- Discovery and Characterization of a Peptoid with Antifungal Activity against Cryptococcus neoformans
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Studies show there is an increasing rate of fungal infections, especially in immunocompromised patients and treatments for fungal genera, such as Aspergillus, Candida, and Cryptococcus, carry significant cytotoxicity with an increasing prevalence of antifungal resistance. We have previously reported a high-throughput assay for identifying peptoids with antimicrobial properties from combinatorial libraries. Here we report the application of this assay in identifying a peptoid with antifungal properties against Cryptococcus neoformans. Termed AEC5, this peptoid has comparable potency to existing clinical antifungal agents, excellent stability, and minimal cytotoxicity in mammalian cells.
- Corson, Ashley E.,Armstrong, Scott A.,Wright, Matthew E.,McClelland, Erin E.,Bicker, Kevin L.
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- Dramatic influence of the orientation of linker between hydrophilic and hydrophobic lipid moiety in liposomal gene delivery
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A number of prior studies have demonstrated that the DNA-binding and gene transfection efficacies of cationic amphiphiles crucially depend on their various structural parameters including hydrophobic chain lengths, headgroup functionalities, and the nature of the linker-functionality used in tethering the polar headgroup and hydrophobic tails. However, to date addressing the issue of linker orientation remains unexplored in liposomal gene delivery. Toward probing the influence of linker orientation in cationic lipid mediated gene delivery, we have designed and synthesized two structurally isomeric remarkably similar cationic amphiphiles 1 and 2 bearing the same hydrophobic tails and the same polar headgroups connected by the same ester linker group. The only structural difference between the cationic amphiphiles 1 and 2 is the orientation of their linker ester functionality. While lipid 1 showed high gene transfer efficacies in multiple cultured animal cells, lipid 2 was essentially transfection incompetent. Findings in both transmission electron microscopic and dynamic laser light scattering studies revealed no significant size difference between the lipoplexes of lipids 1 and 2. Findings in confocal microscopic and fluorescence resonance energy transfer (FRET) experiments, taken together, support the notion that the remarkably higher gene transfer efficacies of lipid 1 compared to those of lipid 2 presumably originate from higher biomembrane fusogenicity of lipid 1 liposomes. Differential scanning calorimetry (DSC) and fluorescence anisotropy studies revealed a significantly higher gel-to-liquid crystalline temperature for the lipid 2 liposomes than that for lipid 1 liposomes. Findings in the dye entrapment experiment were also consistent with the higher rigidity of lipid 2/cholesterol (1:1 mole ratio) liposomes. Thus, the higher biomembrane fusibility of lipid 1 liposomes than that of lipid 2 liposomes presumably originates from the more rigid nature of lipid 2 cationic liposomes. Taken together, the present findings demonstrate for the first time that even as minor a structural variation as linker orientation reversal in cationic amphiphiles can profoundly influence DNA-binding characteristics, membrane rigidity, membrane fusibility, cellular uptake, and consequently gene delivery efficacies of cationic liposomes.
- Rajesh, Mukthavaram,Sen, Joyeeta,Srujan, Marepally,Mukherjee, Koushik,Sreedhar, Bojja,Chaudhuri, Arabinda
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- Novel nitroimidazole alkylsulfonamides as hypoxic cell radiosensitisers
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A novel class of nitroimidazole alkylsulfonamides have been prepared and evaluated as hypoxia-selective cytotoxins and radiosensitisers. The sulfonamide side chain markedly influences the physicochemical properties of the analogues: lowering aqueous solubility and raising the electron affinity of the nitroimidazole group. The addition of hydroxyl or basic amine groups increased aqueous solubility, with charged amine groups contributing to increased electron affinity. The analogues covered the range of electron affinity for effective radiosensitisation with one-electron reduction potentials ranging from -503 to -342 mV. Cytotoxicity under normoxia or anoxia against a panel of human tumour cell lines was determined using a proliferation assay. 2-Nitroimidazole sulfonamides displayed significant hypoxia-selective cytotoxicity (6 to 64-fold), while 4- and 5-nitroimidazole analogues did not display hypoxia-selective cytotoxicity. All analogues sensitised anoxic HCT-116 human colorectal cells to radiation at non-toxic concentrations. 2-Nitroimidazole analogues provided modest sensitisation due to the relatively low concentrations used while several 5-nitroimidazole analogues provided equivalent sensitisation to misonidazole and etanidazole at similar molar concentrations.
