- Antitumor agents. Part 3: Synthesis and cytotoxicity of new trans-stilbene benzenesulfonamide derivatives
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A new series of trans-stilbene benzenesulfonamide derivatives were designed and synthesized as potential antitumor agents. These new compounds were evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. Compounds 9-13 were cytotoxic against several cell lines. Notably, two compounds, 9 and 12, demonstrated selective cytotoxic activity against BT-549 breast cancer (GI50=0.205 μM) and HT-29 colon cancer (GI50=0.554 μM), respectively.
- Yang, Li-Ming,Lin, Shwu-Jiuan,Hsu, Fen-Lin,Yang, Tsang-Hsiung
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- New non-volatile and odorless organosulfur compounds anchored on ionic liquids. Recyclable reagents for Swern oxidation
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A new class of odorless and non-volatile organosulfur compounds grafted to imidazolium ionic liquid scaffold has been synthesized. The sulfoxides can be used effectively for the oxidation of primary allylic and benzylic alcohols into aldehydes and secondary alcohols to ketones under Swern oxidation conditions and the corresponding sulfides can be recovered and recycled.
- He, Xun,Chan, Tak Hang
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- Synthesis and anticancer activity of benzyloxybenzaldehyde derivatives against HL-60 cells
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A series of benzyloxybenzaldehyde derivatives were prepared and tested against the HL-60 cell line for anticancer activity. Preliminary structure-activity relationships were established. It was discovered that 2-(benzyloxy)benzaldehyde (17), 2-(benzyloxy)-4-methoxybenzaldehyde (26), 2-(benzyloxy)-5-methoxybenzaldehyde (27), 2-(benzyloxy)-5-chlorobenzaldehyde (28), 2-[(3-methoxybenzyl)oxy]benzaldehyde (29), 2-[(2-chlorobenzyl)oxy] benzaldehyde (30), and 2-[(4-chlorobenzyl)oxy]benzaldehyde (31) exhibited significant activity at 1-10 μM. Among them, compound 29 was the most potent one. The morphological assessment and DNA fragmentation analysis indicated that these compounds arrested cell cycle progression at G2/M phase and induced cell apoptosis. They resulted in the loss of mitochondrial membrane potential after 12 h of treatment.
- Lin, Chin-Fen,Yang, Jai-Sing,Chang, Chiung-Yun,Kuo, Sheng-Chu,Lee, Miau-Rong,Huang, Li-Jiau
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- Design and discovery of silybin analogues as antiproliferative compounds using a ring disjunctive – Based, natural product lead optimization approach
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The present study reports the synthesis and anticancer activity evaluation of twelve novel silybin analogues designed using a ring disjunctive-based natural product lead (RDNPL) optimization approach. All twelve compounds were tested against a panel of cancer cells (i.e. breast, prostate, pancreatic, and ovarian) and compared with normal cells. While all of the compounds had significantly greater efficacy than silybin, derivative 15k was found to be highly potent (IC50??1?μM) and selective against ovarian cancer cell lines, as well as other cancer cell lines, compared to normal cells. Preliminary mechanistic studies indicated that the antiproliferative efficacy of 15k was mediated by its induction of apoptosis, loss of mitochondrial membrane potential and cell cycle arrest at the sub-G1 phase. Furthermore, 15k inhibited cellular microtubules dynamic and assembly by binding to tubulin and inhibiting its expression and function. Overall, the results of the study establish 15k as a novel tubulin inhibitor with significant activity against ovarian cancer cells.
- Manivannan, Elangovan,Amawi, Haneen,Hussein, Noor,Karthikeyan, Chandrabose,Fetcenko, Aubry,Narayana Moorthy, N.S. Hari,Trivedi, Piyush,Tiwari, Amit K.
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- Benzyloxybenzaldehyde analogues as novel adenylyl cyclase activators
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Several benzyloxybenzaldehyde analogues were prepared and found to have significant inhibitory activity toward neutrophil superoxide formation. Consequently, these compounds were evaluated for cAMP-elevating capability. Among them, benzyloxybenzaldehyde (7), exhibiting activity equivalent to forskolin, was determined as an adenylyl cyclase activator since it elevates cAMP levels by activation of adenylyl cyclase but not by inhibition of phosphodiesterase. Having a chemical structure very different from known adenylyl cyclase activators, compound 7 is recommended by us for use as a new lead compound in the future development of adenylyl cyclase activators.
- Chang, Chiung-Yun,Kuo, Sheng-Chu,Lin, Yi-Lee,Wang, Jih-Pyang,Huang, Li-Jiau
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- Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors
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Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 μM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors. AbbreviationsBBB blood-brain barrierCDC25B cell division cycle 25 homolog BCYP2D6 Cytochrome P450 2D6 bindingDCCM dynamic cross-correlation mapDS Discovery StudioH bond hydrogen bondHIA human intestinal absorptionLAR leukocyte antigen-related phosphataseMD molecular dynamicsMEG-2 maternal-effect germ-cell defective 2MM-PBSA molecular mechanics Poisson Boltzmann surface area)PCA principal component analysisPDB Protein Data BankpNPP p–nitrophenyl phosphatePPB plasma protein bindingPTP1B protein tyrosine phosphotase 1BRMSD root mean square deviationRMSF root mean square fluctuationSHP-1 src homologous phosphatase-1SHP-2 src homologous phosphatase-2SPC single-point chargeTCPTP T cell protein tyrosine phosphataseT2DM Type 2 diabetes mellitusVDW van der Waals Communicated by Ramaswamy H. Sarma.
