- Design, synthesis, and preliminary bioactivity evaluation of N1-hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors
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Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1-hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50?=?0.074?μm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC50?=?0.131?μm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.
- Wang, Xue,Li, Xiaoyang,Li, Jingyao,Hou, Jinning,Qu, Ying,Yu, Chenggong,He, Feng,Xu, Wenfang,Wu, Jingde
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- Cyclotryptophan Mycotoxins: Short Synthesis of the Desymmetrized meso -Chimonantine Core of Leptosin C
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The desymmetrized meso-chimonantine core of leptosin C was prepared in a short stereoselective convergent sequence in 5 steps as the longest linear path from methyl l-tryptophan hydrochloride as starting material. The key step of this approach was a diastereoselective [4+2] cycloaddition between the bromooxindole and tryptophan derivatives allowing to define the adjacent quaternary benzylic centers in a high chemical yield.
- Olaizola, Iurre,Abdine, Racha Abed Ali,Dhimane, Hamid,Dalko, Peter I.
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p. 391 - 396
(2016/12/24)
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- Direct C?H Phosphonylation of Electron-Rich Arenes and Heteroarenes by Visible-Light Photoredox Catalysis
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The direct transformation of ubiquitous, but chemically inert C?H bonds into diverse functional groups is an important strategy in organic synthesis that improves the atom economy and faclitates the preparation and modification of complex molecules. In contrast to the wide applications of aryl phosphonates, their synthesis via direct C?H bond phosphonylation is a less explored area. We report here a general, mild, and broadly applicable visible-light photoredox C?H bond phosphonylation method for electron-rich arenes and heteroarenes. The photoredox catalytic protocol utilizes electron-rich arenes and biologically important heteroarenes as substrates, [Ru(bpz)3][PF6]2 as photocatalyst, ammonium persulfate as oxidant, and trialkyl phosphites as the phosphorus source to provide a wide range of aryl phosphonates at ambient temperature under very mild reaction conditions.
- Shaikh, Rizwan S.,Ghosh, Indrajit,K?nig, Burkhard
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supporting information
p. 12120 - 12124
(2017/09/13)
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- Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases
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The development of small molecules that inhibit protein-protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the development of indole-based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51. RAD51 is an ATP-dependent recombinase that plays a key role in the repair of doublestrand DNA breaks. It both self-associates, forming filament structures with DNA, and interacts with the BRCA2 protein through a common "FxxA" tetrapeptide motif. We elaborated previously identified fragment hits that target the FxxA motif site and developed small-molecule inhibitors that are approximately 500-fold more potent than the initial fragments. The lead compounds were shown to compete with the BRCA2-derived Ac-FHTA-NH2 peptide and the self-association peptide of RAD51, but they had no effect on ATP binding. This study is the first reported elaboration of small-molecular-weight fragments against this challenging target.
- Scott, Duncan E.,Coyne, Anthony G.,Venkitaraman, Ashok,Blundell, Tom L.,Abell, Chris,Hyv?nen, Marko
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supporting information
p. 296 - 303
(2015/02/05)
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- Soluble non-cross-linked poly(norbornene) supports for peptide synthesis with minimal reagents
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Solid-phase peptide synthesis has been an attractive method for synthesizing peptides because it is quick and can be automated. The heterogeneous reaction medium in solid-phase peptide synthesis necessitates the use of large equivalents of reagents to drive the reactions to completion. Peptide synthesis using soluble, yet isolable, supports is an attractive alternative to solid-phase peptide synthesis. Reported herein is a soluble poly(norbornene)-derived support containing multiple attachment sites for high loading capacities and solubilizing oligoether/alkyl groups. The Ala-attached support has been used to synthesize tri- to octapeptides in 28 to 97% yields using only 1.2 equiv of amino acids and coupling reagents. The acyclic hexapeptide precursor to natural product segatalin A was synthesized in 41% yield on the support using one-eighth of the equivalents of coupling reagents compared to that in reported procedures. The support could be recovered in up to 98% yield after peptide synthesis, and the recovered support was utilized to synthesize tri- and tetrapeptides that contain amino acids other than Ala at the C-terminus in ca. 80% yields.
- Naganna, Nimmashetti,Madhavan, Nandita
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p. 11549 - 11557
(2015/02/19)
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- Ligations of N-acyl tryptophan units to give native peptides via 7-, 10-, 11- and 12-membered cyclic transition states
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N-Acyl tryptophan isopeptides undergo acyl transfer in chemical ligations via 7-, 10-, 11- and 12-membered cyclic transition states to yield natural peptides, representing the first examples of successful isopeptide ligations from N-acyl tryptophan units.
- Popov, Vadim,Panda, Siva S.,Katritzky, Alan R.
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p. 1594 - 1597
(2013/04/10)
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- Unexpected cis selectivity in the Pictet-Spengler reaction
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Whilst cis:trans selectivity of about 4:1 can be obtained from Pictet-Spengler reactions between tryptophan methyl esters and aldehydes using conditions of kinetic control, much higher cis selectivity (>95:5) can be obtained when both the tryptophan deriv
- Bailey, Patrick D.,Beard, Mark A.,Phillips, Theresa R.
