- Endohedral Hydrogen Bonding Templates the Formation of a Highly Strained Covalent Organic Cage Compound**
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A highly strained covalent organic cage compound was synthesized from hexahydroxy tribenzotriquinacene (TBTQ) and a meta-terphenyl-based diboronic acid with an additional benzoic acid substituent in 2’-position. Usually, a 120° bite angle in the unsubstituted ditopic linker favors the formation of a [4+6] cage assembly. Here, the introduction of the benzoic acid group is shown to lead to a perfectly preorganized circular hydrogen-bonding array in the cavity of a trigonal-bipyramidal [2+3] cage, which energetically overcompensates the additional strain energy caused by the larger mismatch in bite angles for the smaller assembly. The strained cage compound was analyzed by mass spectrometry and 1H, 13C and DOSY NMR spectroscopy. DFT calculations revealed the energetic contribution of the hydrogen-bonding template to the cage stability. Furthermore, molecular dynamics simulations on early intermediates indicate an additional kinetic effect, as hydrogen bonding also preorganizes and rigidifies small oligomers to facilitate the exclusive formation of smaller and more strained macrocycles and cages.
- Sch?fer, Natalie,Bühler, Michael,Heyer, Lisa,R?hr, Merle I. S.,Beuerle, Florian
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supporting information
p. 6077 - 6085
(2021/03/15)
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- Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation
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Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition.
- Saraswati, A. Prasanth,Relitti, Nicola,Brindisi, Margherita,Osko, Jeremy D.,Chemi, Giulia,Federico, Stefano,Grillo, Alessandro,Brogi, Simone,McCabe, Niamh H.,Turkington, Richard C.,Ibrahim, Ola,O'Sullivan, Jeffrey,Lamponi, Stefania,Ghanim, Magda,Kelly, Vincent P.,Zisterer, Daniela,Amet, Rebecca,Hannon Barroeta, Patricia,Vanni, Francesca,Ulivieri, Cristina,Herp, Daniel,Sarno, Federica,Di Costanzo, Antonella,Saccoccia, Fulvio,Ruberti, Giovina,Jung, Manfred,Altucci, Lucia,Gemma, Sandra,Butini, Stefania,Christianson, David W.,Campiani, Giuseppe
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supporting information
p. 2268 - 2276
(2020/12/17)
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- BIARYL COMPOUND, PREPARATION METHOD AND USE THEREFOR
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The present invention belongs to the technical field of chemical pharmaceuticals, and relates to a compound represented by general formula (I) or formula (II) and a preparation method thereof. The compounds are biaryl derivatives with RORγt activation activity. The biaryl derivatives disclosed in this invention can effectively activate the RORγt protein receptor, and thereby promote the differentiation of Th17 cells and increasing the production of IL-17, which can be used as an immune modulator for the treatment of various cancers or viral infection-related diseases.
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Paragraph 0127-0128
(2020/01/02)
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- Isoflavone amide type derivative, preparation method and medical application thereof
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The invention relates to the field of medicinal chemistry, and relates to an isoflavone amide type derivative, a preparation method and a medical application thereof, in particular to an isoflavone amide type derivative with the general formula (I), a preparation method thereof, medicine compositions including the isoflavone amide type derivative and a medical application thereof, especially an application of the isoflavone amide type derivative as a medicine for preventing or curing hyperlipemia, obesity or type II diabetes. The general formula (I) is shown in the description.
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Paragraph 0015; 0059; 0060; 0061
(2016/10/10)
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- A suitable industrial production pula Qu Sha method for the preparation of
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The invention relates to the field of pharmaceutical chemistry technology, and more specifically relates to an anticarcinogen 10-Propargyl-10-deazaaminopterin (Pralatrexate) and synthesis of an intermediate thereof. The invention has the advantages of simple operation, low contents of related impurities, easiness in purification of intermediate, thereby avoiding purification mode of column chromatography, and the invention can be applied to large scale production of Pralatrexate bulk drug as well as preparation and purification method of important intermediates.
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Paragraph 0037-0038
(2017/01/23)
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- Synthesis of Ketones and Esters from Heteroatom-Functionalized Alkenes by Cobalt-Mediated Hydrogen Atom Transfer
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Cobalt bis(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates and provides a mild and practical alternative to the Tamao-Fleming oxidation of vinylsilanes and the Arndt-Eistert homologation.
- Ma, Xiaoshen,Herzon, Seth B.