- Liu, Wen-Shan,Wang, Rui-Rui,Yue, Hai,Zheng, Zhi-Hui,Lu, Xin-Hua,Wang, Shu-Qing,Dong, Wei-Li,Wang, Run-Ling
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- Synthesis and Structure–Activity Relationships of Novel Benzylamine-Type Antifungals as Butenafine-Related Antimycotics
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Benzylamine-type antimycotics like naftifine, butenafine, or terbinafine are a well-known class of antimycotics since the 1980s. The following paper describes the synthesis and biological evaluation of a series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various substituents at the benzylamine moiety. The compounds were prepared from benzaldehyde derivatives and 2-amino-6-methylheptane by reductive amination with sodium triacetoxyborohydride and subsequent precipitation with hydrogen chloride. The antimycotic activity of the resulting compounds was evaluated in an agar diffusion assay against the yeasts C. glabrata and Yarrowia lipolytica, the mold Aspergillus niger and the dermatophyte H. burtonii. The compounds were also tested in a microdilution assay against the yeast Candida glabrata and the dermatophyte H. burtonii to determine the minimal inhibitory concentrations (MIC). Compounds with an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity against C. glabrata, comparable to terbinafine or clotrimazole.
- Krauss, Jürgen,Stadler, Martina,Bracher, Franz
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- V2O5@TiO2 Catalyzed Green and Selective Oxidation of Alcohols, Alkylbenzenes and Styrenes to Carbonyls
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The versatile application of different functional groups such as alcohols (1° and 2°), alkyl arenes, and (aryl)olefins to construct carbon-oxygen bond via oxidation is an area of intense research. Here, we report a reusable heterogeneous V2O5@TiO2 catalyzed selective oxidation of various functionalities utilizing different mild and eco-compatible oxidants under greener reaction conditions. The method was successfully applied for the alcohol oxidation, oxidative scission of styrenes, and benzylic C?H oxidation to their corresponding aldehydes and ketones. The utilization of mild and eco-friendly oxidizing reagents such as K2S2O8, H2O2 (30 % aq.), TBHP (70 % aq.), broad substrate scope, gram-scale synthesis, and catalyst recyclability are notable features of the developed protocol.
- Upadhyay, Rahul,Kumar, Shashi,Maurya, Sushil K.
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p. 3594 - 3600
(2021/07/02)
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- Cerium-photocatalyzed aerobic oxidation of benzylic alcohols to aldehydes and ketones
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We have developed a cerium-photocatalyzed aerobic oxidation of primary and secondary benzylic alcohols to aldehydes and ketones using inexpensive CeCl3 7H2O as photocatalyst and air oxygen as the terminal oxidant.
- K?nig, Burkhard,Kumar, Sumit,Stahl, Jessica,Yatham, Veera Reddy,Yedase, Girish Suresh
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supporting information
p. 1727 - 1732
(2021/08/05)
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- Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapy
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In anti-tumour therapy, the toll-like receptor 2/4 (TLR2/4) signalling pathway has been a double-edged sword. TLR2/4 agonists are commonly considered adjuvants for immune stimulation, whereas TLR2/4 antagonists demonstrate more feasibility for anti-tumour therapy under specific chronic inflammatory situations. In individuals with cancer retaliatory proliferation and metastasis after surgery, blocking the TLR2/4 signalling pathway may produce favourable prognosis for patients. Therefore, here, we developed a small-molecule co-inhibitor that targets the TLR2/4 signalling pathway. After high-throughput screening of a compound library containing 14 400 small molecules, followed by hit-to-lead structural optimisation, we finally obtained the compound TX-33, which has effective inhibitory properties against the TLR2/4 signalling pathways. This compound was found to significantly inhibit multiple pro-inflammatory cytokines released by RAW264.7 cells. This was followed by TX-33 demonstrating promising efficacy in subsequent anti-tumour experiments. The current results provide a novel understanding of the role of TLR2/4 in cancer and a novel strategy for anti-tumour therapy.
- Chen, Hekai,Kong, Jun,Li, Tian,Xu, Qun,Yin, Hang,Zhang, Liwei
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supporting information
p. 1771 - 1779
(2021/11/19)
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- Chromium-Salen Complex/Nitroxyl Radical Cooperative Catalysis: A Combination for Aerobic Intramolecular Dearomative Coupling of Phenols
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We describe an aerobic intramolecular dearomative coupling reaction of tethered phenols using a catalytic system consisting of a chromium-salen (Cr-salen) complex combined with a nitroxyl radical. This novel catalytic system enables formation of various spirocyclic dienone products including those unable to be accessed by previously reported methods efficiently under mild reaction conditions.
- Nagasawa, Shota,Fujiki, Shogo,Sasano, Yusuke,Iwabuchi, Yoshiharu
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p. 6952 - 6968
(2021/05/29)
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- Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer's disease
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Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 μM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (Ki = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.