- Bonnet, Muriel,Hong, Cho Rong,Gu, Yongchuan,Anderson, Robert F.,Wilson, William R.,Pruijn, Frederik B.,Wang, Jingli,Hicks, Kevin O.,Hay, Michael P.
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- A Straightforward Approach towards Cyclic Photoactivatable Tubulysin Derivatives
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The development of a new photolabile protecting group containing an additional allyl functionality allows the synthesis of cyclic photoactivatable natural products. Cyclization occurs between the allyl moiety in the protecting group and a second double bond in the target molecule by means of ring-closing metathesis. Cyclization should increase the metabolic stability towards proteases. On the other hand, the conformational change should cause diminished biological activity. As illustrated for tubulysin derivatives, cyclic and photoactivatable drug candidates can easily be obtained in only two steps from simple building blocks through Ugi reaction and ring-closing metathesis. The photolabile protecting group is introduced by means of the isocyanide component during the Ugi reaction.
- Hoffmann, Judith,Kazmaier, Uli
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- Bioactive 4-Oxoheptanedioic Monoamide Derivatives of Proteins and Ethanolaminephospholipids: Products of Docosahexaenoate Oxidation
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Oxidative stress causes lipid-derived oxidative modification of biomolecules that has been implicated in many pathological states. Phospholipids containing polyunsaturated fatty acids are major targets of free radical-initiated oxidation. Phospholipids that incorporate docosahexaenoate (DHA) are highly enriched in important neural structures including the brain and retina, where DHA comprises 40% and 60% of total fatty acids, respectively. Oxidative fragmentation of 2-docosahexaenoyl-1-palmityl-sn-glycerophosphocholine generates esters of 4-hydroxy-7-oxohept-5-enoic acid (HOHA) and 4-keto-7-oxohept-5-enoic acid (KOHA) with 2-lysophosphatidylcholine, HOHA-PC, and KOHA-PC. Covalent HOHA adducts that incorporate the primary amino groups of proteins and ethanolamine phospholipids in carboxyethylpyrrole (CEP) derivatives were detected immunologically with anti-CEP antibodies in human tumors, retina, and blood. Now, we generated an anti-OHdiA antibody to test the hypothesis that KOHA adducts, which incorporate the primary amino groups of proteins or ethanolamine phospholipids in 4-oxo-heptanedioic (OHdiA) monoamide derivatives, are present in vivo. However, whereas the anti-CEP antibody is highly specific and does not cross-react with the OHdiA monoamide epitope, the anti-OHdiA monoamide antibody cross-reacted with CEP epitopes making it of little value as an analytical tool for OHdiA monoamides but suggesting the possibility that OHdiA monoamides would exhibit receptor-mediated biological activity similar to that of CEP. An LC-MS/MS method was developed that allows quantification of OHdiA derivatives in biological samples. We now find that KOHA-PC forms OHdiA monoamide adducts of proteins and ethanolamine phospholipids and that OHdiA-protein levels are significantly higher than OHdiA-ethanloamine phospholipid levels in blood from healthy human subjects, 0.45 μM and 0.18 μM, respectively (n = 3, and p = 0.027). OHdiA monoamide epitopes are angiogenic, causing TLR2-dependent adhesion and tube formation by human umbilical vein endothelial cells. OHdiA monoamide epitopes are only slightly less potent than CEP epitopes that contribute to the pathological angiogenesis of age-related macular degeneration and tumor growth.
- Guo, Junhong,Hong, Li,West, Xiaoxia Z.,Wang, Hua,Salomon, Robert G.
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- α-Linolenic Acid-Valproic Acid Conjugates: Toward Single-Molecule Polypharmacology for Multiple Sclerosis
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Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from reported beneficial effects of α-linolenic acid (ALA) and valproic acid (VPA) in MS, and by applying a rational strategy, we developed a small set of codrugs obtained by conjugating VPA and ALA through proper linkers. A cellular profiling identified 1 as a polypharmacological tool able not only to modulate microglia polarization, but also to counteract neurodegeneration and demyelination and induce oligodendrocyte precursor cell differentiation, by acting on multiple biochemical and epigenetic pathways.
