- Polystyrene-Based Deblocking-Scavenging Agents for the 9-Fluorenylmethyloxycarbonyl Amino-Protecting Group
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Piperazino- and piperidino-functionalized polystyrenes have been examined as deblocking-scavenging agents for the 9-fluorenylmethyloxycarbonyl (Fmoc) amino-protecting group.Both commercial and synthesized polystyrenes have been used as supports.In order to introduce the active functional groups, (chloromethyl)polystyrene 2 was treated with tert-butyl piperazine-1-carboxylate followed by acidic deblocking (HCl/dioxane) or, alternatively, was directly aminated by means of 10 molar excess of piperazine or 1,3-bis(4-piperidino)propane.Compounds 7-9 were examined as cross-linking agents in the preparation of appropriate reagents.Most suitable were reagents prepared from commercial macroreticular resins (XE-305) or those cross-linked via DVT (8).Proof that the DBF liberated in the deblocking prozess was scavenged (partially) by the active secondary amine reagents 4 came from (a) a study of the successful regeneration of an active agent from 5 by treatment with alkali (H2O-dioxane) and (b) liberation of 9-methylfluorene from 5 by hydrogenation (NH4OCHO/Pd-C).
- Carpino, Louis A.,Mansour, E. M. E.,Cheng, C. H.,Williams, James R.,MacDonald, Russell,et al.
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- Small-Molecule Inhibition of the UNC-Src Interaction Impairs Dynamic Src Localization in Cells
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Interference with the signaling activity of the N-myristoylated nonreceptor protein tyrosine kinase Src is considered a viable approach in anti-cancer drug discovery. However, ATP-competitive Src inhibitors have not reached the clinic yet and alternative approaches are in high demand. The UNC119A/B proteins bind the myristoylated N terminus of Src and thereby mediate energy-driven spatial cycles that maintain Src enrichment at the plasma membrane, which is critical for Src signaling activity. We describe the discovery of a potent and specific inhibitor of the UNC119-Src interaction with unprecedented chemotype. The inhibitor binds to UNC119 in cells, and induces redistribution of Src to endomembranes and reduction of activating Src autophosphorylation on Y419. UNC119 inhibition in Src-dependent colorectal cancer cells results in the specific reduction of cell growth and clonogenic potential. Our results demonstrate that small-molecule interference with the dynamics of the Src spatial cycle may provide an opportunity to impair oncogenic Src signaling. Garivet et al. discovered a small-molecule UNC119-Src interaction inhibitor, which interferes with Src enrichment at the plasma membrane and reduces clonogenic potential and growth of Src-dependent cells. Small molecule interference with the dynamics of cellular Src localization may provide an alternative approach to target oncogenic Src.
- Garivet, Guillaume,Hofer, Walter,Konitsiotis, Antonios,Klein, Christian,Kaiser, Nadine,Mejuch, Tom,Fansa, Eyad,Alsaabi, Rania,Wittinghofer, Alfred,Bastiaens, Philippe I.H.,Waldmann, Herbert
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- Carbamates as potential prodrugs and a new warhead for HDAC inhibition
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We designed and synthesized carbamates of the clinically-approved HDAC (histone deacetylase) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in order to validate our previously-proposed hypothesis that these carbamates might serve as prodrugs for hydroxamic acid containing HDAC inhibitors. Biochemical assays proved our new compounds to be potent inhibitors of histone deacetylases in vitro, and they also showed antiproliferative effects in leukemic cells. These results, as well as stability analysis led to the suggestion that the intact carbamates are inhibitors of histone deacetylases themselves, representing a new zinc-binding warhead in HDAC inhibitor design. This suggestion was further supported by the synthesis and evaluation of a carbamate derivative of the HDAC6-selective inhibitor bufexamac.
- King, Kristina,Hauser, Alexander-Thomas,Melesina, Jelena,Sippl, Wolfgang,Jung, Manfred
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- Conjugating a groove-binding motif to an Ir(iii) complex for the enhancement of G-quadruplex probe behavior
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In this study, the reported G-quadruplex groove binder benzo[d,e]isoquinoline was linked to a cyclometallated Ir(iii) complex to generate a highly selective DNA probe 1 that retains the favorable photophysical properties of the parent complex. The linked complex 1 showed advantages of both parent complex 2 and groove binder 3. Similar to 3, the conjugated complex 1 exhibits a superior affinity and selectivity for G-quadruplex DNA over other conformations of DNA or proteins, with the fold enhancement ratio obviously improved compared with parent complex 2. The molecular modelling revealed a groove-binding mode between complex 1 and G-quadruplex. Meanwhile 1 also possesses the prominent advantages of transition metal complex probes such as a large Stokes shift and long lifetime phosphorescence, which could be recognized in strong fluorescence media through time-resolved emission spectroscopy (TRES). We then employed 1 to develop a detection assay for AGR2, a potential cancer biomarker, as a "proof-of-principle" demonstration of the application of a linked complex for DNA-based detection in diluted fetal bovine serum. We anticipate that this conjugation method may be further employed in the development of DNA probes and have applications in label-free DNA-based diagnostic platforms.