- Toublet, Fran?ois-Xavier,Lalut, Julien,Hatat, Bérénice,Lecoutey, Cédric,Davis, Audrey,Since, Marc,Corvaisier, Sophie,Freret, Thomas,Sopková-de Oliveira Santos, Jana,Claeysen, Sylvie,Boulouard, Michel,Dallemagne, Patrick,Rochais, Christophe
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- NOVEL AUTOPHAGY-TARGETING CHIMERA (AUTOTAC) COMPOUND, AND COMPOSITION FOR PREVENTING, ALLEVIATING, OR TREATING DISEASES THROUGH TARGET PROTEIN DEGRADATION COMPRISING SAME
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The present invention relates to a novel AUTOTAC chimeric compound in which a new p62 ligand and a target-binding ligand are connected by a linker, a stereoisomer, hydrate, solvate or prodrug thereof, and a pharmaceutical or food composition for the prevention or treatment of diseases by degrading the target protein including the same as an active ingredient. They can target specific proteins to adjust their concentrations, and can also deliver drugs and other small molecule compounds to lysosomes. The AUTOTAC chimeric compound according to the present invention can be usefully used as a pharmaceutical composition for the prevention, amelioration or treatment of various diseases by selectively eliminating specific proteins.
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Paragraph 0112-0113
(2021/06/03)
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- Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance
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ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.
- Kaczor, Aneta,Szemerédi, Nikoletta,Kucwaj-Brysz, Katarzyna,D?browska, Monika,Starek, Ma?gorzata,Latacz, Gniewomir,Spengler, Gabriella,Handzlik, Jadwiga
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p. 2386 - 2401
(2021/06/14)
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- Dibenzazepine-linked isoxazoles: New and potent class of α-glucosidase inhibitors
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α-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33–54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 μM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 μM). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48–50, and 54 showed binding interactions with critical amino acid residues of α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.
- Umm-E-Farwa,Ullah, Saeed,Khan, Maria Aqeel,Zafar, Humaira,Atia-tul-Wahab,Younus, Munisaa,Choudhary, M. Iqbal,Basha, Fatima Z.
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supporting information
(2021/05/10)
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- An alternative route for boron phenoxide preparation from arylboronic acid and its application for C[sbnd]O bond formation
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An efficient synthetic route to benzyl phenyl ether preparation has been successfully developed via a one-pot synthetic protocol utilizing a combination of arylboronic acids, hydrogen peroxide (H2O2), and benzyl halides. The whole procedure consists of two consecutive reactions, formation of boron phenoxide from arylboronic acids and its nucleophilic attack. A simple operation under mild conditions such as room-temperature ionic liquid (choline hydroxide), aerobic environment, and absence of metal- and base-catalysts has been employed. Expansion to utilize benzyl surrogates was also successfully accomplished.
- Joo, Seong-Ryu,Kim, Seung-Hoi,Lim, In-Kyun
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- Vanadium-Catalyzed Oxidative Intramolecular Coupling of Tethered Phenols: Formation of Phenol-Dienone Products
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A mild and efficient method for the vanadium-catalyzed intramolecular coupling of tethered free phenols is described. The corresponding phenol-dienone products are prepared directly in good yields with low catalyst loadings. Electronically diverse tethered phenol precursors are well tolerated, and the catalytic method was effectively applied as the key step in syntheses of three natural products and a synthetically useful morphinan alkaloid precursor.
- Gilmartin, Philip H.,Kozlowski, Marisa C.
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supporting information
p. 2914 - 2919
(2020/04/10)
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- PHENANTHRENE AMPK ACTIVATOR COMPOUNDS, COMPOSITIONS, METHODS AND USES THEREOF
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The present invention relates to a compound having general formula I for use in the activation of AMPK. A composition comprising said compound for use in the activation of AMPK is also provided.
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Page/Page column 44
(2020/11/30)
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- Choline Hydroxide as a Versatile Medium for Catalyst-Free O-Functionalization of Phenols
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A versatile synthetic protocol for benzyl phenyl ether preparation via O-alkylation of phenolic oxygen with readily available benzyl derivatives was demonstrated. The newly designed procedure was carried out using an eco-friendly medium, room-temperature ionic liquid (choline hydroxide), under metal- and base-catalyst-free aerobic conditions. The reaction platform was also successfully applied to phenol protection strategy.
- Joo, Seong-Ryu,Kim, Seung-Hoi,Kwon, Gyu-Tae,Park, Soo-Youl
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p. 1200 - 1205
(2020/11/30)
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- Design, synthesis and biological evaluation of dimethyl cardamonin (DMC) derivatives as P-glycoprotein-mediated multidrug resistance reversal agents
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Background: P-glycoprotein (P-gp) has been regarded as an important factor in the multidrug resistance (MDR) of tumor cells within the last decade, which can be solved by inhibiting P-gp to reverse MDR. Thus, it is an effective strategy to develop inhibitor of P-gp. Objective: In this study, the synthesis of a series of derivatives had been carried out by bioisosterism design on the basis of Dimethyl Cardamonin (DMC). Subsequently, we evaluated their reversal activities as potential P-glycoprotein (P-gp)-mediated Multidrug Resistance (MDR) agents. Methods: Dimethyl cardamonin derivatives were synthesized from acetophenones and the corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. Their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 was evaluated by Doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply. Results and Discussion: The results showed that compounds B2, B4 and B6 had the potency of MDR reversers with little intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7 and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expressionof P-gp at protein levels. Conclusion: The above findings may provide new insights for the research and development of P-gp-mediated MDR reversal agents.
- Liu, Jianwen,Ma, Lei,Shi, Ximeng,Yin, Huanhuan,Zhao, Yuyu,Zhou, Licheng
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p. 1270 - 1282
(2020/10/06)
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- Targeting receptor tyrosine kinase VEGFR-2 in hepatocellular cancer: Rational design, synthesis and biological evaluation of 1,2-disubstituted benzimidazoles
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In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is twofold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.
