22839-16-3Relevant articles and documents
Solvent-freeN-Boc deprotection byex situgeneration of hydrogen chloride gas
De Borggraeve, Wim M.,Gilles, Philippe,Van Mileghem, Seger,Verschueren, Rik H.
supporting information, p. 5782 - 5787 (2021/07/12)
An efficient, scalable and sustainable method for the quantitative deprotection of thetert-butyl carbamate (N-Boc) protecting group is described, using down to near-stoichiometric amounts of hydrogen chloride gas in solvent-free conditions. We demonstrate theex situgeneration of hydrogen chloride gas from sodium chloride and sulfuric acid in a two-chamber reactor, introducing a straightforward method for controlled and stoichiometric release of HCl gas. The solvent-free conditions allow deprotection of a wide variety ofN-Boc derivatives to obtain the hydrochloride salts in quantitative yields. The procedure obviates the need for any work-up or purification steps providing an uncomplicated green alternative to standard methods. Due to the solvent-free, anhydrous conditions, this method shows high tolerance towards acid sensitive functional groups and furnishes expanded functional group orthogonality.
Preparation of enantiopure methionine, arginine, tryptophan, and proline benzyl esters in green ethers by Fischer–Speier reaction
Bolchi, Cristiano,Bavo, Francesco,Regazzoni, Luca,Pallavicini, Marco
, p. 1261 - 1268 (2018/06/11)
The simplest way to prepare the tosylate salts of amino acid benzyl esters, whose enantiomers are very important synthetic intermediates, is treatment of amino acid with benzyl alcohol and p-toluenesulfonic acid in a refluxing water-azeotroping solvent (Fischer–Speier esterification). However, to this day, the literature proposes only hazardous solvents, such as benzene, carbon tetrachloride, and chloroform, which must be absolutely avoided, or solvents, such as toluene and benzyl alcohol, which cause racemization because of too high boiling water azeotropes. On the other hand, the alternative successful use of cyclohexane, which we have recently reported for several amino acid benzyl esters, is inapplicable or not very efficient for ‘problematic’ amino acid such as tryptophan, arginine, and methionine, for which, indeed, the simple Fischer–Speier esterification is not described or poorly exemplified in the literature. Therefore, more polar solvents, in particular the green ethers CPME, TAME, and Me-THF, were selected and first considered for the preparation of methionine benzyl ester, previously accomplished in cyclohexane with modest yield. After discarding CPME and TAME, because causing racemization and decomposing under acidic conditions, respectively, we focused on Me-THF. In this ether, the benzyl esters of Met, Arg, and Trp could be obtained in good yield and, as proved by chiral HPLC or H NMR analysis, enantiomerically pure. The procedure was successfully extended to proline benzyl ester, which could be prepared enantiomerically pure and in quantitative yield both in cyclohexane and in Me-THF, thus avoiding the recently reported use of carbon tetrachloride.
Amino acid benzyl ester hydrochloride salt preparation method
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Paragraph 0047-0049, (2018/03/13)
The present invention discloses a preparation method for amino acid benzyl ester hydrochloride. The method comprises: by taking a metal chloride as a catalyst, in a suitable solvent, firstly generating amino acid hydrochloride by amino acid and hydrogen chloride; and then, esterifying the amino acid hydrochloride with benzyl alcohol at a reflux temperature, wherein water generated is removed by azeotrope; promoting esterification reaction; after the reaction is completed, filtering a thermal reaction liquid to remove the catalyst; removing a low-boiling-point substance (solvent) under low pressure; and performing post-treatment processes such as recrystallization and the like, thereby obtaining the object product, namely amino acid benzyl ester hydrochloride. Recrystallized mother liquor is recycled for more than 5 times. The method has advantages of relatively low raw material cost, relatively high conversion rate, relatively simple post-treatment, no use of chlorinating agents such as thionyl chloride and the like, less three waste emission, and the like, and is suitable for industrial production.
Design, synthesis, and preliminary bioactivity evaluation of N1-hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors
Wang, Xue,Li, Xiaoyang,Li, Jingyao,Hou, Jinning,Qu, Ying,Yu, Chenggong,He, Feng,Xu, Wenfang,Wu, Jingde
, p. 38 - 46 (2016/12/16)
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.
Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors
Kavanagh, Madeline E.,Gray, Janine L.,Gilbert, Sophie H.,Coyne, Anthony G.,McLean, Kirsty J.,Davis, Holly J.,Munro, Andrew W.,Abell, Chris
supporting information, p. 1924 - 1935 (2016/10/06)
The cyclo-dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor-like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors′ binding mode provides insight into the effect of weak nitrogen-donor ligands on the P450 heme, an improved understanding of factors governing CYP121–ligand recognition and speculation into the biological role of the enzyme for Mtb.
Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases
Scott, Duncan E.,Coyne, Anthony G.,Venkitaraman, Ashok,Blundell, Tom L.,Abell, Chris,Hyv?nen, Marko
supporting information, p. 296 - 303 (2015/02/05)
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.
A class of novel carboline intercalators: Their synthesis, in vitro anti-proliferation, in vivo anti-tumor action, and 3D QSAR analysis
Wu, Jianhui,Li, Chunyu,Zhao, Ming,Wang, Wenjing,Wang, Yuji,Peng, Shiqi
experimental part, p. 6220 - 6229 (2010/10/04)
Based on DOCK scores 18 N-(3-benzyloxycarbonylcarboline-1-yl)ethylamino acid benzylesters (6a-r) were synthesized as anti-tumor agents. Their IC 50 values against five human carcinoma cell lines ranged from 11.1 μM to more than 100 μM. The in vivo assay identified five derivatives of them had no anti-tumor action, the anti-tumor activity of nine derivatives of them equaled that of cytarabine, and the anti-tumor activity of three derivatives of them was higher than that of cytarabine. The UV and fluorescence spectra, as well as the relative viscosity and melting temperature measurements of calf thymus DNA (CT DNA) with and without the representative compound suggested that DNA intercalation could be their action mechanism. The 3D QSAR analysis of N-(3-benzyloxycarbonylcarboline-1-yl)ethylamino acid benzylesters (6a-r) revealed that their in vivo anti-tumor activity significantly depends on the molecular electrostatic and steric fields of the side chain of the amino acid residue.
Esterification of unprotected a-Amino acids in ionic liquids as the reaction media
Biondini, Daniele,Brinchi, Lucia,Germani, Raimondo,Goracci, Laura,Savelli, Gianfranco
experimental part, p. 39 - 44 (2010/08/22)
Ionic liquid 1,3-dimethylimidazolium methanesulfonate was used to prepare a-amino acids benzylic esters from unprotected amino acids and benzyl chloride. Esterification of several amino acids was achieved with satisfactory yields: by-products can be removed by a simple work-up procedure to afford the pure product. The described method is simple, mild, rapid and save.