- Rossi, Michele,Petralla, Sabrina,Protti, Michele,Baiula, Monica,Kobrlova, Tereza,Soukup, Ondrej,Spampinato, Santi Mario,Mercolini, Laura,Monti, Barbara,Bolognesi, Maria Laura
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- Target-selective photodegradation of HIV-1 protease and inhibition of HIV-1 replication in living cells by designed fullerene-sugar hybrids
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Sweet degradation: A designed fullerene-sugar hybrid selectively caused the degradation of HIV-1 protease, an important target of anti-HIV therapy. Degradation was achieved at irradiation with long-wavelength UV (365 nm) or visible light (diffuse sunlight) in the absence of any additives and under neutral conditions. Moreover, the hybrid inhibited HIV-1 replication in living cells infected with HIV-1.
- Tanimoto, Shuho,Sakai, Satoshi,Kudo, Eriko,Okada, Seiji,Matsumura, Shuichi,Takahashi, Daisuke,Toshima, Kazunobu
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Read Online
- N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity
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Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.
- Aakula, Balakishan,Hill, Michelle L.,Karade, Sharanbasappa S.,Kiappes, J. L.,Manne, Rajkumar,Mariuzza, Roy A.,Treston, Anthony M.,Warfield, Kelly L.,Zitzmann, Nicole
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p. 18010 - 18024
(2021/12/17)
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- Introduction of mercaptoethyl at sorafenib pyridine‐2‐amide motif as a potentially effective chain to further get sorafenib‐PEg‐DGL
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The crystal structure of the sorafenib and B‐RAF complex indicates that the binding cavity occupied by the pyridine‐2‐carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti‐cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine‐2‐amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC50 58.79 and 63.67 μM, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib‐PEG‐DGL, which could be developed as a delivery vehicle to improve the concentration of anti‐tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.
- Chen, Ying,Kuerbana, Kudelaidi,Wan, Qi,Wang, Ke,Ye, Li,Yu, Zhihui
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- NOVEL STING AGONISTS
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The present invention provides compounds of Formula I′: wherein , W, X, Y, Z, Z1, Z2, R1, R2, R3, R4 and R5 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the STING protein and thus can be used as medicaments for treating or preventing disorders affected by the agonism of STING.
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Paragraph 0492; 0493
(2020/05/14)
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- Route exploration and synthesis of the reported pyridone-based PDI inhibitor STK076545
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The enzyme protein disulfide isomerase (PDI) is essential for the correct folding of proteins and the activation of certain cell surface receptors, and is a promising target for the treatment of cancer and thrombotic conditions. A previous high-throughput screen identified the commercial compound STK076545 as a promising PDI inhibitor. To confirm its activity and support further biological studies, a resynthesis was pursued of the reported β-keto-amide with an N-alkylated pyridone at the α-position. Numerous conventional approaches were complicated by undesired fragmentations or rearrangements. However, a successful 5-step synthetic route was achieved using an aldol reaction with an α-pyridone allyl ester as a key step. An X-ray crystal structure of the final compound confirmed that the reported structure of STK076545 was achieved, however its lack of PDI activity and inconsistent spectral data suggest that the commercial structure was misassigned.
- Dockendorff, Chris,Flaumenhaft, Robert,Greve, Eric,Lin, Lin,Lindeman, Sergey V.,Scartelli, Christina
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p. 6665 - 6681
(2020/09/21)
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- FUSED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION METHODS THEREOF AND MEDICAL USES THEREOF
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The present invention relates to fused heterocyclic derivatives, processes for their preparation and their use in medicine. Specifically, the present invention relates to a novel derivative represented by the formula (I′), or its pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the derivative or its pharmaceutically acceptable salt thereof, and the method for preparing the derivative and its pharmaceutically acceptable salt thereof. The present invention also relates to the use of the derivative and its pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the derivative and its pharmaceutically acceptable salt thereof in the preparation of medicines, in particularly as IDO inhibitor medicines, for treating and/or preventing cancers. Wherein each substituent of the formula (I′) is the same as defined in the specification.
