- Pd-Catalyzed ipso, meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C-H Activation Cascade with Dimethyl Carbonate as the Methyl Source
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A methyl group can have a profound impact on the pharmacological properties of organic molecules. Hence, developing methylation methods and methylating reagents is essential in medicinal chemistry. We report a palladium-catalyzed dimethylation reaction of ortho-substituted iodoarenes using dimethyl carbonate as a methyl source. In the presence of K2CO3 as a base, iodoarenes are dimethylated at the ipso- and meta-positions of the iodo group, which represents a novel strategy for meta-C-H methylation. With KOAc as the base, subsequent oxidative C(sp3)-H/C(sp3)-H coupling occurs; in this case, the overall transformation achieves triple C-H activation to form three new C-C bonds. These reactions allow expedient access to 2,6-dimethylated phenols, 2,3-dihydrobenzofurans, and indanes, which are ubiquitous structural motifs and essential synthetic intermediates of biologically and pharmacologically active compounds.
- Wu, Zhuo,Wei, Feng,Wan, Bin,Zhang, Yanghui
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supporting information
p. 4524 - 4530
(2021/05/04)
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- MUSCARINIC ACETYLCHOLINE RECEPTOR SUBTYPE 4 ANTAGONISTS IN THE TREATMENT OF ANEMIA
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This disclosure generally relates to treating anemias. More specifically, the disclosure relates to use of muscarinic acetylcholine receptor subtype 4 antagonists, such as small molecule compounds, to promote self-renewal of burst forming unit erythroid (BFU-E) cells and treat anemias.
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Paragraph 00153-00154
(2020/10/20)
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- PYRROLOBENZODIAZEPINE PRODRUGS AND ANTIBODY CONJUGATES THEREOF
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The invention relates generally to pyrrolobenzodiazepine monomer and dimer prodrugs having a glutathione-activated disulfide prodrug moiety, a DT-diaphorase-activated quinone prodrug moiety or a reactive oxygen species-activated aryl boronic acid or aryl boronic ester prodrug moiety. The invention further relates to pyrrolobenzodiazepine prodrug dimer-antibody conjugates.
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- Palladium-catalyzed amination and amidation of benzo-fused bromine-containing heterocycles
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Amination and amidation of bromoindole, 6-bromo-1,2,3,4-tetrahydrocarbazol- 1-one, and 8-bromo-2,4,5,6-tetrahydro-1H-pyrazino[3,2,1-jk]carbazole derivatives was effected in the presence of palladium complexes. The use of the catalytic system Pd2dba3·CHCl3-2-[di(tert-butyl) phosphino]biphenyl in the amination and of Pd2dba3· CHCl3-Xantphos [or 3,5-(CF3)2Xantphos] in the amidation ensured moderate to high yields of the corresponding products.
- Sergeev,Artamkina,Velezheva,Fedorova,Beletskaya
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p. 860 - 874
(2007/10/03)
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- 1H NMR studies on the reductively triggered release of heterocyclic and steroid drugs from 4,7-dioxoindole-3-methyl prodrugs
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Hypoxia is a feature of several disease states, including cancer and rheumatoid arthritis. Prodrug systems which, after bioreduction, selectively release active drugs in these tissues may be important in therapy. An improved preparation of 1,2-dimethyl-3-hydroxymethyl-5-methoxyindole-4,7-dione was developed. Mitsunobu coupling with (5-substituted) isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) gave 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and N-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethyl)isoquinolin-1-ones. Similar coupling with the anticancer drug pentamethylmelamine gave its potential prodrug 1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N- methylaminomethyl)-5-methoxyindole-4,7-dione. Treatment of sodium prednisolone hemisuccinate with 3-chloromethyl-1,2-dimethyl-5-methoxyindole-4,7-dione gave an analogous candidate prodrug of the anti-inflammatory drug prednisolone. In a chemical model system for bioreduction, SnCl2 in CDCl3/CD3OD triggered rapid stoichiometric release of isoquinolin-1-ones from the O-linked prodrugs but not from the N-linked analogues. Use of this system allowed the release process to be monitored in situ by 1H NMR spectroscopy. Diethyl hydrazine-1,2-dicarboxylate was found to reduce SnIV to SnII, making the overall reductive release catalytic in tin. The reduced (hydroquinone) prodrug may have a short lifetime under these reductive conditions, meaning that only good leaving groups are expelled. Thus 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and analogues may be useful as reductively triggered prodrugs.
