- HDAC DEGRADER
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The disclosure provides compounds of formula (I). The compounds may be used to degrade the Histone Deacetylase (HDAC) family of enzymes, particularly HDAC1, 2 and 3 that exist in corepressor complexes. Accordingly, the compounds may
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Page/Page column 37-38; 46
(2021/07/31)
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- BIVALENT TARGETED CONJUGATES
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The invention provides conjugates that comprise a bivalent targeting moiety, a nucleic acid, and optional linking groups as well as synthetic intermediates and synthetic methods useful for preparing the conjugates, compositions comprising the bidentate targeting ligands and the conjugates, as well as methods for targeting therapeutic nucleic acids with the bidentate conjugates. The conjugates are useful to target therapeutic nucleic acids.
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Page/Page column 67; 70
(2020/05/28)
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- THERAPEUTIC METHODS
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The invention provides methods and compositions for delivering a nucleic acid to a cell or the cytosol of the target cell. The method includes contacting the cell with, 1) a membrane-destabilizing polymer; and 2) a nucleic acid conjugate. The nucleic acid conjugate includes a targeting ligand bound to an optional linker and a nucleic acid.
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Page/Page column 204; 239; 241
(2020/05/28)
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- PROTAC-mediated degradation of class i histone deacetylase enzymes in corepressor complexes
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We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition.
- Adams, Grace E.,Cowley, Shaun Michael,Hodgkinson, James T.,Millard, Christopher J.,Norris, James K. S.,Schwabe, John W. R.,Smalley, Joshua P.,Song, Yun
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supporting information
p. 4476 - 4479
(2020/05/13)
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- TRITERPENE SAPONIN SYNTHESIS, INTERMEDIATES AND ADJUVANT COMBINATIONS
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The present application relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, and intermediates thereto. The application also provides pharmaceutical compositions comprising compounds of the present invention and methods of using said compounds or compositions in the treatment of and immunization for infectious diseases.
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Page/Page column 82; 100; 101
(2018/11/10)
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- BOLAAMPHIPHILIC COMPOUNDS, COMPOSITIONS AND USES THEREOF
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Bolaamphiphilic compounds are provided according to formula (I): where HG1, HG2 and L1 are as defined herein. Provided bolaamphilphilic compounds and the pharmaceutical compositions thereof are useful for delivering HIV active drugs into animal or human brain.
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Paragraph 00269; 00270
(2014/03/26)
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- Improved Syntheses of Benzyl Hydraphile Synthetic Cation-Conducting Channels
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The tris(macrocycle)s that function in bilayer membranes as ion channels have recently shown versatile new applications such as antibiotic synergists and as agents for direct injection chemotherapy. This report records the development of new and versatile approaches to these molecules that produce significantly better overall yields for a group of previously reported hydraphiles having spacer chains ranging from octylene to hexadecylene.
- Curvey, Nichole S.,Luderer, Sarah E.,Walker, John K.,Gokel, George W.
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p. 2771 - 2779
(2015/02/19)
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- Synthesis of fluorescent carboxylic acid ligands for construction of monolayers on nanostructures
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Two new long-chain carboxylic acids (1, 2) bearing strong fluorescent group pyrene as ligands for Self-Assembled Monolayers (SAMs) have been synthesized. The multistep targeted synthesis is accomplished by use of Pyren-1-yl methylamine hydrochloride and employing simplified synthetic protocols. Compound 2 contains a chiral center purposely introduced along the atom chain in order to make it suitable for chiro-optical studies of the resulting SAMs.
- Jadhav, Sushilkumar A.
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p. 1640 - 1646,7
(2020/09/09)
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- Synthesis, characterization, and in vitro transfection activity of charge-reversal amphiphiles for DNA delivery
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A series of charge-reversal lipids were synthesized that possess varying chain lengths and end functionalities. These lipids were designed to bind and then release DNA based on a change in electrostatic interaction with DNA. Specifically, a cleavable ester linkage is located at the ends of the hydrocarbon chains. The DNA release from the amphiphile was tuned by altering the length and position of the ester linkage in the hydrophobic chains of the lipids through the preparation of five new amphiphiles. The amphiphiles and corresponding lipoplexes were characterized by DSC, TEM, and X-ray, as well as evaluated for DNA binding and DNA transfection. For one specific charge-reversal lipid, stable lipoplexes of approximately 550 nm were formed, and with this amphiphile, effective in vitro DNA transfection activities was observed.
- Zhang, Xiao-Xiang,Prata, Carla A. H.,Berlin, Jason A.,McIntosh, Thomas J.,Barthelemy, Philippe,Grinstaff, Mark W.
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body text
p. 690 - 699
(2012/02/16)
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- Molecules for Gene Delivery and Gene Therapy, and Methods of Use Thereof
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One aspect of the present invention relates to a synthetic non-viral vector composition for gene therapy. Another aspect of the invention relates to the use of the composition for in vitro, ex vivo and/or in vivo transfer of genetic material. The invention also encompasses a pharmaceutical composition (useful for delivery of nucleic acids to a cell), containing a non-cationic amphiphilic molecule or macro-molecule; or a cationic amphiphilic molecule or macromolecule that transforms from a cationic entity to an anionic, neutral, or zwitterionic entity upon a chemical, photochemical, or biological reaction. Another aspect of the invention relates to multicationic compounds that are composed of three or more amino acids. The present invention also relates to the use of the pharmaceutical composition for delivery of nucleic acids to a cell. Moreover, the invention encompasses the non-viral vector compositions tethered to a surface. The surface-tethered compositions are useful for the delivery of nucleic acids to cells in contact with the surface. An additional embodiment of the invention relates to a hydrogel comprising a composition of the invention, and methods of using same for the delivery of genetic material to a cell.