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Paragraph 0246; 0252; 0549-0552
(2019/07/03)
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- MODULATORS OF G-PROTEIN COUPLED RECEPTORS
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This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize or partially agonize or antagonize) glucagon?like peptide?1 receptor ("GLP?1R") and/or the gastric inhibitory polypeptide receptor ("GIPR"). The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP?1R and/or GIPR activities is benficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, the modulation results in an enhancment of (e.g., an increase in) existing levels (e.g., normal or below normal levels) of GLP?1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) -arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.
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Page/Page column 242; 243
(2019/10/15)
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- ANDROGEN RECEPTOR ANTAGONISTS
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Compounds that inhibit the androgen receptor, pharmaceutical compositions comprising one or more of the compounds, as well as methods of treating cancer using such compounds are described.
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Paragraph 0500
(2019/08/26)
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- Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides
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Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay.
- Bonnet, Muriel,Hong, Cho Rong,Wong, Way Wua,Liew, Lydia P.,Shome, Avik,Wang, Jingli,Gu, Yongchuan,Stevenson, Ralph J.,Qi, Wen,Anderson, Robert F.,Pruijn, Frederik B.,Wilson, William R.,Jamieson, Stephen M. F.,Hicks, Kevin O.,Hay, Michael P.
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p. 1241 - 1254
(2018/02/17)
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- INHIBITORS FOR PROLIFERATING CELL NUCLEAR ANTIGEN AND USES
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The present invention relates to series of compounds as an inhibitor targeting Proliferating Cell Nuclear Antigen (PCNA). Pharmaceutical compositions of those compounds and methods of using them in the treatment of cancer are within the scope of this disclosure.
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Paragraph 00129
(2017/07/06)
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- Enantioselective Iridium-Catalyzed Allylic Cyclizations
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A method for the enantioselective synthesis of carbo- and heterocyclic ring systems enabled through the combination of Lewis acid activation and iridium-catalyzed allylic substitution is described. The reaction proceeds with branched, allylic alcohols and carbon nucleophiles as well as heteronucleophiles to give a diverse set of ring systems in good yields and with high enantioselectivities. The utility of the method is highlighted by the asymmetric syntheses of erythrococcamides A and B.
- Schafroth, Michael A.,Rummelt, Stephan M.,Sarlah, David,Carreira, Erick M.
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supporting information
p. 3235 - 3238
(2017/06/23)
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- 3-PHOSPHOGLYCERATE DEHYDROGENASE INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00396
(2017/10/06)
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- 3-PHOSPHOGLYCERATE DEHYDROGENASE INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00251; 00252; 00253
(2017/09/27)
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- SELECTIVE HDAC6 INHIBITORS
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The present invention provides hydroxamic acids of the formula described herein, that have activity toward inhibiting histone deacetylases, and in particular HDAC6. Also contemplated are pharmaceutical compositions and methods of use of an effective amount of the hydroxamic acid compounds provided, for treating a disease in a subject. In certain embodiments, the subject is afflicted with cancer, neurodegenerative disease, or HIV infection.
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Page/Page column 43
(2015/07/15)
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- DITHIOLAN-3-YLPENTANOATE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR THE TREATMENT OF PAIN
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The disclosure herein provides 1-carbamoyloxyethyl 5-(1,2-dithiolan-3-yl)pentanoate derivatives of formula I, formula II and formula III. The disclosure also provides a method of synthesizing the compound of formula I, formula II and formula III. The compound of formula I, formula II and formula III or its pharmaceutical acceptable salts, as well as polymorphs, solvates, and hydrates, thereof may be formulated as pharmaceutical composition. The pharmaceutical composition of compound of formula I, formula II and formula III or the final compound of formula I, formula II or formula III may be formulated for non-invasive peroral, topical (example transdermal), enteral, transmucosal, targeted delivery, sustained release delivery, delayed release, pulsed release and parenteral methods. Such compositions may be used to treat chronic pain manifested with chronic diseases or its associated complications.