- Ferrer, Sandra,Naughton, Declan P.,Threadgill, Michael D.
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p. 3445 - 3454
(2007/10/03)
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- Indolequinone antitumor agents: Reductive activation and elimination from (5-methoxy-1-methyl-4,7-dioxoindol-3-yl)methyl derivatives and hypoxia- selective cytotoxicity in vitro
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A series of indolequinones bearing a variety of leaving groups at the (indol-3-yl)methyl position was synthesized by functionalization of the corresponding 3-(hydroxymethyl)indolequinone, and the resulting compounds were evaluated in vitro as bioreductively activated cytotoxins. The elimination of a range of functional groups-carboxylate, phenol, and thiol- was demonstrated upon reductive activation under both chemical and quantitative radiolytic conditions. Only those compounds which eliminated such groups under both sets of conditions exhibited significant hypoxia selectivity, with anoxic:oxic toxicity ratios in the range 10-200. With the exception of the 3-hydroxymethyl derivative, radiolytic generation of semiquinone radicals and HPLC analysis indicated that efficient elimination of the leaving group occurred following one-electron reduction of the parent compound. The active species in leaving group elimination was predominantly the hydroquinone rather than the semiquinone radical. The resulting iminium derivative acted as an alkylating agent and was efficiently trapped by added thiol following chemical reduction and by either water or 2-propanol following radiolytic reduction. A chain reaction in the radical-initiated reduction of these indolequinones (not seen in a simpler benzoquinone) in the presence of a hydrogen donor (2-propanol) was observed. Compounds that were unsubstituted at C-2 were found to be up to 300 times more potent as cytotoxins than their 2-alkyl-substituted analogues in V79-379A cells, but with lower hypoxic cytotoxicity ratios.
- Naylor, Matthew A.,Swann, Elizabeth,Everett, Steven A.,Jaffar, Mohammed,Nolan, John,Robertson, Naomi,Lockyer, Stacey D.,Patel, Kantilal B.,Dennis, Madeleine F.,Stratford, Michael R. L.,Wardman, Peter,Adams, Gerald E.,Moody, Christopher J.,Stratford, Ian J.
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p. 2720 - 2731
(2007/10/03)
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- A SIMPLE SYNTHESIS OF 2-VINILINDOLES
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A two step synthesis of 2-vinyl indoles is described.Reaction of the anions of 2-methylindole-3-carboxylates (1) and (5) with ketones and aldehydes leads directly to 2-vinylindole-3-carboxylic acids (3) and esters (7), respectively.Decarboxylation of the acids (3) yields the desired 2-vinylindoles (4).
- Macor, John E.,Newman, Michael E.,Ryan, Kevin
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p. 2509 - 2512
(2007/10/02)
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- Synthesis of Pyranoindoles as Conformationally Restricted Analogues of the Serotonin Antagonist ICS 205-930 and as Precursors to 2-Vinylindoles
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A useful synthesis of some pyranoindoles is described that allows access to conformationally restricted analogues of the serotonin (5HT3) antagonist, ICS 205-930.These pyranoindoles can be converted in one step to 2-vinylindole derivatives.
- Macor, John E.,Ryan, Kevin,Newman, Michael E.
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p. 4785 - 4795
(2007/10/02)
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- An Application of the Nenitszescu Reaction to the Synthesis of 1,2-Annulated Indoles and Benzindoles
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The Nenitszescu reaction has been investigated as a means of preparing several indoles, benzindoles and 1,2-annulated indoles (5), (9), (13), (17) and (18) and a number of their derivatives.Reactions between benzoquinone and enaminones to form Michael
- Parr, Rodney W.,Reiss, James A.
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p. 1263 - 1270
(2007/10/02)
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