were obtained by the reaction of alkyl 2-cyano-3,3-dimethylthioacrylate or cyarylamide (7a-7e) and α- aminobenzylphosphonate (5a-5e) under reflux condition using ethanol as solvent. Their structures were clearly verified by spectroscopic data (IR and 1H, 13C, and 31P NMR) and elemental analysis. These compounds were shown to be antivirally active in the bioassay. It was found that title compounds 8d and 8e had the same inactivation effect against tobacco mosaic virus (EC50 = 55.5 and 55.3 μg/mL) as the commercial product ningnanmycin (EC50 = 50.9 μg/mL). To the best of our knowledge, this is the first report on the synthesis and antiviral activity of cyanoacrylate derivatives containing an α-aminophosphonate moiety.
- Long, Ning,Cai, Xue-Jian,Song, Bao-An,Yang, Song,Chen, Zhuo,Bhadury, Pinaki S.,Hu, De-Yu,Jin, Lin-Hong,Xue, Wei
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body text
p. 5242 - 5246
(2010/04/06)
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- NOVEL COMPOUNDS FOR MODULATING CELL PROLIFERATION
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Novel styrylacrylonitrile compounds which are useful in treating a variety of cell proliferative disorders such as cancer are disclosed.
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Page/Page column 88-89
(2008/06/13)
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- COMPOUNDS FOR TREATMENT OF CELL PROLIFERATIVE DISEASES
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The present invention concerns compounds and their use to treat cell proliferative diseases such as cancer. Compounds of the present invention display significant potency as kinase inhibitors, cause the downregulation of c-myc, and inhibit the growth and survival of cancerous cell lines.
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Page/Page column 22
(2008/06/13)
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- Tyrenes: Synthesis of new antiproliferative compounds with an extended conjugation
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A series of substituted styryl-acrylonitriles was designed and synthesized. The new compounds, called tyrenes, were tested for the ability to inhibit acute lymphocytic leukemia (ALL) cancer cell growth, as well as on their toxicity to normal bone marrow (NBM) cells. The results showed that 3,4-dihydroxystyryl- acrylonitriles, in particular CR-4, revealed great potency as antitumor agents, and also exhibited low toxicity to normal cells. The effectiveness of these compounds with extended conjugation may be due to their possible functioning as reactive Michael acceptors.
- Demin, Peter,Rounova, Olga,Grunberger, Thomas,Cimpean, Lorand,Sharfe, Nigel,Roifman, Chaim M.
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p. 3019 - 3026
(2007/10/03)
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- Rapid microwave-assisted solution phase synthesis of substituted 2-pyridone libraries
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2-Pyridone and 2-quinolone analogues are well-known biologically active heterocyclic scaffolds. Libraries of 3,5,6-substituted 2-pyridone derivatives are generated by rapid microwave assisted solution phase methods using a one-pot, two-step protocol. The three-component condensation of CH-acidic carbonyl compounds, N,N-dimethylformamide dimethylacetal and methylene active nitriles, leads to 2-pyridones and fused analogues in moderate to good overall yields and high purities. The proposed mechanism of this novel multi-component reaction, structure elucidation of products and intermediates are discussed.
- Gorobets, Nikolay Yu.,Yousefi, Behrooz H.,Belaj, Ferdinand,Kappe, C. Oliver
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p. 8633 - 8644
(2007/10/03)
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- Kinetics and mechanism of aminolysis of aliphatic esters in aprotic solvents
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Kinetic studies were carried out on the aminolysis reactions of substituted aliphatic esters in a variety of aprotic solvents. The reaction rate is strongly affected by inductive and steric effects of substituents in the acyl group, rising more than 104-fold from cyanoacetate to trifluoroacetate. The quantitative treatment of solvent effects revealed a rate decrease by the polarity and π-basicity of the solvents, and also an accelerating effect of the polarizability of solvents. Cyclic transition states were assumed for both the first and second-order (in amine) reactions. Copyright
- Talvik, Agu-Tonis,Tuulmets, Ants,Vaino, Evi
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p. 747 - 750
(2007/10/03)
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- α-Cyanocinnamide derivatives: A new family of non-peptide, non-sulfhydryl inhibitors of ras farnesylation
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Farnesylation of Ras and other proteins is required for their membrane attachment and normal function. Here we report on the synthesis of α-cyanocinnamide derivatives, a new family of farnesyltransferase inhibitors. These compounds are nonpeptidic and do not contain sulfhydryl groups. The most potent compound is a pure competitive inhibitor with respect to the Ras protein and mixed competitive with respect to farnesyl diphosphate. Selectivity studies against geranylgeranyltransferase and biological activities of selected compounds are described. Copyright (C) 1999.
- Poradosu, Enrique,Gazit, Aviv,Reuveni, Hadas,Levitzki, Alexander
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p. 1727 - 1736
(2007/10/03)
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- Structure-activity relationship of N-(phenylalkyl)cinnamides as novel NR2B subtype-selective NMDA receptor antagonists
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A novel series of N-(phenylalkyl)cinnamides related to N-(4- phenylbutyl)-3,4-dihydroxy-β-cyanocinnamide (6, an EGFR-K inhibitor with high antiproliferative activity) was synthesized and tested for antagonism at N-methyl-D-aspartate (NMDA) receptor subtypes. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The N- (phenylalkyl)cinnamides are selective antagonists of NR1(A)/2B receptors. Assayed under steady-state conditions, N-(4-phenylbutyl)-4-hydroxycinnamide (16) has an IC50 value of 77 nM and > 1000-fold selectivity with respect to NR1(A)/2A and NR1(A)/2C receptors. Potency at α1 adrenergic receptors is low for the four cinnamides tested. Inhibition of NR1(A)/2B receptors does not correlate with EGFR and ErbB2/neu tyrosine kinase inhibitor activity. The N-(phenylalkyl)cinnamide series we describe provides a novel and structurally diverse framework for designing new NR2B-selective NMDA antagonists as potential CNS therapeutics.
- Tamiz, Amir P.,Cai, Sui Xiong,Zhou, Zhang-Lin,Yuen, Po-Wai,Schelkun, Robert M.,Whittemore, Edward R.,Weber, Eckard,Woodward, Richard M.,Keana, John F. W.
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p. 3412 - 3420
(2007/10/03)
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- Tyrphostins. 2. Heterocyclic and α-Substituted Benzylidenemalonitrile Tyrphostins as Potent Inhibitors of EGF Receptor and ErbB2/neu Tyrosine Kinases
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We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins.The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalonitrile moiety.In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides.Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2).These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.
- Gazit, Aviv,Osherov, Nir,Posner, Israel,Yaish, Pnina,Poradosu, Enrique,et al.
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p. 1896 - 1907
(2007/10/02)
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- Rapid, Low-Temperature Amidation of Ethyl Cyanoacetate with Lithium Amides Derived from Primary and Secondary Amines
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A facile, rapid method for amidating ethyl cyanoacetate with lithium amides derived from various primary and secondary amines, including sterically demanding amines is described.
- Bhawal, Baburao M.,Khanapure, Subhash P.,Biehl, Edward R.
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p. 3235 - 3243
(2007/10/02)
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- Derivatives of 3-carboxy pyrid-2-ones
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Novel compounds belonging to the class of 1-substituted benzylpyrid-2-one-4,6-dialkyl and 4,5,6-trisubstituted-3-carboxylic acids, amides, esters and physiologically acceptable salts. These compounds possess biological activity and in particular are gametocides and plant growth regulators. Novel 1-substituted benzyl-3-cyano-4,5,6-trisubstituted pyrid-2-ones are also disclosed as intermediates.
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