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Page/Page column 20; 21
(2015/09/23)
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- HYDRAZINYL-PYRROLO COMPOUNDS AND METHODS FOR PRODUCING A CONJUGATE
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The present disclosure provides conjugate structures and hydrazinyl-pyrrolo compound structures used to produce these conjugates. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same. Aspects of the present disclosure include a pharmaceutical composition. The pharmaceutical composition includes a conjugate as described herein and a pharmaceutically acceptable excipient. Aspects of the present disclosure include a method of delivering a conjugate to a subject. The method includes administering to the subject an effective amount of a conjugate as described herein. Aspects of the present disclosure include a method of treating a condition in a subject.
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Paragraph 00734; 00735
(2015/06/11)
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- ANTI-HER2 ANTIBODY-MAYTANSINE CONJUGATES AND METHODS OF USE THEREOF
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The present disclosure provides anti-HER2 antibody-maytansine conjugate structures. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same.
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Page/Page column 00521; 00522; 00523
(2015/12/24)
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- Fluorous Peptide Nucleic Acids: PNA Analogues with Fluorine in Backbone (γ-CF2-apg-PNA) Enhance Cellular Uptake
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Fluorous PNA analogues possessing fluorine as inherent part of aminopropylglycine (apg) backbone (γ-CF2-apg PNA) have been synthesized and evaluated for biophysical and cell penetrating properties. These form duplexes of higher thermal stability with cRNA than cDNA, although destabilized compared to duplexes of standard aeg-PNA. Cellular uptake of the fluorinated γ-CF2-apg PNAs in NIH 3T3 and HeLa cells was 2-3-fold higher compared to that of nonfluorinated apg PNA, with NIH 3T3 cells showing better permeability compared to HeLa cells. The backbone fluorinated PNAs, which are first in this class, when combined with other chemical modifications may have potential for future PNA-based antisense agents.
- Ellipilli, Satheesh,Ganesh, Krishna N.
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p. 9185 - 9191
(2015/09/28)
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- Prodrugs of neuraminidase inhibitors
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A new class of neuramidase inhibitor prodrugs is provided characterized by a prodrug moiety of a carboxyl group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide or a carbonyl ethoxy tripeptide, a guanidine group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, a carbonyl ethoxy tripeptide; a primary alcohol modified to form an esterified single amino acid, dipeptide or tripeptide of zanavimir of the unaltered therapeutic agent. Exemplary therapeutic agents so modified to form prodrugs include zanavimir, oseltamivir and peramivir. The prodrug has increased oral bioavailability relative to the unaltered neuraminidase inhibitor and is effective in the inhibition of viral infections involving neuraminidase in the viral reproductive cycle.
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Page/Page column 27; 28
(2015/12/01)
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- PYRIMIDONE DERIVATIVES AND THEIR USE IN THE TREATMENT, AMELIORATION OR PREVENTION OF A VIRAL DISEASE
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The present invention relates to a compound having the general formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which are useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.
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Paragraph 1044-1045
(2014/07/22)
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- Cu-promoted single-pot intramolecular esterification of C-3 functionalized azetidin-2-one: An efficient diastereoselective access to azido-/amino-aza- lactones
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A facile, single pot diastereoselective access to seven and eight membered aza-heterocycles was developed by using β-lactam-synthon approach. The developed protocol does not involve the typical intricacies viz. the use of expensive transition metal catalysts and high boiling solvents, associated with the convenient protocols.
- Kumar, Kewal,Kumar, Sumit,Singh, Tejinder,Anand, Amit,Kumar, Vipan
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p. 3957 - 3959
(2014/07/08)
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- NITROIMIDAZOLE COMPOUNDS AND THEIR USE IN CANCER THERAPY
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The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, formula (I) wherein m, n, X, Y and Z are as defined herein. Also provided are pharmaceutical compositions containing compounds of Formula (I), and methods of treating cancer and/or improving the response of tumors to radiotherapy by administering a compound of Formula (I) to a warm-blooded animal.