- Wang, Modi,Mao, Zhifeng,Kang, Tian-Shu,Wong, Chun-Yuen,Mergny, Jean-Louis,Leung, Chung-Hang,Ma, Dik-Lung
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- Synthesis of new soluble dendrimers on poly(ethylene glycole) sublayer
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A rational method of synthesis was developed for new soluble dendrimers on poly(ethylene glycole) sublayer with a high density of functional groups applying 2,4,6-trichloro-1,3,5-triazine as a dendron and piperazine as linker and functional group carrier. The density of functional groups in the synthesized soluble dendrimers calculated from the elemental analysis for chlorine was 2.19 mmol of NH groups per 1 g of polymer. These new water-soluble dendrimers can be used not only as convenient soluble polymer sublayers but also for efficient trapping in purification of reaction products from impurities.
- Lu,Xie,Chen,Yang
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Read Online
- Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis
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8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay.
- Av-Gay, Yossef,Imming, Peter,Narula, Gagandeep,Richter, Adrian,Rudolph, Ines,Wagner, Christoph,Seidel, Rüdiger W.
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supporting information
(2021/12/27)
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- Synthesis, biological evaluation and molecular docking studies of novel 1,2,3-triazole-quinazolines as antiproliferative agents displaying ERK inhibitory activity
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ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 μM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.
- Nunes, Paulo Sérgio Gon?alves,da Silva, Gabriel,Nascimento, Sofia,Mantoani, Susimaire Pedersoli,de Andrade, Peterson,Bernardes, Emerson Soares,Kawano, Daniel Fábio,Leopoldino, Andreia Machado,Carvalho, Ivone
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supporting information
(2021/05/26)
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- Synthesis of Azocanes from Piperidines via an Azetidinium Intermediate
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α-Trifluoromethyl azocanes are accessible from 2-(trifluoropropan-2-ol) piperidines by metal-free ring-expansion involving a bicyclic azetidinium intermediate. The opening of the azetidinium intermediate was achieved by various nucleophiles (amines, alcoholates, carboxylates, phosphonates, halides and pseudo-halides) with an excellent regio- diastereo- and enantioselectivity and in good yields. The relative configuration of the piperidines and azocanes were assigned and the deprotected azocanes offer opportunities for further derivatization.
- Leverenz, Malte,Masson, Guillaume,Pardo, Domingo Gomez,Cossy, Janine
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supporting information
p. 16325 - 16328
(2021/10/25)
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- Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists
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The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists’ potency from pIC50 values of 5.7–7.6, ADME properties (logD7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.
- Budde, Thomas,Grey, Lucie,Heitman, Laura H.,Hundehege, Petra,Isaak, Andreas,Junker, Anna,Koch, Oliver,Michetti, Lucia,Patberg, Marius,Schulte, Janine,Vinnenberg, Laura,van der Horst, Cas,Füsser, Friederike,Ortiz Zacarías, Natalia V.
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- Design, synthesis and anticancer activity of 2-amidomethoxy-1,4-naphthoquinones and its conjugates with Biotin/polyamine
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In continuation with the previous work, a series of 5-hydroxy-2-amidomethoxy-1,4-naphthoquinones were prepared to establish the structure-activity relationship studies toward anticancer activity (IC50 in μM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among the synthesized compounds, naphthoquinone amines, 5 (0.8; 0.6; 0.8), 14 (0.8; 0.6; 0.5) and the amine precursor, 4 (1.3; 0.3; 1.0) displayed potent anticancer activities. A tumor targeting drug delivery system was achieved by synthesizing the conjugate 6 (1.4; 0.5; 1.1) of naphthoquinone-amine 5 and Biotin which also proved its potency. Finally, to introduce polyamine conjugate, spermidine was attached with 2-amidomethoxy-1,4-naphthoquinone. The naphthoquinone-spermidine conjugate 27 (1.2; 1.7; 1.7) also retained the activity. Thus, potent naphthoquinone amines were explored and Biotin/polyamine conjugate was developed as tumor targeting drug delivery system.
- Manickam, Manoj,Boggu, Pulla Reddy,Pillaiyar, Thanigaimalai,Nam, Yeo Jin,Abdullah, Md.,Lee, Seung Jin,Kang, Jong Seong,Jung, Sang-Hun
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supporting information
(2020/12/03)
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- Preparation method of N-t-butyloxycarbonyl piperazine
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The invention discloses a preparation method of N-t-butyloxycarbonyl piperazine, and belongs to the field of synthesis of drug intermediates. According to the method, ethylenediamine is taken as a raw material, and the N-t-butyloxycarbonyl piperazine is prepared through ring closing, acylation reaction and reduction reaction. The invention provides the preparation method of the N-t-butyloxycarbonyl piperazine. The method is simple and convenient to operate, high in atom utilization rate and good in product purity.