- Abdel-Mohsen, Heba T.,Abdullaziz, Mona A.,Ali, Mamdouh M.,El Diwani, Hoda I.,El Kerdawy, Ahmed M.,Flanagan, Keith J.,Mahmoud, Abeer E. E.,Ragab, Fatma A. F.,Senge, Mathias O.
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- Ancillary ligands switch the activity of Ru–NHC-based oxidation precatalysts
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Herein we demonstrate how the inner-sphere coordinating ligands switch the activity of Ru–NHC-based oxidation precatalysts in the oxidative conversion of olefins to carbonyl compounds, with the help of a series of systematically varied imidazolydene-NHC (Im-NHC) and triazolydene-NHC (Tz-NHC)-based ruthenium(II)-complexes. It is shown that the catalytic activity of the para-cymene-containing precatalysts varies in the order of [(Tz-NHC)Ru(para-cymene)Cl]+ > [(Im-NHC)Ru(para-cymene)Cl]+, while the order of activity of the MeCN-containing precatalysts is found to be reversed, i.e., [(Im-NHC)Ru(MeCN)4]2+ > [(Tz-NHC)Ru(MeCN)4]2+. Along with the electronic influence of the NHC ligands, the effect of the lability of the para-cymene and MeCN ligands, and the overall charge of the complexes might be attributed toward such a switching of catalytic activity. This finding led to develop a new precatalyst with improved activity which was further utilized in selective oxidation of a series of styrene substrates containing other oxidation-sensitive functionalities.
- Gupta, Suraj K.,Mandal, Tanmoy,Gangber, Tejaswinee,Singh, Vivek,Choudhury, Joyanta
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supporting information
(2019/10/28)
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- A molybdenum based metallomicellar catalyst for controlled and chemoselective oxidation of activated alcohols in aqueous medium
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A surfactant based oxodiperoxo molybdenum complex, which could activate molecular oxygen, has been employed as a catalyst for controlled oxidation of benzylic alcohols to corresponding carbonyls. The oxidation reactions were carried out under aqueous environment, however, in the absence of any extraneous base or co-catalyst. Sensitive/oxidizable functional groups like cyano, sulfide, hydroxyl, aryl-hydroxyl, alkene (internal/terminal), alkyne (internal/terminal), and acetal were tolerated during the transformations. Such selectivity is attributed to the mild nature of the catalyst. The methodology could also be scaled-up for multi-gram synthesis and the protocol is likely to find practical use since it requires an inexpensive recyclable-catalyst and easily available oxidant (under green conditions). A plausible mechanism is proposed with the help of preliminary computational study.
- Thiruvengetam, Prabaharan,Chakravarthy, Rajan Deepan,Chand, Dillip Kumar
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p. 123 - 133
(2019/07/19)
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- DIRECT AMPK ACTIVATOR COMPOUNDS
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The present invention relates to a compound having general formula I for use in the activation of AMPK. A composition comprising said compound for use in the activation of AMPK is also provided. Said compounds are 9,10 dihydrophenanthrenes, in particular selected from the group consisting of: (i) Lusianthridin i.e. 7- Methoxy-9,10-dihydrophenanthrene-2,5-diol, (ii) 7-Methoxy-9,10- dihydrophenanthrene-2,3,5-triol, (iii) 9,10-dihydrophenanthrene-2,5- diol, (iv) 9,10-Dihydrophenanthrene-2,4,7-triol (v) 9,10-Dihydro-7- methoxy-3,5-phenanthrenediol, and the activation of AMPK improves the condition, disorder, or disease related to cardiometabolic health, obesity, type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease, and cancer.
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Page/Page column 44; 45
(2019/12/25)
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- Synthesis and biological evaluation of tryptophan-derived rhodanine derivatives as PTP1B inhibitors and anti-bacterial agents
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Several series of novel tryptophan-derived rhodanine derivatives were synthesized and identified as potential competitive PTP1B inhibitors and antibacterial agents. Among the compounds studied, 10b was found to have the best in vitro inhibition activity against PTP1B (IC50 = 0.36 ± 0.02 μM). In addition, the compounds also showed potent inhibition against other PTPs, especially CDC25B. Molecular docking analysis demonstrated that compounds 7c and 10b could occupy both the catalytic site and the adjacent pTyr binding site simultaneously. The compounds also showed higher levels of activity against gram-positive strains, the gram-negative strain Escherichia coli 1924, and multidrug-resistant gram-positive bacterial strains. Compounds 7c, 8c, 9e, 10a, and 10c had comparable or more potent antibacterial activity than the positive controls.
- Liu, Hongyan,Sun, Danwen,Du, Hang,Zheng, Changji,Li, Jingya,Piao, Huri,Li, Jia,Sun, Liangpeng
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p. 163 - 173
(2019/04/13)
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- Coordination Booster-Catalyst Assembly: Remote Osmium Outperforming Ruthenium in Boosting Catalytic Activity
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Presented herein is a set of bimetallic and trimetallic “coordination booster-catalyst” assemblies in which the coordination complexes [RuII(terpy)2] and [OsII(terpy)2] acted as boosters for enhancement of the catalytic activity of [RuII(NHC)(para-cymene)]-based catalytic site. The boosters accelerated the oxidative loss of para-cymene from the catalytic site to generate the active catalyst during the oxidation of alkenes and alkynes into corresponding aldehydes, ketones and diketones. It was found that the boosting efficiency of the [OsII(terpy)2] units was considerably higher than its congener [RuII(terpy)2] unit in these assemblies. Mechanistic studies were conducted to understand this unique improvement.