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Page/Page column 29; 30
(2014/03/25)
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- 2,3-DISUBSTITUTED 1 -ACYL-4-AMINO-1,2,3,4-TETRAHYDROQUINOLINE DERIVATIVES AND THEIR USE AS BROMODOMAIN INHIBITORS
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The present invention relates to novel compounds of formula (I), wherein R1 is C1-4alkyl; R2 is C1-4alkyl, C3-7cycloalkyl, -CH2CF3, -CH2OCH3 or heterocyclyl; R3 is C1-4alkyl, -CH2F, -CH2OH or -CH2O(O)CH3; R4 when present is as defined in claim 1; R5 when present is H, halo, hydroxy or C1-6alkoxy; A is -NH-, -O-, -S-, -SO-, -SO2-, -N(C1-4alkyl)- or -NC(O)(CH3)-; V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents; W is CH or N; X is C or N; Y is C or N; and Z is CH or N; subject to the proviso that no more than 2 of W, X, Y and Z are N, pharmaceutical compositions containing such compounds and to their use as bromodomain inhibitors.
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Page/Page column 185
(2014/09/29)
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- Selective derivatization of oxime-blocked tolylene-2,4-diisocyanate
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A selective reaction of cyclohexanone oxime-blocked tolylene-2,4- diisocyanate (2,4-TDI) with amino siloxane was observed, in which amines were capable of discriminating two reactive groups in the 2,4-TDI molecule. Thus, tolylene-2-tert-butyldimethylsilyloxyethyl carbamide-4-cyclohexanone oxime carbamate was synthesized and its precise structure was determined by single-crystal X-ray diffraction. Moreover, it was found that oxime-blocked isocyanate could react selectively with the NH2 group with the OH group unprotected in ethanolamine.
- Sang, Yang,Yang, Peng-Fei,Li, Tian-Duo
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p. 1019 - 1022
(2013/11/06)
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- SPIROHYDANTOIN COMPOUNDS AND THEIR USE AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
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The present invention relates to a compound of formula (1-1 ) in free form or in pharmaceutically acceptable salt form in which the substituents are as defined in the specification; to its preparation, to its use as a medicament and to medicaments comprising it. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
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Page/Page column 83
(2013/09/12)
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- Efficient synthesis and cell-based silencing activity of siRNAS that contain triazole backbone linkages
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An efficient synthesis of siRNAs modified at the backbone with a triazole functionality is reported. Through the use of 4,4×-dimethoxytrityl (DMT) phosphoramidite chemistry, triazole backbone dimmers were site-specifically incorporated throughout various siRNAs targeting both firefly luciferase and glyceraldehyde- 3-phosphate dehydrogenase (GAPDH) gene transcripts as representatives of an exogenous and endogenous gene, respectively. Following the successful silencing of the firefly luciferase reporter gene, triazole-modified siRNAs were also found to be capable of silencing GAPDH in a dose-dependent manner. Backbone modifications approaching the 3×-end on the sense strand were tolerated without compromising siRNA potency. This study highlights the compatibility of triazole-modified siRNAs within the RNAi pathway, and the modification's potential to impart favorable properties to siRNAs designed to target other endogenous genes.
- Efthymiou, Tim C.,Huynh, Vanthi,Oentoro, Jaymie,Peel, Brandon,Desaulniers, Jean-Paul
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supporting information; experimental part
p. 1722 - 1726
(2012/04/04)
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- Reductive cyclization of bromoenynamides with alcohols as hydride source: Synthesis and reactions of 2-amidodienes
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Under basic conditions in alcoholic solvents, bromoenynamides undergo palladium-catalyzed cyclization to cyclic 2-amidodienes in good to excellent yields. This process represents the first use of an alcohol as a hydride source in an alkyne carbopalladation/termination sequence, with the site selectivity of the reduction showing a strong dependence on the tethering ring size (5-8), and the nature of the alcohol and base. Reaction of the dienes with a range of dienophiles (including alkenes, alkynes and arynes) under various conditions gives bi- and tricyclic azacycles, which can be further oxidized to the aromatic azacycles. Copyright
- Greenaway, Rebecca L.,Campbell, Craig D.,Chapman, Helen A.,Anderson, Edward A.