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Paragraph 0015; 0018
(2021/07/31)
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- A Greener Approach for the Chemoselective Boc Protection of Amines Using Sulfonated Reduced Graphene Oxide as a Catalyst in Metal- And Solvent-Free Conditions
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Sulfonated reduced graphene oxide (SrGO) has displayed great potential as a solid acid catalyst due to its efficiency, cost-effectiveness, and reliability. In this study, SrGO was synthesized by the introduction of sulfonic acid-containing aryl radicals onto chemically reduced graphene oxide using ultrasonication. The SrGO catalyst was characterized by Fourier Transform Infrared (FTIR) spectroscopy, Raman spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM). Further, SrGO was effectively utilized as a metal-free and reusable solid acid catalyst for the chemoselective N - t -Boc protection of various aromatic and aliphatic amines under solvent-free conditions. The N - t -Boc protection of amines was easily achieved under ambient conditions affording high yields (84-95percent) in very short reaction times (5 min-2 h). The authenticity of the approach was confirmed by a crystal structure. The catalyst could be easily recovered and was reused up to seven consecutive catalytic cycles without any substantial loss in its activity.
- Awasthi, Satish K.,Mishra, Anupam,Mittal, Rupali
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p. 591 - 601
(2020/02/13)
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- Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines
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The F1FO-ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.
- Anbarasu, Sivaraj,Bates, Roderick W.,Dick, Thomas,Dr?ge, Peter,Grüber, Gerhard,Harikishore, Amaravadhi,Hotra, Adam,Kalia, Nitin Pal,Kalyanasundaram, Revathy,Lakshmanan, Umayal,Makhija, Harshyaa,Ng, Pearly Shuyi,Parthasarathy, Krupakar,Pethe, Kevin,Poulsen, Anders,Pradeep, Chaudhari Namrata,Ragunathan, Priya,Sae-Lao, Patcharaporn,Sarathy, Jickky Palmae,Saw, Wuan-Geok,Seankongsuk, Pattarakiat,Shin, Joon,Tan, Jocelyn Hui Ling
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supporting information
p. 13295 - 13304
(2020/06/03)
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- QUINOLINE-BASED COMPOUNDS AND METHODS OF INHIBITING CDK8/19
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Disclosed herein are quinoline-based compounds and method for inhibiting CDK8 or CDK19 for the intervention in diseases, disorders, and conditions. The quinoline-based composition comprise substituents at quinoline ring positions 4 and 6, wherein the substituent at position 4 is selected from a substituted or unsubstituted arylalkylamine or a substituted or unsubstituted arylhetrocyclylamine. Pharmaceutical compositions comprising the substituted qunioline compositions, methods of inhibiting CDK8 or CDK19, and methods of treating CDK8/19-associated diseases, disorders, or conditions are also disclosed.
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Paragraph 0141
(2020/03/09)
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- A phenotypic approach to probing cellular outcomes using heterobivalent constructs
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Various conjugation techniques are used to affect the intracellular delivery of bioactive small molecules. However, the ability to track changes in the phenotype when applying these tools remains poorly studied. We addressed this issue by having prepared a focused library of heterobivalent constructs based on Rho kinase inhibitor HA-100. By comparing the induction of the phenotype of interest, cell viability and cellular uptake, we demonstrate that various conjugates indeed lead to divergent cellular outcomes.
- Bhadoria, Rohit,Lohk, Christer,Ping, Kefeng,Starkov, Pavel,J?rving, Ivar
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supporting information
p. 4216 - 4219
(2020/04/22)
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- One-pot synthesis of a white-light emissive bichromophore operated by aggregation-induced dual emission (AIDE) and partial energy transfer
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Merocyanine-triarylamine bichromophores are readily synthesized by sequentially Pd-catalyzed insertion-alkynylation-Michael-Suzuki four-component reactions. White-light emissive systems form upon aggregation in 1 : 99 and 0.1 : 99.9 vol percent CH2Cl2-cyclohexane mixtures, ascribed to aggregation-induced dual emission (AIDE) in combination with partial energy transfer between both chromophore units as supported by spectroscopic studies.
- Biesen, Lukas,Deni?en, Melanie,Hannen, Ricarda,Hoffmann, Katrin,Itskalov, Dana,Müller, Thomas J. J.,Nirmalananthan-Budau, Nithiya,Reiss, Guido J.,Resch-Genger, Ute
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supporting information
p. 7407 - 7410
(2020/07/15)
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- Design, Synthesis and Evaluation of AdSS Bisubstrate Inhibitors
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Many cancers lack the expression of methylthioadenosine phosphorylase (MTAP). These cancers require adenylosuccinate synthetase (AdSS) for nucleic acid synthesis. By inhibiting adenylosuccinate synthetase, we potentially have a new therapeutic agent. Bisubstrate inhibitors were synthesized and evaluated against purified AdSS. The best activity was obtained with adenosine bearing a four-carbon linker that connects the N-formyl-N-hydroxy moiety to the 6-position of the purine nucleoside.