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- A new helper phospholipid for gene delivery
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Enhanced gene transfection activity is observed when using a new helper lipid with DOTAP, compared to DOPE. The Royal Society of Chemistry.
- Prata, Carla A. H.,Li, Yougen,Luo, Dan,McIntosh, Thomas J.,Barthelemy, Philippe,Grinstaff, Mark W.
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p. 1566 - 1568
(2008/12/23)
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- Heterocyclic amide hydraphile synthetic cation transporters
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A family of hydraphile ionophores has been prepared in which various ~CH2N~ to ~CON~ replacements have been made to assess the effect on Na+ transport through phospholipid bilayers. When the central relay (see graphical abstract) was
- Wang, Wei,Yamnitz, Carl R.,Gokel, George W.
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experimental part
p. 825 - 839
(2009/09/08)
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- Process for production of pentahydroxyhexylcarbamoyl alkanoic acids
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The present invention relates to improved processes for the production of compounds of formula I:
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Page/Page column 10
(2008/06/13)
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- Functional synthetic molecules and macromolecules for gene delivery
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The present invention describes a synthetic non-viral vector composition for gene therapy and the use of such compositions for in vitro, ex vivo and/or in vivo transfer of genetic material. The invention proposes a pharmaceutical composition containing 1) a non-cationic amphiphilic molecule or macromolecule and its use for delivery of nucleic acids or 2) a cationic amphiphilic molecule or macromolecule that transforms from a cationic entity to an anionic, neutral, or zwitterionic entity by a chemical, photochemical, or biological reaction and its use for delivery of nucleic acids. Moreover this invention describes the use of these non-viral vector compositions in conjunction with a surface to mediate the delivery of nucleic acids. An additional embodiment is the formation of a hydrogel with these compositions and the use of this hydrogel for the delivery of genetic material. A further embodiment of this invention is the use of a change in ionic strength for the delivery of genetic material.
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Page/Page column 58-59
(2008/06/13)
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- Charge-reversal amphiphiles for gene delivery
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Delivering a missing gene or a functional substitute of a defective gene has the potential to revolutionize current medical care. Of the two gene delivery approaches, viral and synthetic vectors, synthetic cationic vectors possess several practical advant
- Prata, Carla A. H.,Zhao, Yuxing,Barthelemy, Philippe,Li, Yougen,Luo, Dan,McIntosh, Thomas J.,Lee, Stephen J.,Grinstaff, Mark W.
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p. 12196 - 12197
(2007/10/03)
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- Syntheses of Phospholipids Containing 2-Nitrobenzyl Ester Moieties at the Terminals of Alkyl Chains and Properties of Photodegradable Liposomes from the Lipids
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Phospholipid 1a bearing 2-nitrobenzyl ester moieties as a photocleavable group at the terminal of alkyl chains was synthesized from the corresponding terminal carboxy-bearing phospholipid 2 by the reaction with 2-nitrophenyl-substituted diazomethane. Phospholipid, 1b bearing α-methyl-2-nitrobenzyl group, 1c bearing 4,5-dimethoxy-2-nitrobenzyl group, and 1d bearing α-methyl-4,5-dimethoxy-2-nitrobenzyl group were similarly synthesized by the use of the respective diazo compounds. The order of photolysis rates of 2-nitrobenzyl ester linkage of phospholipids by ultrahigh-pressure mercury lamp is 1b≥1d > 1a > 1c. Liposomes of 1a-1d containing calcein in the inner aqueous layer were prepared by vortexing, sonication, and gel-filtration. UV irradiation resulted in fast release of the entrapped fluorescence dye. The order of release rates : 1b≥1d > 1c> 1a is consistent with that of photolysis rates except for 1c, which has poor retention of the dye.
- Yamaguchi, Kazuo,Tsuda, Yoshihiro,Shimakage, Taka-Aki,Kusumi, Akihiro
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p. 1923 - 1929
(2007/10/03)
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- Indole derivatives useful as testosterone 5α-reductase inhibitors
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A compound of the formula (I): STR1 wherein R 1 is an optionally protected carboxy(lower)alkyl, R 2 is a hydrogen, an optionally substituted aryl or a carboxy,X is a bond, --0--, --NH-- or a cycloalkylene, andY is an alkylene which may be interrupted by an oxygen atom, an alkenylene or an alkadienylene,or a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a testosterone 5α-reductase inhibitor and effective against testosterone 5α-reductase-mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism), androgenic alopecia (or male-pattern baldness), acne (e.g. acne vulgaris, pimple), and other hyperandrogenisms.
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- SELECTIVE MONOETHERIFICATION AND MONOESTERIFICATION OF DIOLS AND DIACIDS UNDER PHASE-TRANSFER CONDITIONS
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Research on the selectivity of etherification reactions of diols and esterification reactions of diacids by alkyl halides under phase-transfer catalysis has shown that under such conditions, selectivity of monoetherification increases in the order prim sec tert diols, though overall yield of monoether decreases from sec to tert diols.Monoesterification of diacids was accomplished with a high degree of selectivity.Optimal extraction of diols and diacids was found to correspond in general to chain lengths of around 5 carbons.This could mean that the complex formed between the catalyst and the anion to react is stabilized for certain carbon lengths by inner solvation in virtue of its spatial conformation.
- Zerda, Jaime de la,Barak, Gabriela,Sasson, Yoel
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p. 1533 - 1536
(2007/10/02)
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