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supporting information
p. 3187 - 3194
(2013/01/15)
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- BROMODOMAIN INHIBITORS AND USES THEREOF
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The present invention relates to compounds useful as inhibitors of bromodomain-containing proteins. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
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Page/Page column 149-150
(2012/11/14)
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- PYRIDO PYRIMIDINES
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Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of proliferative diseases, including cancer, Down syndrome or early onset Alzheimer's disease.
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Page/Page column 30
(2012/07/28)
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- Synthesis and properties of oligonucleotides that contain a triazole-linked nucleic acid dimer
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New chemically modified oligonucleotides at the site of the backbone are needed to improve the properties of oligonucleotides. A practical synthesis for a triazole-linked nucleoside dimer based on a PNA-like structure has been developed. This involves synthesizing two uracil-based monomers that contain either an azide or an alkyne functionality, followed by copper-catalyzed 1,3-dipolar cycloaddition. This dimer was incorporated within an oligonucleotide via phosphoramidite chemistry and UV-monitored thermal denaturation data illustrates slight destabilization relative to its target complementary sequence. This chemically modified dimer will allow for a future investigation of its properties within DNA and RNA-based applications.
- Efthymiou, Tim C.,Desaulniers, Jean-Paul
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experimental part
p. 533 - 539
(2011/08/03)
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- Target-selective photodegradation of oligosaccharides by a fullerene-boronic acid hybrid upon visible light irradiation
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A fullerene derivative was found to be capable of photodegrading oligosaccharides under irradiation with not only UV but also visible light. Furthermore, target-selective photodegradation of oligosaccharides (β-d-galactofuranosides) was achieved by a designed and synthesized fullerene-boronic acid hybrid upon irradiation with visible light in the absence of any additives under neutral conditions.
- Takahashi, Daisuke,Hirono, Shingo,Toshima, Kazunobu
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supporting information; experimental part
p. 11712 - 11714
(2011/12/15)
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- PROSTAGLANDIN TRANSPORTER INHIBITORS AND USES THEREOF
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Disclosed are compounds for inhibiting prostaglandin transporter (PGT) activity, pharmaceuticals compositions including the compounds, and methods of treating subjects using the compounds.
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Page/Page column 47
(2011/04/24)
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- Synthesis of indolequinones from bromoquinones and enamines mediated by Cu(OAc)2H2O
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A Cu(II)-mediated synthesis of indolequinones from the corresponding bromoquinones and enamines is reported. The key oxidative cyclization proceeds in good yield for a broad range of substrates and can be performed on a multigram scale, allowing access to biologically interesting structures.
- Inman, Martyn,Moody, Christopher J.
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supporting information; experimental part
p. 6023 - 6026
(2010/11/20)
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- FRICTIONLESS MOLECULAR ROTARY MOTORS
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A rotaxane consisting of a cucurbituril and an uncharged guest molecule, having low or null affinity therebetween is provided as well as processes for providing the same. Various uses as energy converters (“frictionless” molecular motors), biochips and biosensors using the same are also provided.
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Page/Page column 40
(2010/02/17)
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- Synthesis and evaluation of new spacers for use as dsDNA end-Caps
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A series of aliphatic and aromatic spacer molecules designed to cap the ends of DNA duplexes have been synthesized. The spacers were converted into dimethoxytrityl-protected phosphoramidites as synthons for oligonucleotides synthesis. The effect of the spacers on the stability of short DNA duplexes was assessed by melting temperature studies. End-caps containing amide groups were found to be less stabilizing than the hexaethylene glycol spacer. End-caps containing either a terthiophene or a naphthalene tetracarboxylic acid diimide were found to be significantly more stabilizing. The former showed a preference for stacking above an A·T base pair. Spacers containing only methylene (-CH2-) and amide (-CONH-) groups interact weakly with DNA and consequently may be optimal for applications that require minimal influence on DNA structure but require a way to hold the ends of double-stranded DNA together.
- Ng, Pei-Sze,Laing, Brian M.,Balasundarum, Ganesan,Pingle, Maneesh,Friedman, Alan,Bergstrom, Donald E.