- Tibrewal, Nidhi,Elliott, Gregory I.
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supporting information
p. 2269 - 2272
(2020/09/17)
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- Synthetic method N-Boc piperazine
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The invention discloses a synthetic method of N-Boc piperazine. According to the method, diethylamine alcohol is taken as a starting material, and three steps of chlorination, Boc protection and aminolysis cyclization are carried out to synthesize N-Boc piperazine. The method is readily available in raw materials, mild in reaction conditions, low in product cost, high in yield, high in purity andsuitable for industrial production.
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Paragraph 0021; 0029-0032; 0033-0036; 0037-0040
(2020/03/19)
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- Amidines analogs thereof to catalyze the nitrogen mixed fat surrounds uncle-butoxy carbonyl list protection method (by machine translation)
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The present invention is a method under the catalysis of the analogs of the amidines, to two nitrogen heterolipid animal fat link Boc protection of single green synthesis method. It is characterized in that the various two nitrogen heterolipid animal fat link compound water and alcohol as the solvent, in the presence of a certain amount of acid, joins the trunk and its analogs catalyst, di-T-butyl ester for (Boc anhydride) as Boc protecting reagent, the temperature of the reaction is carried out, the final by reduced pressure distillation to obtain the target product is separated from the single N - Boc - two nitrogen heterolipid [...] compound. The invention innovative use of the amidines its analogues as single Boc protecting catalyst, more traditional synthetic method more green environmental protection, safety, and cost saving. (by machine translation)
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Paragraph 0029-0032
(2019/10/02)
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- Base-Mediated 1,6-Aza-Michael Addition of Heterocyclic Amines and Amides to para-Quinone Methides Leading to Meclizine-, Hydroxyzine-and Cetirizine-like Architectures
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An expeditious, cost-effective synthetic methodology for a wide range of nitrogen-containing unsymmetrical trisubstituted methanes (TRSMs) is reported. The synthesis involves base-mediated 1,6-conjugate addition of heterocyclic amines and amides to substituted para-quinone methides, giving the unsymmetrical TRSMs in moderate to very good yields (up to 83percent) in one pot. The low cost, mild temperature, high atom economy and yields, easy scale-up and broad substrate scope are some of the salient features of this protocol. Further, the methodology could be extended for the synthesis of meclizine-, -hydroxyzine-and cetirizine-like molecules. The structure of one such compound, 2,6-di-tert-butyl-4-((4-chlorophenyl)(4-methylpiperazin-1-yl)methyl)phenol, was determined by single crystal X-ray analysis.
- Panda, Gautam,Roy, Deblina
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p. 4434 - 4442
(2019/11/21)
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- EF2-KINASE ENZYME INHIBITING NOVEL COMPOUNDS
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The invention is related to synthesis of novel compounds that inhibit the EF2-Kinase enzyme which is effective in breast, pancreas, brain, ovary, lung, skin (melanoma) and blood cancers.
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Page/Page column 16
(2020/01/08)
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- UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H4 Receptors
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Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH4Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH4Rs: UR-DEBa148 (N-neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), 43), the most potent [pEC50 (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(R)-4-[3-(dimethylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), 46, pEC50 (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H4R ligand. After radiolabeling, binding studies with [3H]UR-DEBa176 ([3H]46) at the h/m/rH4Rs revealed comparable Kd values (41/17/22 nM), low nonspecific binding (11-17%, aKd), and fast associations/dissociations (25-30 min) and disclosed [3H]UR-DEBa176 as useful molecular tool to determine h/m/rH4R binding affinities for H4R ligands.
- Bartole, Edith,Littmann, Timo,Tanaka, Miho,Ozawa, Takeaki,Buschauer, Armin,Bernhardt, Günther
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supporting information
p. 8338 - 8356
(2019/10/11)
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- Robust Buchwald-Hartwig amination enabled by ball-milling
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An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.
- Cao, Qun,Nicholson, William I.,Jones, Andrew C.,Browne, Duncan L.
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supporting information
p. 1722 - 1726
(2019/02/20)
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- Design, synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging
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Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [125I]8 and [125I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [125I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [125I]11. Incubation of [125I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [125I]8. In biodistribution experiments using tumor-bearing mice, [125I]8 accumulation in the tumor 1 h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [125I]IIQP, used in our previous research. These results indicate that [125I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands.