- Mandal, Tanmoy,Singh, Vivek,Choudhury, Joyanta
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supporting information
p. 4774 - 4779
(2019/11/11)
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- Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry
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The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
- Cao, Jiangying,Ma, Chunhua,Zang, Jie,Gao, Shuai,Gao, Qianwen,Kong, Xiujie,Yan, Yugang,Liang, Xuewu,Ding, Qin'ge,Zhao, Chunlong,Wang, Binghe,Xu, Wenfang,Zhang, Yingjie
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p. 3145 - 3157
(2018/06/01)
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- Design, Synthesis, and Application of Chiral C2-Symmetric Spiroketal-Containing Ligands in Transition-Metal Catalysis
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We present an expedient and economical route to a new spiroketal-based C2-symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium-catalyzed hydroarylations (up to 95 % ee), palladium-catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium-catalyzed Heck couplings (up to 94 % ee), and rhodium-catalyzed dehydroalanine hydrogenation (up to 93 % ee).
- Argüelles, Alonso J.,Sun, Siyuan,Budaitis, Brenna G.,Nagorny, Pavel
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supporting information
p. 5325 - 5329
(2018/03/27)
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- Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents
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3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3-triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents.
- Bi, Fangchao,Ji, Shengli,Venter, Henrietta,Liu, Jingru,Semple, Susan J.,Ma, Shutao
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supporting information
p. 884 - 891
(2018/02/15)
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- METHODS FOR MAKING CATECHIN DERIVATIVES
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Disclosed herein are methods for making a catechin derivative, or a salt thereof. The methods can include: contacting an alcohol protected aromatic aldehyde and a triphenyl phosphonium ylide to make an alcohol protected aromatic olefin; hydrogenating the alcohol protected aromatic olefin to make alcohol protected aromatic compound; and deprotecting the alcohol protected aromatic compound to make the catechin derivative.
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Page/Page column 0043
(2017/07/05)
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- SULFAMATE DERIVATIVE COMPOUNDS, PROCESSES FOR PREPARING THEM AND THEIR USES
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The present invention relates to a pharmaceutical composition for treating or preventing CNS disorders containing a sulfamate derivative compound and/or pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a method for treatment or prevention CNS disorders comprising administering a sulfamate derivative compound in a pharmaceutically effective amount to a subject in need of treatment or prevention of CNS disorders.
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Page/Page column 21
(2017/09/15)
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- Synthesis and evaluation of small molecules bearing a benzyloxy substituent as novel and potent monoamine oxidase inhibitors
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A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds 9e (IC50 = 0.35 μM) and 10e (IC50 = 0.19 μM) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (9e, SI > 285.7-fold and 10e, SI = 146.8-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that electron-withdrawing groups in the open small molecules were more suitable for MAO-B inhibition, and substitutions at the benzyloxy of the open small molecules, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been done to explain the potent MAO-B inhibition of the open small molecules. Furthermore, the representative compounds 9e and 10e showed low neurotoxicity in SH-SY5Y cells in vitro. So the small molecules bearing the benzyloxy substituent could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.
- Lan, Jin-Shuai,Zhang, Tong,Liu, Yun,Zhang, Yong,Hou, Jian-wei,Xie, Sai-Sai,Yang, Jing,Ding, Yue,Cai, Zhen-zhen
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p. 471 - 478
(2017/03/08)
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- Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS1 by Docking-Aided Structure-Activity Analysis
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The ligands of certain G-protein-coupled receptors (GPCRs) have been identified as endogenous lipids, such as lysophosphatidylserine (LysoPS). Here, we analyzed the molecular basis of the structure-activity relationship of ligands of GPR34, one of the LysoPS receptor subtypes, focusing on recognition of the long-chain fatty acid moiety by the hydrophobic pocket. By introducing benzene ring(s) into the fatty acid moiety of 2-deoxy-LysoPS, we explored the binding site's preference for the hydrophobic shape. A tribenzene-containing fatty acid surrogate with modifications of the terminal aromatic moiety showed potent agonistic activity toward GPR34. Computational docking of these derivatives with a homology modeling/molecular dynamics-based virtual binding site of GPR34 indicated that a kink in the benzene-based lipid surrogates matches the L-shaped hydrophobic pocket of GPR34. A tetrabenzene-based lipid analogue bearing a bulky tert-butyl group at the 4-position of the terminal benzene ring exhibited potent GPR34 agonistic activity, validating the present hydrophobic binding pocket model.