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experimental part
p. 3645 - 3647
(2009/09/30)
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- Polymer-supported O-benzyl and O-allylisoureas: Convenient preparation and use in ester synthesis from carboxylic acids
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Polymer-supported O-methyl, O-benzyl, and O-allyl-isoureas were prepared by copper(II)-catalyzed reaction of polymer-supported carbodiimide with the corresponding alcohols. These polymer-supported reagents were successfully employed to convert a series of carboxylic acids to methyl, benzyl, or allyl esters, in good yields. The products were obtained with high purity (>95% by NMR) after a simple resin filtration-solvent evaporation sequence.
- Crosignani, Stefano,White, Peter D.,Steinauer, Rene,Linclau, Bruno
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p. 853 - 856
(2007/10/03)
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- A practical synthesis of benzyl esters and related derivatives
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The benzyl ester is one of the earliest and best known of the carboxyl protecting groups. Its advantages over the corresponding methyl or ethyl ester derivatives lie in its ease of removal under very mild conditions, such as catalytic hydrogenation. The classical Fischer esterification of carboxylic acids in benzyl alcohol is not as easy as the analogous reaction in methanol or ethanol, due to the higher degree of steric hindrance imposed by the bulkier benzyl group and the difficulties encountered in evaporating the excess of high boiling benzyl alcohol at temperatures that could lead to decomposition of the products. Alternative routes such as the substitution of the silver or sodium salts with benzyl bromide, or the use of phenyldiazomethane have been described, but these are not always suitable, and the last method is inapropriate on large scale because of the explosive nature of the reagent. Klemm, Hintze and Gercken have also proposed a milder method adapted from earlier work by Vowinkel which involves the use of N,N'- dicyclohexyl-O-benzylisourea (DBI), itself obtained from N,N'-dicyclohexyl- carbodiimide (DCC) and benzyl alcohol. Another original route to benzyl esters is based on the thermal decomposition of benzyldimethylanilinium salts of carboxylic acids in refluxing toluene. This method needed modification for the preparation of acid sensitive tryptophan benzyl ester. More recently, benzyl trichloroacetimidate was found to convert carboxylic acids into the corresponding benzyl esters under catalysis by a Lewis acid such as boron trifluoride. As a complement to these earlier procedures, we now describe a mild, efficient, and practical benzylation method based on some new aspects of the chemistry of xanthates.
- Faure-Tromeur, Melanie,Zard, Samir Z.
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p. 7301 - 7304
(2007/10/03)
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- Application of a unique automated synthesis system for solution-phase peptide synthesis
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An automated synthesis system, which is suitable for repetitive syntheses using similar reaction procedures, was used to synthesize systematically a library of all possible dipeptides (25) and tripeptides (125) from 5 protected amino acids. The apparatus has also been applied to the automated synthesis of 10 fragment tripeptide derivatives that are constituents of the hormone PACAP-27. The measured molecular optical rotation values of the library of 125 tripeptides were found to correlate well with calculated values obtained by summation of the molecular optical rotation values for the constituent amino acids.
- Sugawara,Kobayashi,Okamoto,Kitada,Fujino
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p. 1272 - 1280
(2007/10/02)
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- Identification of L-Tryptophan Derivatives with Potent and Selective Antagonist Activity at the NK1 Receptor
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As part of a program of screening the Merck sample collection, N-ethyl-L-tryptophan benzyl ester was identified as a weak antagonist at the substance P (NK1) receptor.Structure-activity studies showed that the indole ring system could be replaced by 3,4-dichlorophenyl, α- or β-naphthyl, or benzthiophene with retention or only small loss of affinity.It was found that acylation of the tryptophan nitrogen gave compounds with higher affinity than N-ethyl or other basic amines.Optimization of substitution on the benzyl ester led to the identification of the 3,5-bis(trifluoromethyl) benzyl ester of N-acetyl-L-tryptophan 26 as a potent and selective substance P receptor antagonist.Compound 26 blocked substance P induced dermal extravasation in vivo and was the most potant compound from this structurally novel class of antagonists which further adds to the diversity of small molecules that bind to the (NK1) receptor.
- MacLeod, Angus M.,Merchant, Kevin J.,Brookfield, Frederic,Kelleher, Fintan,Stevenson, Graeme,et al.
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p. 1269 - 1274
(2007/10/02)
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- SYNTHESIS OF A GLYCOTRIPEPTIDE AND A GLYCOSOMATOSTATIN CONTAINING THE 3-O-(2-ACETAMIDO-2-DEOXY-β-D-GLUCOPYRANOSYL)-L-SERINE RESIDUE
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3-O-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-N-(tert-butyloxycarbonyl)-L-serine was synthesized and condensed by the solid-phase procedure to give the sequence Gly-3)-Ser>-Ala-OH and β-D-GlcpNAc-(1->3)-Ser-13-somatostat
- Lavielle, Solange,Ling, Nicolas C.,Saltman, Robert,Guillemin, Roger C.
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p. 229 - 236
(2007/10/02)
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