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p. 8673 - 8695
(2016/10/17)
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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 52; 53
(2015/07/15)
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- Upgrading malic acid to bio-based benzoates via a Diels-Alder-initiated sequence with the methyl coumalate platform
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The conversion of naturally-occurring malic acid to the 2-pyrone methyl coumalate was optimized using a variety of acid catalysts. Coupling methyl coumalate with electron-rich dienophiles in an inverse electron-demand Diels-Alder (IEDDA)/decarboxylation/elimination domino sequence resulted in an investigation of the scope and limitations of the methodology. The thermal, metal-free, and one-pot procedure allows regioselective access to diverse aromatic compounds including tricyclic, biphenyl, and pyridinyl systems for elaboration. A comparison with analogous pyrones demonstrates the striking efficacy of methyl coumalate as a versatile platform for the generation of biorenewable functionalized benzoates. This journal is
- Lee, Jennifer J.,Pollock Iii, Gerald R.,Mitchell, Donald,Kasuga, Lindsay,Kraus, George A.
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p. 45657 - 45664
(2015/02/19)
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- Rhodium-catalyzed oxygenative addition to terminal alkynes for the synthesis of esters, amides, and carboxylic acids
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A gem of a couple: The title reaction of terminal alkynes with O and Nnucleophiles proceeds in the presence of [Rh(cod)Cl}2], P(4-FC 6H4)3, and 4-picoline N-oxide. Alcohols, amines, and water add to the terminal alkynes to give esters, amides, and carboxylic acids, respectively. The reaction involves formation of a rhodium vinylidene, oxidation to a ketene by oxygen transfer, and nucleophilic addition.
- Kim, Insu,Lee, Chulbom
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supporting information
p. 10023 - 10026
(2013/10/01)
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- Paracyclophanes: Extending the bridges. Synthesis
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Preparatively satisfactory routes to [3.2]paracyclophane (10), [4.2]paracyclophane (14), [4.3]paracyclophane (19) as well as several derivatives of these compounds - among others the bromides 25, the ester 31, the diesters 40-43 - are described using well-established methods of cyclophane chemistry (ring-closure reactions leading to thiacyclophanes, ring contraction by sulfone pyrolysis). The parent systems and their derivatives are now available in gram quantities allowing a study of their chemical properties. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.
- Pechlivanidis, Zissis,Hopf, Henning,Ernst, Ludger
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experimental part
p. 223 - 237
(2009/06/21)
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- AMINOALKYLAZOLE DERIVATIVES AS HISTAMINE-3 ANTAGONISTS
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The present invention provides a compound of formula I: and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
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Page/Page column 26-27
(2009/02/11)
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- N-substituted-azacyclylamines as histamine-3 antagonists
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The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
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Page/Page column 31
(2010/11/28)
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- Ni-catalyzed activation of α-chloroesters: a simple method for the synthesis of α-arylesters and β-hydroxyesters
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Coupling reactions of α-chloroesters with aryl halides (α-arylation) or carbonyl compounds (Reformatsky) using nickel catalyst allow, under mild conditions, the preparation of various functionalized aryl propionic acid derivatives or β-hydroxyesters. In the synthesis of aryl propionic acid derivatives, the process is efficient with aryl halides bearing either electron-withdrawing or electron-donating groups.
- Durandetti, Muriel,Gosmini, Corinne,Périchon, Jacques
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p. 1146 - 1153
(2007/10/03)
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- Synthesis of esters by selective methanolysis of the trifluoromethyl group
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The trifluoromethyl group of certain compounds containing one or two trifluoromethyl groups can be converted to the carbomethoxy group by treatment with sodium methoxide followed by aqueous acidic work-up. α-Trifluoromethyl esters can be obtained by selective methanolysis of the 1,1,1,3,3,3-hexafluoroisopropyl group in some cases. The structural requirements for the transformation are delineated, and a mechanistic study confirms the proposed mechanism, a dehydrofluorination-addition-elimination process.
- Ramig, Keith,Englander, Miriam,Kallashi, Florida,Livchits, Lilia,Zhou, Jessica
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p. 7731 - 7734
(2007/10/03)
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- Heteroaromatic glucokinase activators
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2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 2-position being a substituted phenyl group and at the 3-position being a cycloalkyl ring, said propionamides being glucokinase activators which increase insulin secretion in the treatment of type II diabetes.
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- A simple method for the preparation of monomethyl esters of dicarboxylic acids by selective esterification of the nonconjugated carboxyl group in the presence of an aromatic or conjugated carboxyl group
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Various dicarboxylic acids have been converted selectively into monomethyl esters in which the nonconjugated carboxyl group is selectively esterified in the presence of an aromatic or conjugated carboxyl group at room temperature (~ 25-27°C) in methanol using a catalytic amount of thionyl chloride.