- Effendi, Nurmaya,Mishiro, Kenji,Takarada, Takeshi,Yamada, Daisuke,Nishii, Ryuichi,Shiba, Kazuhiro,Kinuya, Seigo,Odani, Akira,Ogawa, Kazuma
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p. 383 - 393
(2019/01/04)
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- Design, synthesis, biological evaluation and molecular docking study of arylcarboxamido piperidine and piperazine-based hydroxamates as potential HDAC8 inhibitors with promising anticancer activity
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HDAC8 has been established as one of the vital targets as far as the cancer is concerned. Different compounds having potential HDAC inhibitory activity have been approved by USFDA. However, none of these compounds are selective towards specific HDAC isoform. In this current study, some new hydroxamate derivatives with alkylpiperidine and alkylpiperazine linker moieties have been designed, synthesized and biologically evaluated. All these compounds are effective HDAC8 inhibitors comprising more or less similar cytotoxic potential against different cancer cell lines. It is observed that the piperazine scaffold containing compound is more active than the compound with piperidine scaffold for exerting HDAC8 inhibitory activity. Moreover, the 4-quinolyl cap group is better than the biphenyl group which is better than the benzyl group for producing higher HDAC8 inhibition as well as cytotoxicity. These compounds displayed selective HDAC8 inhibition over HDAC3. Moreover, these compounds showed an increased caspase3/7 activity suggesting their anticancer potential through modulation of apoptotic pathways. Molecular docking study with three potent compounds was performed with both HDAC3 and HDAC8 enzymes to understand the selectivity profile of these compounds. Compound containing 4-quinolyl cap group with alkyl piperazinyl urea linker moiety has been emerged out as the lead molecule that may be further modified to design more effective and selective HDAC8 inhibitors in future.
- Trivedi, Prakruti,Adhikari, Nilanjan,Amin, Sk. Abdul,Bobde, Yamini,Ganesh, Routholla,Jha, Tarun,Ghosh, Balaram
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- Novel linker compound and Site-Specific compounds of Antibody-Drug Conjugate Comprising the Same
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The present invention relates to a novel linker compound, and relates to a site-specific antibody-drug conjugate (ADC) compound comprising the same, a method for manufacturing the same, and an anticancer composition comprising the same as an active component. The linker compound produces a uniform ADC compound with excellent site specificity in manufacturing an ADC compound, and the ADC compound comprising the same exhibits an excellent anticancer effect.COPYRIGHT KIPO 2020
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Paragraph 0369; 0491-0496
(2020/02/07)
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- Synthesis method of single BOC protection double-amino compound
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The invention relates to the field of fine chemical engineering, in particular to a synthesis method of a single BOC protection double-amino compound. The synthesis method comprises the steps that firstly, an acid compound and double-amino are subjected to complex reaction, then moderate BOX acid anhydride is added for reaction, and a product is obtained. The method is simple in reaction step, high in product yield and purity and suitable for industrial production.
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Paragraph 0026; 0027
(2018/06/21)
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- Pyrazolo[1,5-a]pyrimidine compounds and application thereof
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The invention discloses pyrazolo[1,5-a]pyrimidine compounds and application thereof, and belongs to the field of medicines. Some of the pyrazolo[1,5-a]pyrimidine compounds has the inhibitory activityof 40% or more against CDK2, so that the compounds have good inhibitory activity against CDK2 and can be used as a CDK2 inhibitor. The compounds have stronger inhibitory activity against CDK2 and haveimportant guiding significance for the development of drugs suitable for use as CDK2 inhibitors.
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Paragraph 0075; 0076; 0077
(2018/09/20)
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- BENZIMIDAZOL DERIVATIVES FOR TREATING FILOVIRUS INFECTION
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The present invention relates to compounds comprising a benzimidazole scaffold, and the use of such compounds for the treatment of viral diseases. The invention also relates to pharmaceutical compositions comprising said compounds as an active ingredient. In particular the compounds of the invention comprising a benzimidazole scaffold are used for the treatment of filoviruses or retroviruses, and preferably for the treatment of Ebola virus or HIV virus.
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Page/Page column 56
(2018/04/13)
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- Identification of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate-nitrostyrene hybrid as potent antiproliferative and apoptotic inducing agent against cervical cancer cell lines
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The present study seeks to describe the design and synthesis of six new Michael adducts of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate with nitrostyrenes and their in vitro antiproliferative activity against human cervical cancer cell lines [HeLa (HPV 18 positive), CaSki (HPV 16 positive) and ViBo (HPV negative) cervical cancer cell lines]. Virtual screening of the physicochemical properties of all compounds have also been presented. All the compounds exploited significant antiproliferative activity on the three cervical cancer cell lines. Compound 8a was found to be most potent, displaying in vitro antiproliferative activity against HeLa, CaSki and ViBo cervical cancer cell lines superior to Cisplatin and Paclitaxel with IC50 values 0.99 ± 0.007, 2.36 ± 0.016 and 0.73 ± 0.002 μM respectively. In addition, compound 8a did not trigger the necrosis cell death to the test cancer cell lines. Further mechanistic study revealed that compound 8a could inhibit the cancer cell proliferation by inducing apoptosis through caspase-3 activation. Moreover, cell cycle analysis indicated that compound 8a could arrest the cell cycle at the G1 phase for HeLa and CaSki cancer cells. At the predetermined IC50 values on cancer cells, compound 8a did not induce any necrotic (cytotoxic) death to the normal human lymphocytes. In the present design, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane system was found to be superior than the piperazine counterpart 11.