- Sayama, Misa,Inoue, Asuka,Nakamura, Sho,Jung, Sejin,Ikubo, Masaya,Otani, Yuko,Uwamizu, Akiharu,Kishi, Takayuki,Makide, Kumiko,Aoki, Junken,Hirokawa, Takatsugu,Ohwada, Tomohiko
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supporting information
p. 6384 - 6399
(2017/08/02)
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- Benzyloxynitrostyrene analogues – A novel class of selective and highly potent inhibitors of monoamine oxidase B
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This study examines a series of novel 3-benzyloxy-β-nitrostyrene analogues as a novel class of inhibitors of the monoamine oxidase (MAO) enzymes. MAO inhibitors are considered useful for the treatment of depression and Parkinson's disease, and have recently attracted attention as potential therapeutic agents for a range of disorders including Alzheimer's disease, prostate cancer and certain cardiomyopathies. This study shows that the 3-benzyloxy-β-nitrostyrene analogues are potent inhibitors of the MAO-B isoform with IC50values in the nanomolar range (39–565 nM). Significantly, effectiveness towards MAO-B inhibition seems to be governed by the introduction of a 4″-fluoro-substituent on the benzyloxy ring, with compound 2b exhibiting the highest degree of MAO-B inhibition potency (IC50= 0.039 μM) and selectivity (SI = 166) among the compounds investigated. Since some of the 3-benzyloxy-β-nitrostyrene analogues possess potencies that are comparable to that of the reversible inhibitor, safinamide (IC50= 0.080 μM), it may be concluded that this class may be promising leads for the development of reversible and selective MAO-B inhibitors, that may be useful for the management of Parkinson's disease.
- Van der Walt, Mietha M.,Terre'Blanche, Gisella,Petzer, Jacobus P.,Petzer, Anél
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p. 1193 - 1199
(2016/11/23)
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- Phenolic compounds containing benzyloxy phenyl and preparation method and application of phenolic compounds
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The invention discloses phenolic compounds (I) containing benzyloxy phenyl and a preparation method and application of the phenolic compounds. Pharmacological experiments prove that the phenolic compounds have high inhibiting activity on sphingosine kinase SphK, and part of the compounds has a certain inhibiting effect on inflammatory bowel disease induced by tumor and DSS. The phenolic compounds and the pharmaceutical preparations thereof can be used for preparing drugs for treating a series of cancer and inflammatory diseases such as colon cancer, lung cancer, breast cancer, liver cancer, stomach cancer, inflammatory bowel disease, hepatitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis.
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Paragraph 0246; 0247; 0248; 0249; 0250
(2017/09/19)
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- New compounds having skin whitening, antioxidant and PPAR activity, and medical use thereof
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PURPOSE: A novel compound with skin whitening, antioxidation, and PPAR activation effects, and a medical use thereof are provided to be used for a pharmaceutical composition or a cosmetic product. CONSTITUTION: A compound is denoted by chemical formula 1. A skin whitening composition contains the compound as an active ingredient. An antioxidative composition for preventing or treating oxidative diseases contains the compound of chemical formula 1 as an active ingredient. The oxidative diseases are selected among skin aging, pigmentation, wrinkling, psoriasis, or eczema. The composition prevents or treats diseases which are regulated by PPAR(peroxisome proliferator-activated receptor) activity. The PPAR includes PPAR alpha or PPAR gamma.
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Paragraph 0443-0444
(2017/04/14)
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- Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice
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Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N′-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure-activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human.
- Xi, Meiyang,Ge, Jun,Wang, Xiaojian,Sun, Chenbin,Liu, Tianqi,Fang, Liang,Xiao, Qiong,Yin, Dali
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p. 3218 - 3230
(2016/07/06)
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- Thiazoline ketone derivative and its pharmaceutical composition and application
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The invention discloses 5-substituted methylene-4-thiazolinone compounds disclosed as chemical general formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are defined in the specification. The invention also discloses a pharmaceutical composition comprising compounds I or pharmaceutically acceptable salts thereof as an active component and one or more pharmaceutically acceptable carriers, excipients or diluters. The compounds disclosed in the specification have favorable activity on inhibiting protein tyrosine phosphatase 1B(PTP-1B) and protein tyrosine phosphatase (SHP-2), and especially can be applied to the aspects of drugs for treating diabetes and resisting cancers.
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Paragraph 0097; 0098; 0099; 0100; 0101; 0102
(2016/10/07)
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- Synthesis and Biological Evaluation of Nitrated 7-, 8-, 9-, and 10-Hydroxyindenoisoquinolines as Potential Dual Topoisomerase i (Top1)-Tyrosyl-DNA Phosphodiesterase i (TDP1) Inhibitors
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The structure-activity relationships and hit-to-lead optimization of dual Top1-TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual Top1-TDP1 inhibition. The 9-hydroxy series exhibited potencies and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the Top1-mediated DNA cleavage assay. One member of this series was a more potent Top1 inhibitor at a concentration of 5 nM and produced a more stable ternary drug-DNA-Top1 cleavage complex than CPT. (Chemical Equation Presented).
- Nguyen, Trung Xuan,Abdelmalak, Monica,Marchand, Christophe,Agama, Keli,Pommier, Yves,Cushman, Mark
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p. 3188 - 3208
(2015/04/27)
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- Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products
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Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.