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experimental part
p. 1545 - 1553
(2011/10/09)
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- PHOSPHONATED RIFAMYCINS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
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The present invention relates to phosphonated Rifamycins, and methods of making and using such compounds. These compounds are useful as antibiotics for prophylaxis and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
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Page/Page column 157
(2010/04/03)
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- 3-SUBSTITUTED-4-OXO-3,4-DIHYDRO-IMIDAZO-[5,1-D][1,2,3,5-TETRAZINE-8-CARBOXYLIC ACID AMIDES AND THEIR USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 3-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid amide (collectively referred to herein as 3TM compounds). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative disorders such as cancer, etc., and methods of preparing such compounds.
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Page/Page column 82
(2009/07/18)
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- Tethered thiazolidinone dimers as inhibitors of the bacterial type III secretion system
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Disruption of protein-protein interactions by small molecules is achievable but presents significant hurdles for effective compound design. In earlier work we identified a series of thiazolidinone inhibitors of the bacterial type III secretion system (T3SS) and demonstrated that this scaffold had the potential to be expanded into molecules with broad-spectrum anti-Gram negative activity. We now report on one series of thiazolidinone analogs in which the heterocycle is presented as a dimer at the termini of a series of linkers. Many of these dimers inhibited the T3SS-dependent secretion of a virulence protein at concentrations lower than that of the original monomeric compound identified in our screen.
- Kline, Toni,Barry, Kathleen C.,Jackson, Stona R.,Felise, Heather B.,Nguyen, Hai V.,Miller, Samuel I.
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supporting information; experimental part
p. 1340 - 1343
(2009/10/15)
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- Heterocyclic Compounds as MEK Inhibitors
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The present invention relates to compounds of formula I and pharmaceutically acceptable salts. These compounds can act as potential MEK inhibitors in the treatment of hyperproliferative diseases, like cancer and inflammation. The present invention also reveals methods of preparation thereof.
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Page/Page column 40-41
(2009/12/02)
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- SELECTIVE INHIBITORS FOR CYCLIN-DEPENDENT KINASES
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This invention provides a class of compounds which are useful for specifically inhibiting cyclin-dependent kinases. This class of compounds finds use in treating diseases resulting from inappropriate activity of cyclin-dependent kinases, including cancer, viral infections (e.g., HIV) neurodegenerative disorders (e.g. Alzheimer's disease), and cardiovascular disorders (e.g. atherosclerosis). Moreover, certain members of this class are particularly useful for inhibiting cyclin-dependent kinase 7 and are especially useful for the treatment of breast cancer.
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Page/Page column 132
(2009/01/24)
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- Palladium-catalyzed monoamination of dihalogenated benzenes
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The palladium-catalyzed monoamination of symmetric dibromobenzenes can be performed using a catalyst based on Pd2dba3 and BINAP in the presence of NaO(t-Bu). The analogous transformation of non-symmetric bromoiodobenzenes is most effectively performed with Xantphos as the ligand, while reactions with BINAP were non-selective. These transformations can be scaled uneventfully to >10 g quantities. They do not require drybox or Schlenk techniques, and all reagents are weighed out in air. The resulting monobromoanilines are versatile intermediates for further synthetic transformations.
- Larsen, Simon Birks?,Bang-Andersen, Benny,Johansen, Tommy N?rskov,J?rgensen, Morten
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p. 2938 - 2950
(2008/09/19)
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- Synthesis of β-lactam scaffolds for ditopic peptidomimetics
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(Chemical Equation Presented) Ring opening of α-substituted-α- methoxycarbonyl-N-nosylaziridines provides a practical access to enantiopure α,α′-disubstituted β-lactam scaffolds, novel types of ditopic reverse turn surrogates. The procedure is general, short, and high yielding and starts from handy α-substituted serinates and α-amino acid derivatives.
- Palomo, Claudio,Aizpurua, Jesus M.,Balentova, Eva,Jimenez, Azucena,Oyarbide, Joseba,Fratila, Raluca M.,Miranda, Jose Ignacio
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p. 101 - 104
(2007/10/03)
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- CETP INHIBITORS
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Compounds of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. I
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Page/Page column 47-48
(2008/06/13)
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