- Endcaps for stabilizing short DNA duplexes
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The syntheses of endcaps for covalently linking the 3′ and 5′ hydroxyl groups of blunt end double-stranded DNA are described. Endcap diols were converted into DMTr protected phosphoramidites and incorporated between nucleotides 4 and 5 of a self-complementary octamer. The stabilizing effect of the endcaps on duplex DNA was determined by Tm experiments on the self-complementary octamer.
- Ng, Pei-Sze,Pingle, Maneesh R.,Balasundarum, Ganesan,Friedman, Alan,Zu, Xiaolin,Bergstrom, Donald E.
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Read Online
- Highly Regioselective 5-endo-tet Cyclization of 3,4-Epoxy Amines into 3-Hydroxypyrrolidines Catalyzed by La(OTf)3
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Highly regioselective intramolecular aminolysis of 3,4-epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti-Baldwin 5-endo-tet cyclization. This reaction affords 3-hydroxy-2-alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide.
- Hoshino, Yoshihiko,Iwabuchi, Yoshiharu,Kuriyama, Yuse,Sasano, Yusuke,Uesugi, Shun-ichiro,Yamaichi, Aoto
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Read Online
- Probing the ligand preferences of the three types of bacterial pantothenate kinase
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Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4′-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of PanK.
- Guan, Jinming,Barnard, Leanne,Cresson, Jeanne,Hoegl, Annabelle,Chang, Justin H.,Strauss, Erick,Auclair, Karine
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Read Online
- METHODS OF TREATING CREATINE TRANSPORTER DEFICIENCY
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Disclosed are methods of treating creatine transporter deficiency, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound that increases transport of a substrate by a mutant or wild-type creatine transporter. Also disclosed are methods of increasing transport of guanidinoacetic acid or a salt thereof across the blood-brain barrier of a mammal, and methods of decreasing accumulation or the concentration of guanidinoacetic acid or a salt thereof in a mammalian cell.
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Paragraph 0387-0389
(2021/10/02)
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- SMALL MOLECULES TARGETING MUTANT MAMMALIAN PROTEINS
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Disclosed are compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with a mutation in a protein.
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Paragraph 0527-0528
(2021/12/03)
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- MUSCARINIC ACETYLCHOLINE M1 RECEPTOR ANTAGONISTS
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Provided herein, inter alia, are compounds which are useful as antagonists of the muscarinic acetylcholine receptor M1 (mAChR M1); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.
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Paragraph 0473-0474
(2021/04/17)
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- NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF
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The present invention relates to compounds of formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said compound of formula (I) comprises at least one covalently bound -ONO2 or -ONO moiety and at most four covalently bound -ONO2 or -ONO moieties, and wherein AR, R1, X, R3 and R4 are as defined in claim 1; and pharmaceutical compositions thereof, and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.
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Page/Page column 110
(2021/12/28)
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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 0507; 0512; 0513
(2020/05/14)
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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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- 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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- Metal-Free Oxidation of Primary Amines to Nitriles through Coupled Catalytic Cycles
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Synergism among several intertwined catalytic cycles allows for selective, room temperature oxidation of primary amines to the corresponding nitriles in 85-98 % isolated yield. This metal-free, scalable, operationally simple method employs a catalytic quantity of 4-acetamido-TEMPO (ACT; TEMPO=2,2,6,6-tetramethylpiperidine N-oxide) radical and the inexpensive, environmentally benign triple salt oxone as the terminal oxidant under mild conditions. Simple filtration of the reaction mixture through silica gel affords pure nitrile products.
- Lambert, Kyle M.,Bobbitt, James M.,Eldirany, Sherif A.,Kissane, Liam E.,Sheridan, Rose K.,Stempel, Zachary D.,Sternberg, Francis H.,Bailey, William F.