- Laskar, Sujay,Sánchez-Sánchez, Luis,Flores, Sebastián M.,López-Mu?oz, Hugo,Escobar-Sánchez, María L.,López-Ortiz, Manuel,Hernández-Rodríguez, Marcos,Regla, Ignacio
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p. 621 - 635
(2018/02/09)
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- Synthesis and structures of zwitterionic polymers to induce electrostatic interaction with PDMS surface treated by air-plasma
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Various zwitterionic polymers, sulfobetaine and phosphoryl choline derivatives were synthesized in order to investigate zwitterionic polymer structures toward surface modification of PDMS, where the adsorption of zwitterionic polymers on polydimethylsiloxane surface treated with air-plasma was induced by the electrostatic interaction,. The electrostatic interaction was evaluated with hydrophilicity. The results suggested that a sulfobetaine polymer with higher molecular weight, lower molecular weight distribution, and shorter alkyl chain afforded high electrostatic interaction. A sulfobetaine polymer bearing phenylazide group showed similar electrostatic interaction with the PDMS surface, and it is a promising material for surface modification ofpolydimethylsiloxane.
- Tanaka, Mutsuo,Hirata, Yoshiki,Sawaguchi, Takahiro,Kurosawa, Shigeru
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p. 330 - 343
(2018/06/29)
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- PROCESSES FOR THE PREPARATION OF 7-{4-[4-(1-BENZOTHIOPHEN-4-YL)PIPERAZIN-1-YL]BUTOXY}QUINOLIN-2(1H)-ONE
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The Present Invention relates to process for the preparation of 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one represented by the following structural formula-1.
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Page/Page column 34
(2018/05/27)
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- 2,2,6,6-Tetramethylpiperidin-1-yloxycarbonyl: A Protecting Group for Primary, Secondary, and Heterocyclic Amines
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The 2,2,6,6-tetramethylpiperidin-1-yloxycarbonyl (Tempoc) protecting group is readily introduced by the reaction of amines with a new acyl transfer reagent, 4-nitrophenyl (2,2,6,6-tetramethylpiperidin-1-yl) carbonate (NPTC). Tempoc has a reactivity profile that complements the commonly used t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) protecting groups. Deprotection can be achieved under mild reductive conditions with in situ generated Cu(I) species or by thermolytic cleavage at 135 °C. Mechanistic studies on the deprotection of Tempoc-indole suggest a combination of ionic and radical fragmentation pathways under thermal conditions.
- Lizza, Joseph R.,Bremerich, Maximilian,McCabe, Stephanie R.,Wipf, Peter
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supporting information
p. 6760 - 6764
(2018/10/25)
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- Unlocking the potential of phenacyl protecting groups: CO2-based formation and photocatalytic release of caged amines
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Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.
- Speckmeier, Elisabeth,Klimkait, Michael,Zeitler, Kirsten
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p. 3738 - 3745
(2018/04/14)
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- Diamines compound single-Boc protection method
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The invention relates to a diamines compound single-Boc protection method. The method includes following steps: enabling t-butylazidoformate and the diamines compound to react in an organic solvent at 0-30 DEG C to obtain a single-Boc-protected diamines compound. T-butylazidoformate is used as a Boc protection reagent, so that reaction selectivity can be improved effectively; a byproduct is nitrogen which escapes directly from a reaction system. By the method, the defect that a byproduct-isobutene is generated when Boc anhydride is taken as a raw material is overcome, and the problems of thick reaction system and difficulty in purification are solved thoroughly. The method is high in reaction efficiency, simple in aftertreatment and suitable for industrial production.
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Paragraph 0018; 0041; 0043
(2017/08/31)
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- A benzo [b] thiophene preparation method and intermediate
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The invention provides a preparation method for benzo[b]thiophene. The preparation method comprises the following steps: substitution; ring closure; hydrolysis; decarboxylation; etc. The method effectively reduces generation of by-products, improves reaction yield, avoids usage of expensive reagents, decreases total cost and is applicable to industrial production. The invention further provides a novel compound. The novel compound is a key intermediate for preparation of benzo[b]thiophene and has a structure as shown in a formula 3 which is described in the specification. The invention also provides a preparation method for the compound 3, and the method has high yield and is simple to operate.
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Paragraph 0105; 0106; 0107; 0108
(2017/08/25)
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF BENZO[B]THIOPHENE COMPOUNDS
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A process for preparing compounds of formula (I), or a salt or solvate thereof, including Brexpiprazole, which process comprises cyclization of a compound of formula (II) or (III), or a salt orsolvate thereof. The invention also refers to intermediates of said process.
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Page/Page column 29; 30
(2017/05/07)
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- Electrophilic Zinc Homoenolates: Synthesis of Cyclopropylamines from Cyclopropanols and Amines
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Metal homoenolates, produced via C-C bond cleavage of cyclopropanols, have been extensively investigated as nucleophiles for the synthesis of β-substituted carbonyl derivatives. Herein, we demonstrate that zinc homoenolates can react as carbonyl-electrophiles in the presence of nucleophilic amines to yield highly valuable trans-cyclopropylamines in good yields and high diastereoselectivities. GSK2879552, a lysine demethylase 1 inhibitor currently in clinical trials for the treatment of small cell lung carcinoma, was synthesized using this strategy.