- Tangdenpaisal, Kassrin,Worayuthakarn, Rattana,Karnkla, Supatra,Ploypradith, Poonsakdi,Intachote, Pakamas,Sengsai, Suchada,Saimanee, Busakorn,Ruchirawat, Somsak,Chittchang, Montakarn
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p. 925 - 937
(2015/03/31)
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- Simple, copper(I)-catalyzed oxidation of benzylic/allylic alcohols to carbonyl compounds: Synthesis of functionalized cinnamates in one pot
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An environmentally benign [Cu(I)]-catalyzed oxidation of activated (benzylic/allylic) alcohols to the corresponding carbonyl compounds is presented. Interestingly, the reaction was also compatible with benzylic alcohols containing ortho-bromo substituents on the aromatic ring without competing with the expected intermolecular Buchwald coupling. Significantly, the catalytic system enables the synthesis of cinnamate-esters in a sequential domino one-pot fashion via oxidation followed by Wittig-Horner protocol. Copyright
- Reddy, Alavala Gopi Krishna,Mahendar, Lodi,Satyanarayana, Gedu
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supporting information
p. 2076 - 2087
(2014/07/07)
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- NOVEL COMPOUND HAVING SKIN-WHITENING, ANTI-OXIDIZING AND PPAR ACTIVITIES AND MEDICAL USE THEREFOR
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Provided are a novel compound having skin-whitening, anti-oxidizing and PPAR activities and a medical use thereof, and the compound has skin-whitening activities for the suppression of tyrosinase, and accordingly, is useful for use in skin-whitening pharmaceutical composition or cosmetic products; has anti-oxidant activities, and accordingly, is useful for the prevention and treatment of skin-aging; and has PPAR activities, and in particular, PPARα and PPARγ activities, and accordingly, is useful for use in pharmaceutical compositions or health foods which are effective for the prevention and treatment of obesity, metabolic disease, or cardiovascular disease.
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Paragraph 0284; 0285
(2014/02/16)
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- NOVEL COMPOUND HAVING SKIN-WHITENING, ANTI-OXIDIZING AND PPAR ACTIVITIES AND MEDICAL USE THEREFOR
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Provided are a novel compound having skin-whitening, anti-oxidizing and PPAR activities and a medical use thereof, and the compound has skin-whitening activities for the suppression of tyrosinase, and accordingly, is useful for use in skin-whitening pharmaceutical composition or cosmetic products; has anti-oxidant activities, and accordingly, is useful for the prevention and treatment of skin-aging; and has PPAR activities, and in particular, PPARα and PPARγ activities, and accordingly, is useful for use in pharmaceutical compositions or health foods which are effective for the prevention and treatment of obesity, metabolic disease, or cardiovascular disease.
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Paragraph 0314-0315
(2014/02/16)
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- Design and synthesis of l- and d-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase
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Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 μM) and 2 (IC50 = 10.6 μM) as represented by hybrid compound 27 (IC 50 = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC50 = 19.3 μM) and 45 (IC50 = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition.
- Patel, Bhargav A.,Krishnan, Ramalingam,Khadtare, Nikhil,Gurukumar,Basu, Amartya,Arora, Payal,Bhatt, Aaditya,Patel, Maulik R.,Dana, Dibyendu,Kumar, Sanjai,Kaushik-Basu, Neerja,Talele, Tanaji T.
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p. 3262 - 3271
(2013/07/05)
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- Diaryl-1,2,4-oxadiazole antioxidants: Synthesis and properties of inhibiting the oxidation of DNA and scavenging radicals
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Six 1,2,4-oxadiazole derivatives were prepared in order to compare their abilities to protect DNA against radical-mediated oxidation and to scavenge radicals. These derivatives had a structure based on disubstituted 1,2,4-oxadiazole, in which a vanillin group (A ring) and a substituted benzene group (B ring) were the substituents. The functional group at B ring was assigned as ortho- or meta-hydroxylbenzene group, ortho-chlorobenzene group, no group contained, and pyridine group or vanillin group at B ring. It was found that the compound with two vanillin groups attaching to oxadiazole can trap 2.05 radicals in protecting DNA against 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation, and the compound with an ortho-hydroxylbenzene group at B ring can trap 1.78 radicals. The compound with an ortho-chlorobenzene group at B ring exhibited the highest ability to inhibit ·OH-induced oxidation of DNA, while the compound with a meta-hydroxylbenzene group at B ring inhibited Cu2+/glutathione (GSH)-induced oxidation of DNA efficiently. The ortho- and para-hydroxylbenzene groups at B ring made the compounds possess the highest rate constant (k) in scavenging 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+.) and 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH). Therefore, only a few hydroxyl groups can markedly enhance the activity of the core-branched antioxidant, which may be a novel structural feature in designing antioxidant.
- Zhao, Chao,Liu, Zai-Qun
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p. 842 - 849
(2013/04/24)
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- Antioxidant effectiveness generated by one or two phenolic hydroxyl groups in coumarin-substituted dihydropyrazoles
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A cascade operation was designed to synthesize nine coumarin-substituted dihydropyrazoles with only one or two phenolic hydroxyl groups contained. Antioxidant abilities of the obtained compounds were evaluated by inhibiting 2,2′-azobis(2-amidinopropanehydrochloride) (AAPH)-, Cu2+/ glutathione (GSH)-, and .OH-induced oxidation of DNA. It was found that less phenolic hydroxyl groups can enhance the abilities of coumarin-substituted dihydropyrazoles to protect DNA against the oxidation. Moreover, these coumarin-substituted dihydropyrazoles were employed to scavenge 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+.), 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, respectively. It was found that double phenolic hydroxyl groups were more beneficial for enhancing the abilities of coumarin-substituted dihydropyrazoles to quench the aforementioned radicals. Therefore, dihydropyrazole linked with coumarin exhibited powerful antioxidant effectiveness even in the case of less phenolic hydroxyl groups involved.