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supporting information
p. 5156 - 5159
(2016/04/09)
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- Chemo- and Site-Selective Alkyl and Aryl Azide Reductions with Heterogeneous Nanoparticle Catalysts
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Site-selective modification of bioactive natural products is an effective approach to generating new leads for drug discovery. Herein, we show that heterogeneous nanoparticle catalysts enable site-selective monoreduction of polyazide substrates for the generation of aminoglycoside antibiotic derivatives. The nanoparticle catalysts are highly chemoselective for reduction of alkyl and aryl azides under mild conditions and in the presence of a variety of easily reduced functional groups. High regioselectivity for monoazide reduction is shown to favor reduction of the least sterically hindered azide. We hypothesize that the observed selectivity is derived from the greater ability of less-hindered azide groups to interact with the surface of the nanoparticle catalyst. These results are complementary to previous Staudinger reduction methods that report a preference for selective reduction of electronically activated azides.
- Udumula, Venkatareddy,Nazari, S. Hadi,Burt, Scott R.,Alfindee, Madher N.,Michaelis, David J.
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p. 4423 - 4427
(2016/07/12)
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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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- HETEROCYCLIC-SUBSTITUTED PYRIDYL COMPOUNDS USEFUL AS KINASE INHIBITORS
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Compounds having the following formula: wherein A is, or; and X is N or C-R7, or an enantiomer, diastereomer or a pharmaceutically-acceptable salt thereof, are useful as kinase modulators, including IRAK-4 modulation.
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Paragraph 00329
(2013/07/25)
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- TRIAZOLYL-SUBSTITUTED PYRIDYL COMPOUNDS USEFUL AS KINASE INHIBITORS
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Compounds having the following formula:(I) wherein:A is an optionally substiuted triazole, or a stereoisomer or a pharmaceutically-acceptable salt thereof, are useful as kinase modulators, including IRAK-4 modulation.
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Paragraph 00328
(2013/07/25)
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- THIAZOLYL- OR THIADIAZOLYL-SUBSTITUTED PYRIDYL COMPOUNDS USEFUL AS KINASE INHIBITORS
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Compounds having the following formula (I) or an enantiomer, diastereomer or a pharmaceutically-acceptable salt thereof, wherein X is N or C-R7, are useful as kinase modulators, including IRAK-4 modulation.
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Paragraph 00330
(2013/07/25)
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- DNA-programmed Glaser-Eglinton reactions for the synthesis of conjugated molecular wires
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Wire self-assembly: Short oligo(phenylene ethynylene) modules (black structures, see picture) are assembled by attached DNA strands, which also direct the formation of 1,3-diyne linkages between the modules by the Cu-mediated Glaser-Eglinton reaction to selectively form dimer, trimer, and tetramer conjugated wires of up to 8 nm in length.
- Ravnsbaek, Jens B.,Jacobsen, Mikkel F.,Rosen, Christian B.,Voigt, Niels V.,Gothelf, Kurt V.
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supporting information; experimental part
p. 10851 - 10854
(2012/01/02)
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- Fully substituted carbon centers by diastereoselective spirocyclization: Stereoselective synthesis of (+)-lepadiformine C
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Reductive lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A1,3-strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.
- Perry, Matthew A.,Morin, Matthew D.,Slafer, Brian W.,Wolckenhauer, Scott A.,Rychnovsky, Scott D.
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supporting information; experimental part
p. 9591 - 9593
(2010/09/05)
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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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- NEW MACROLIDES USEFUL AGAINST INFLAMMATORY AND ALLERGIC DISSEASES
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Macrolide compounds of formula I: with PDF4 inhibiting activity are described, wherein R1 is a residue -Y-X-Q; Y is S, SO or SO2; X is a bond or a linear group consisting of hydrogen atoms and with up to 9 atoms selected from C, N, O and/or S,
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Page/Page column 52
(2008/06/13)
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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 133
(2009/01/24)
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- Synthesis of sultam scaffolds via intramolecular oxa-michael and diastereoselective baylis-hillman reactions
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(Chemical Equation Presented) A divergent synthetic approach to new sultams utilizing intramolecular oxa-Michael and Baylis-Hillman reactions of readily prepared vinyl sulfonamides and suitably protected amino alcohols, is reported. A variety of seven- an
- Zhou, Aihua,Hanson, Paul R.