- Mills, L. Reginald,Barrera Arbelaez, Luis Miguel,Rousseaux, Sophie A. L.
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supporting information
p. 11357 - 11360
(2017/08/30)
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- Endosome Targeting meso-Tetraphenylchlorin-Chitosan Nanoconjugates for Photochemical Internalization
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Four amphiphilic covalently linked meso-tetraphenylchlorin-chitosan nanoconjugates were synthesized and evaluated for use in photochemical internalization (PCI) in vitro and in vivo. The synthetic protocol for the preparation of two different hydrophobic chlorin photosensitizers, 5-(4-aminophenyl)-10,15,20-triphenylchlorin and 5-(4-carboxyphenyl)-10,15,20-triphenylchlorin, was optimized. These monofunctional photosensitizers were covalently attached to carrier chitosan via silyl-protected 3,6-di-O-tert-butyldimethylsilyl-chitosan (Di-TBDMS-chitosan) with 0.10 degree of substitution per glucosamine (DS). Hydrophilic moieties such as trimethylamine and/or 1-methylpiperazine were incorporated with 0.9 DS to give fully water-soluble conjugates after removal of the TBDMS groups. A dynamic light scattering (DLS) study confirmed the formation of nanoparticles with a 140-200 nm diameter. These nanoconjugates could be activated at 650 nm (red region) light, with a fluorescence quantum yield (ΦF) of 0.43-0.45, and are thus suitable candidates for use in PCI. These nanoconjugates were taken up and localized in the endocytic vesicles of HCT116/LUC human colon carcinoma cells, and upon illumination they substantially enhanced plasmid DNA transfection. The nanoconjugates were also evaluated in preliminary in vivo experiments in tumor-bearing mice, showing that the nanoconjugates could induce a strong photodynamic therapy (PDT) and also PCI effects in treatment with bleomycin.
- Gaware, Vivek S.,H?kerud, Monika,Juzeniene, Asta,H?gset, Anders,Berg, Kristian,Másson, Már
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p. 1108 - 1126
(2017/04/26)
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- C-3 NOVEL TRITERPENE WITH C-17 AMINE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to to C-3 novel triterpene with C-17 amine derivatives of formula (I); or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R1, R2, R3, R4, R5 and 'n' are as defined herein. The present invention also relates to pharmaceutical compositions comprising compounds of formula (I) and process for preparing them, and their use for the treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 29
(2017/09/15)
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- NOVEL BETULINIC SUBSTITUTED AMIDE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to novel betulinic substituted amide compounds of formula (I); and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and are Formula (II) as defined herein. The invention novel betulinic substituted amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 42-43
(2017/02/24)
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- COMPOUNDS FOR BINDING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
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The present disclosure relates to novel compounds, methods, and compositions capable of binding to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity. The compounds of the disclosure include compounds Formula (I).
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Paragraph 0200
(2017/09/15)
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- TG2 INHIBITOR COMPOUNDS AND USES THEREOF
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There are provided Tissue Transglutaminase (TG2) inhibitor compounds, and compositions and methods of use thereof for the prevention or treatment of a cancer. Compounds of Formula I, and pharmaceutically acceptable salts thereof, are provided: Formula (I).
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Paragraph 00356; 00366
(2017/11/16)
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- Synthesis method of 1-BOC-piperazine
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The invention discloses a synthesis method of 1-BOC-piperazine. The method includes: firstly reacting 2-morpholone and BOC acid anhydride to generate N-BOC-morpholone, and then carrying out reaction with ammonia gas to produce 1-BOC-piperazine. The method has the advantages of simple reaction steps, high product yield and high purity, thus being suitable for industrial production. (reaction equation).
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Paragraph 0025; 0027; 0029; 0030; 0033
(2017/05/13)
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- Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure
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The present invention relates to a compound having a cardiotonic activating function and a pharmaceutical composition containing the same. The composition comprising the compound according to the present invention is effective in preventing or treating heart failure. In addition, the compound is represented by chemical formula 2 or is pharmaceutically acceptable salt thereof.COPYRIGHT KIPO 2016
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Paragraph 0721-0724
(2017/02/02)
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- Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family
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Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.