- Xi, Gao-Lei,Liu, Zai-Qun
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p. 385 - 393
(2013/10/01)
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- The first synthesis of [11C]J147, a new potential PET agent for imaging of Alzheimer's disease
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J147 was synthesized from 2,4-dimethylphenylhydrazine hydrochloride and 3-methoxybenzaldehyde in 2 steps with 71% overall yield. The precursor desmethyl-J147 was synthesized from 3-hydroxybenzaldehyde and 2,4-dimethylphenylhydrazine hydrochloride in 4 steps with 63% overall yield. [11C]J147 was prepared from desmethyl-J147 with [11C] CH3OTf through O-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 35-50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.
- Wang, Min,Gao, Mingzhang,Zheng, Qi-Huang
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p. 524 - 527
(2013/02/25)
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- Synthesis of new antimicrobial pyrrolo[2,1-a]isoquinolin-3-ones
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The attractive structure of the pyrroloisoquinoline moiety, together with its potential antimicrobial activity, encouraged us to prepare six 8-substituted and seven 8,9-disubstituted-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-3- ones in a few steps with good yields. We applied a convenient methodology via double intramolecular cyclization conducted by a Bischler-Napieralski cyclodehydration-imine reduction sequence, which is widely employed in the synthesis of isoquinoline alkaloids. Therefore, we synthesized three series of these pyrrolo[2,1-a]isoquinolin-3-ones characterized by the substituent at the 8-position or 8,9-positions of the aromatic ring: (a) different side chains are attached to an 8-OH group (series 1); (b) a chlorine atom is attached to the 8-position (series 2); and (c) 8- and 9-carbons are bearing an identical group (series 3). The compounds bearing a benzylic moiety at the 8-position, for example, 8-benzyloxy-pyrrolo[2,1-a]isoquinolin-3-one (1a) and 8-(4-fluorobenzyloxy)-pyrrolo[2,1-a]isoquinolin-3-one (1e), as well as, a 8-chloro-9-methoxy moiety including the 8-chloro-9-methoxy-pyrrolo[2,1-a] isoquinolin-3-one (2a), provided the most fungicide and bactericide agents, respectively.
- Moreno, Laura,Parraga, Javier,Galan, Abraham,Cortes, Diego,Cabedo, Nuria,Primo, Jaime
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p. 6589 - 6597,9
(2012/12/12)
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- IMIDAMIDE SPHINGOSINE KINASE INHIBITORS
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Imidamide (amidine) analogs that can inhibit the activity of sphingosine kinase 1 and sphingosine kinase 2 (SphK1 and SphK2) are provided. The compounds can prevent angiogenesis in tumors.
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Page/Page column 29
(2012/09/05)
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- Chemical synthesis and evaluation of 17α-alkylated derivatives of estradiol as inhibitors of steroid sulfatase
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Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure-activity relationship study of this family of 17α-derivatives of E2.
- Fournier, Diane,Poirier, Donald
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experimental part
p. 4227 - 4237
(2011/11/12)
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- Design, synthesis and SAR study of hydroxychalcone inhibitors of human β-secretase (BACE1)
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According to the structural characteristics of isoliquiritigenin from Glycyrrhiza uralensis, a series of hydroxychalcones has been designed, synthesized and evaluated for their in vitro inhibitory activities of β-secretase (BACE1). Structure-activity relationship study suggested that inhibitory activity against BACE1 was governed to a greater extent by the hydroxyl substituent on A-and B-ring of the chalcone, and the most active compound was substituted with four hydroxyl group (17, IC50=0.27 μM).
- Ma, Lei,Yang, Zhengyi,Li, Chenjing,Zhu, Zhiyuan,Shen, Xu,Hu, Lihong
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experimental part
p. 643 - 648
(2012/04/10)
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- Structural necessity of indole C5-O-substitution of seco-duocarmycin analogs for their cytotoxic activity
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A series of racemic indole C5-O-substituted seco-cyclopropylindole (seco-CI) compounds 1-5 were prepared by coupling in the presence of EDCI of 1-(tertbutyloxycarbonyl)- 3-(chloromethyl)indoline (seg-A) with 5-hydroxy-, 5-O-methylsulfonyl, 5-O-aminosulfonyl, 5-O-(N,N-dimethylaminosulfonyl)- and 5-O-benzyl-1H-indole-2- carboxylic acid as seg-B. Compounds 1-5 were tested for cytotoxic activity against four human cancer cell lines (COLO 205, SK-MEL-2, A549, and JEG-3) using a MTT assay. Compounds 2 and 3 with small sized sulfonyl substituents like 5-O-methylsulfonyl and 5- O-aminosulfonyl exhibit a similar level of activity as doxorubicin against all cell lines tested.
- Choi, Taeyoung,Ma, Eunsook
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experimental part
p. 7971 - 7984
(2011/03/22)
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- Total synthesis of (+)-korupensamine B via an atropselective intermolecular biaryl coupling
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The asymmetric total synthesis of nonracemic korupensamine B is reported. It includes a newly designed and highly trans-diastereoselective (>20:1 dr) route to the tetrahydroisoquinoline ring and an unprecedented atropdiastereoselective Suzuki-Miyaura coupling for construction of the fully fashioned naphthylisoquinoline framework that invokes π stacking as a possible source of stereocontrol.
- Huang, Shenlin,Petersen, Tue B.,Lipshutz, Bruce H.
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supporting information; experimental part
p. 14021 - 14023
(2011/01/04)
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- S1P RECEPTORS MODULATORS
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The invention relates to novel compounds that have S1P receptor modulating activity and, preferably, apoptotic activity and/or anti proliferative activity against cancer cells and other cell types. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, cancer. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as cancer.
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Page/Page column 98
(2010/04/30)
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