- Ram, Ram N.,Meher, Nabin Kumar
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p. 282 - 283
(2007/10/03)
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- Repaglinide and related hypoglycemic benzoic acid derivatives
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The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
- Grell, Wolfgang,Hurnaus, Rudolf
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p. 5219 - 5246
(2007/10/03)
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- Selective esterification of aliphatic nonconjugated carboxylic acids in the presence of aromatic or conjugated carboxylic acids catalysed by NiCl2.6H2O
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Unhindered aliphatic nonconjugated carboxylic acids were esterified selectively in the presence of aromatic or conjugated acids on heating in the corresponding alcoholic solutions at reflux for 3-13 hr with 10 mol% of NiCl2.6H2O catalyst.
- Ram, Ram N.,Charles
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p. 7335 - 7340
(2007/10/03)
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- Analogues of methotrexate in rheumatoid arthritis. 2. Effects of 5- deazaaminopterin, 5,10-dideazaaminopterin, and analogues on type II collagen- induced arthritis in mice
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Twenty-six compounds derived from the 5-deaza- and 5,10- dideazaaminopterin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-deaza series were prepared by alkylation of an appropriate N- substituted (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2- thenoyl)-L-glutamate diester with a 2,4-diamino-5-alkyl-6-(bromomethyl)-5- deazapteridine. The resultant 5-deazaaminopterin diesters were saponified to provide the target 5-deaza analogues. 5,10-Dideazaaminopterins were synthesized by similar alkylation of the carbanions of appropriate 4- carboxyphenylacetic, (5-carboxy-2-thienyl)acetic, or (5-carboxy-2- pyridyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4- deoxy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponified and then readily decarboxylated by heating in Me2SO solution to provide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Peptide coupling with diethyl L-glutamate followed by ester hydrolysis at room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position were generally quite effective as antiinflammatory agents. Thus 5-propyl-5-deazaaminopterin, 5-methyl-10- propargyl-5-deazaaminopterin, 5-methyl-10-allyl-5-deazaaminopterin, 5-ethyl- 5-deazamethotrexate, and 2,5-disubstituted thiophene analogue of 5-methyl-5- deazaaminopterin showed potencies greater than methotrexate by intraperitoneal or oral administration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideazaaminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C-10 was generally detrimental to antiinflammatory activity in this series.
- Piper, James R.,DeGraw, Joseph I.,Colwell, William T.,Johnson, Cheryl A.,Smith, R. Lane,Waud, William R.,Sirotnak, Francis M.
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p. 377 - 384
(2007/10/03)
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- THE REGULATING ACTION OF HYDROGEN CHLORIDE ON THE ACETYLATION AND FORMYLATION OF TRIPTYCENE AND ACYLTRIPTYCENES
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Hydrogen chloride has an appreciable effect on the reactivity of acyltriptycenes in acetylation and formylation reactions.Either activation or passivation of the triptycene is observed, depending on the amount of hydrogen chloride.By studying the relationships governing this effect it was possible to improve the procedures for the synthesis of triacyl- and triformyltriptycenes significantly.
- Sereda, G. A.,Skvarchenko, V. R.
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p. 442 - 444
(2007/10/02)
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- CARBONYLATION OF p-HALOGENOBENZYL CYANIDES IN THE PRESENCE OF COBALT OCTACARBONYL. TEST FOR RADICAL-ANION MECHANISM
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In the reaction of p-halogenobenzyl cyanides with sodium thiophenolate under the conditions of an SRN1 reaction the intermediately formed radical-anion undergoes fragmentation in two concurrent directions, i.e., with elimination of the cyanide ion and with elimination of the halide ion.The presence of the two fragmentation paths was used as evidence for the radical-anion nature of the intermediates in the carbonylation of aryl halides.
- Dneprovskii, A. S.,Tuchkin, A. I.
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p. 435 - 441
(2007/10/02)
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- Use of Phosphorus Pentoxide. Preparation of Half-esters through Selective Esterification
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Methyl 2-,3-,4-carboxyphenylacetate and methyl 2-,3-,4-carboxyphenoxyacetate have been prepared through selective esterification of the aliphatic carboxylic acid function of the corresponding dicarboxylic acids using a mixture of phosphorus pentoxide (1 part), anhydrous copper sulphate (5 parts) and anhydrous sodium sulphate (5 parts).All the isomeric half-esters have been prepared through partial hydrolysis of the corresponding dimethylesters.
- Banerjee, Amalendu,Adak, Mohini Mohan,Das, Sankar,Banerjee, Santa,Sengupta, Saumitra
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