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supporting information; scheme or table
p. 2951 - 2954
(2009/04/18)
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- A study of vinyl radical cyclization using N-alkenyl-7-bromo-substituted hexahydroindolinones
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(Chemical Equation Presented) A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecula
- Padwa, Albert,Rashatasakhon, Paitoon,Ozdemir, Ayse Daut,Willis, Jerremey
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p. 519 - 528
(2007/10/03)
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- Activation of silylphosphines by diethyl azodicarboxylate: Novel silylation of alcohols
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A novel activation mode of silylphosphines and an application of that to silylation of alcohols were described. Silylphosphines were found to be instantly activated by means of DEAD and PPTS to form reactive silyl cation equivalents. By using the activate
- Hayashi, Minoru,Matsuura, Yutaka,Watanabe, Yutaka
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p. 1409 - 1411
(2007/10/03)
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- Synthesis of hydroxy pyrrolidines and piperidines via free-radical cyclisations
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The tin hydride-mediated cyclisation of a variety of α- and β-amino aldehydes to form substituted pyrrolidines and piperidines under mild, neutral reaction conditions has been investigated. The amino aldehyde precursors, prepared from the corresponding amino ester or alcohol, are purified or immediately reacted with Bu3SnH-AIBN in boiling benzene. The method is shown to be general and cyclisation of the intermediate O-stannyl ketyl is observed using a variety of (electron poor or rich) acceptor carbon-carbon double bonds to afford hydroxy-pyrrolidines or -piperidines after work-up. Related cyclisations using an alkyne or α,β-unsaturated amide radical acceptor are shown to be problematic and low-yielding. Radical cyclisation of allylic O-stannyl ketyls, generated from reaction of α,β-unsaturated ketones with tin hydride, are also shown to have application in pyrrolidine/piperidine synthesis. A dilution study suggests that the cyclisation onto a cinnamyl double bond is irreversible.
- Parsons, Andrew F.,Pettifer, Robert M.
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p. 651 - 660
(2007/10/03)
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- Novel route to the synthesis of hydroxylated pyrrolidine derivatives via the intramolecular reaction of γ-aminoallylstannane with aldehyde. Total synthesis of (+)-preussin
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The thermal cyclization of γ-aminoallylstannane (8) having an aldehyde group gave β-hydroxypyrrolidine derivative (9a) as a sole product. This methodology was applied successfully to the total synthesis of (+)-preussin.
- Kadota, Isao,Saya, Shioko,Yamamoto, Yoshinori
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p. 335 - 348
(2007/10/03)
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- Synthesis of a Structural Analog of Ptilomycalin A
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Ptilomycalin A analog 2 was prepared by coupling amido alcohol 9 with guanidinium carboxylate 31.The synthesis of 2 requires 13 steps via a longest linear sequence from acrylate 22.
- Grillot, Anne-Laure,Hart, David J.
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p. 11377 - 11392
(2007/10/02)
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- GUANIDINIUM CARBOXYLATES: PREPARATION OF 3-CARBOXYOCTAHYDRO-9aH-PYRIMIDIN-9a-YLIUM CHLORIDE
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The title guanidinium carboxylate (2) was prepared from tert-butyl 2-bromomethylacrylate (3) using an 11-reaction sequence in 12percent overall yield.Sequential addition of two differentiated amino groups to the starting acrylate played a key role in the
- Grillot, Anne-Laure,Hart, David J.
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p. 435 - 438
(2007/10/02)
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- Convergent approach to tetracyclic [ABCE] intermediates in Aspidosperma alkaloids synthesis
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An efficient convergent synthesis of tetracyclic amidoalcohol 5, key intermediate in the synthesis of Aspidosperma alkaloids framework, starting from trans-hexahydrocarbazol-4-one 1 and substituted iodoacetamides 6 was achieved.
- Dufour,Gramain,Husson,Sinibaldi,Troin
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p. 189 - 200
(2007/10/02)
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