- Tintori, Cristina,Brai, Annalaura,Dasso Lang, Maria Chiara,Deodato, Davide,Greco, Antonia Michela,Bizzarri, Bruno Mattia,Cascone, Lorena,Casian, Alexandru,Zamperini, Claudio,Dreassi, Elena,Crespan, Emmanuele,Maga, Giovanni,Vanham, Guido,Ceresola, Elisa,Canducci, Filippo,Ari?n, Kevin K.,Botta, Maurizio
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p. 2747 - 2759
(2016/04/10)
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- Chemical Inhibition of Human Thymidylate Kinase and Structural Insights into the Phosphate Binding Loop and Ligand-Induced Degradation
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Targeting thymidylate kinase (TMPK) that catalyzes the phosphotransfer reaction for formation of dTDP from dTMP is a new strategy for anticancer treatment. This study is to understand the inhibitory mechanism of a previously identified human TMPK (hTMPK) inhibitor YMU1 (1a) by molecular docking, isothermal titration calorimetry, and photoaffinity labeling. The molecular dynamics simulation suggests that 1a prefers binding at the catalytic site of hTMPK, whereas the hTMPK inhibitors that bear pyridino[d]isothiazolone or benzo[d]isothiazolone core structure in lieu of the dimethylpyridine-fused isothiazolone moiety in 1a can have access to both the ATP-binding and catalytic sites. The binding sites of hTMPK inhibitors were validated by photoaffinity labeling and mass spectrometric studies. Taking together, 1a and its analogues stabilize the conformation of ligand-induced degradation (LID) region of hTMPK and block the catalytic site or ATP-binding site, thus attenuating the ATP binding-induced closed conformation that is required for phosphorylation of dTMP.
- Chen, Yi-Hsuan,Hsu, Hua-Yi,Yeh, Ming-Tyng,Chen, Chen-Cheng,Huang, Chang-Yu,Chung, Ying-Hsuan,Chang, Zee-Fen,Kuo, Wei-Chen,Chan, Nei-Li,Weng, Jui-Hsia,Chung, Bon-Chu,Chen, Yu-Ju,Jian, Cheng-Bang,Shen, Ching-Chieh,Tai, Hwan-Ching,Sheu, Sheh-Yi,Fang, Jim-Min
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p. 9906 - 9918
(2016/11/19)
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- Synthesis and investigation of novel benzimidazole derivatives as antifungal agents
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The rise and emergence of resistance to antifungal drugs by diverse pathogenic fungal strains have resulted in an increase in demand for new antifungal agents. Various heterocyclic scaffolds with different mechanisms of action against fungi have been investigated in the past. Herein, we report the synthesis and antifungal activities of 18 alkylated mono-, bis-, and trisbenzimidazole derivatives, their toxicities against mammalian cells, as well as their ability to induce reactive oxygen species (ROS) in yeast cells. Many of our bisbenzimidazole compounds exhibited moderate to excellent antifungal activities against all tested fungal strains, with MIC values ranging from 15.6 to 0.975?μg/mL. The fungal activity profiles of our bisbenzimidazoles were found to be dependent on alkyl chain length. Our most potent compounds were found to display equal or superior antifungal activity when compared to the currently used agents amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole against many of the strains tested.
- Chandrika, Nishad Thamban,Shrestha, Sanjib K.,Ngo, Huy X.,Garneau-Tsodikova, Sylvie
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supporting information
p. 3680 - 3686
(2016/07/20)
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- Design, synthesis, and evaluation of the anticancer properties of a novel series of carboxamides, sulfonamides, ureas, and thioureas derived from 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl substituted with pyrazolo[1,5-a]pyrimidine derivatives
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Abstract: A series of novel carboxamides, sulfonamides, ureas, and thioureas derived from 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl substituted with pyrazolo[1,5-a]pyrimidine analog were designed and synthesized. The newly synthesized compounds were characterized by 1H NMR, 13C NMR, ESI–MS, and IR and were tested for their in vitro antiproliferative activity by MTT assay. Out of these twenty derivatives, five compounds showed good anticancer activity against HeLa cell line. These are superior with less than 10?μg/cm3 of IC50 when compared to the marketed anticancer drug paclitaxel with 30?μg/cm3 of IC50 against Hela cell line. Graphical abstract: [Figure not available: see fulltext.]
- Ajeesh Kumar,Nair, Kanya B.,Bodke, Yadav D.,Sambasivam, Ganesh,Bhat, Kishore G.
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p. 2221 - 2234
(2016/11/17)
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- COMPOUND AND METHOD
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The present invention provides a method of expressing an antigenic molecule or a part thereof on the surface of a cell using a photochemical internalisation method and a virosome or a virus-like particle (VLP) which comprises the antigenic molecule. In preferred embodiments the antigenic molecule is an antigen from influenza or papillomavirus. The method may be used to stimulate an immune response and for various therapeutic or prophylactic methods. Pharmaceutical compositions or kits comprising the components for use in the method, cells produced by the method and their use in therapy and prophylaxis also form aspects of the invention.
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- COMPOUND AND METHOD
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The present invention provides a method of expressing an antigenic molecule or a part thereof on the surface of a cell using a photochemical internalisation method in which a cytokine, preferably GM-CSF, is used to enhance the method. The method may be used to stimulate an immune response and for various therapeutic or prophylactic methods. Pharmaceutical compositions or kits comprising the components for use in the method, cells produced by the method and their use in therapy and prophylaxis also form aspects of the invention.
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Page/Page column 35
(2016/03/22)
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