- A New Pathway for Protein Haptenation by β-Lactams
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The covalent binding of β-lactams to proteins upon photochemical activation has been demonstrated by using an integrated approach that combines photochemical, proteomic and computational studies, selecting human serum albumin (HSA) as a target protein and ezetimibe (1) as a probe. The results have revealed a novel protein haptenation pathway for this family of drugs that is an alternative to the known nucleophilic ring opening of β-lactams by the free amino group of lysine residues. Thus, photochemical ring splitting of the β-lactam ring, following a formal retro-Staudinger reaction, gives a highly reactive ketene intermediate that is trapped by the neighbouring lysine residues, leading to an amide adduct. For the investigated 1/HSA system, covalent modification of residues Lys414 and Lys525, which are located in sub-domains IIIA and IIIB, respectively, occurs. The observed photobinding may constitute the key step in the sequence of events leading to photoallergy. Docking and molecular dynamics simulation studies provide an insight into the molecular basis of the selectivity of 1 for these HSA sub-domains and the covalent modification mechanism. Computational studies also reveal positive cooperative binding of sub-domain IIIB that explains the experimentally observed modification of Lys414, which is located in a barely accessible pocket (sub-domain IIIA).
- Pérez-Ruíz, Raúl,Lence, Emilio,Andreu, Inmaculada,Limones-Herrero, Daniel,González-Bello, Concepción,Miranda, Miguel A.,Jiménez, M. Consuelo
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Read Online
- Mesomorphic properties and X-ray diffraction studies of 4-alkanoyloxybenzylidene-4′-fluoroaniline
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A new homologous series of Schiff base esters comprising a terminal fluoro substituent was studied. Molecular polarizability is enhanced by the presence of fluoro substituent, subsequently, affecting intermolecular interactions and resulting in smectic molecular arrangement. All members can be differed from the number of carbons at the alkanoyloxy chain (Cn-1H2n-1COO-, n = 10, 12, 14, 16, 18). The structure of the title compound was confirmed by spectroscopic (IR and NMR) techniques along with mass spectrometric analysis. Their mesomorphic properties were studied by using differential scanning calorimetry and optical polarizing microscopy techniques. Early members (n = 10, 12 and 14) exhibited monotropic smectic A phase while the longer chain members (n = 16 and 18) are non mesogenic compounds. X-ray diffraction analysis was used and confirmed monolayer of smectic A phase in n-dodecanoyloxy derivative.
- Ha, Sie-Tiong,Lee, Teck-Leong,Lee, Siew-Ling,Yeap, Guan-Yeow,Lin, Hong-Cheu,Ito, Masato M.
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Read Online
- Additional effect of para-hydroxyl on the reduction potentials of the N-benzylidenebenzenamines
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The reduction potential ERed of disubstituted N-benzylidenebenzenamines XArCH NArY (abbreviated as XBAY) is a measure of the electron acceptance ability of the Lowest-energy Unoccupied Molecular Orbital (LUMO) in molecule, which is closely related to the electronic effects of substituents X and Y in molecule. Previous studies on the ERed of XBAY reported by Luo, Wang, and Yuan all did not involve these molecules containing hydroxyl. In this work, 28 samples of disubstituted N-benzylidenebenzenamines containing para-hydroxyl, (abbreviated as 4-OHBAY or XBAOH-4′) were synthesized, and their ERed values were measured. Then, 127 compounds were taken as a complicated ERed data set, which involved 28 compounds (4-OHBAY and XBAOH-4′) of this work and 99 compounds XBAY reported by Luo. Based on these data ERed set, through a quantitative regression analysis method and comparison of the factors affecting the ERed, the following results are obtained: (a) Because the phenolic hydroxyl OH can dissociate H+ to form phenolic oxygen anion, the change regularity of ERed of compounds 4-OHBAY and XBAOH-4′ is somewhat different from that of ERed of XBAY compounds without hydroxyl OH. That is, hydroxyl OH has an additional effect on the ERed, which decreases the ERed value. (b) The additional effects of 4-OH on the ERed is different from that of 4′-OH. The effect of hydroxyl OH attached to the aldehyde aromatic ring on the ERed is more than that of OH attached to the amine aromatic ring.
- Cao, Chao-Tun,Zhou, Wei,Cao, Chenzhong
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- Iron-Catalyzed Nitrene Transfer Reaction of 4-Hydroxystilbenes with Aryl Azides: Synthesis of Imines via C=C Bond Cleavage
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C=C bond breaking to access the C=N bond remains an underdeveloped area. A new protocol for C=C bond cleavage of alkenes under nonoxidative conditions to produce imines via an iron-catalyzed nitrene transfer reaction of 4-hydroxystilbenes with aryl azides is reported. The success of various sequential one-pot reactions reveals that the good compatibility of this method makes it very attractive for synthetic applications. On the basis of experimental observations, a plausible reaction mechanism is also proposed.
- Peng, Yi,Fan, Yan-Hui,Li, Si-Yuan,Li, Bin,Xue, Jing,Deng, Qing-Hai
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p. 8389 - 8394
(2019/10/16)
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- Effect of substituents on the UV spectra of supermolecular system: Silver nanoparticles with bi-aryl Schiff bases containing hydroxyl
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Effect of substituents on the ultraviolet (UV) spectra of supermolecular system involving silver nanoparticles (AgNPs) and Schiff bases was investigated. AgNPs and 49 samples of model compounds (MC), bi-aryl Schiff bases containing hydroxyl (XBAY, involving 4-OHArCH?NArY, 2-OHArCH?NArY, XArCH?NAr-4′-OH, and XArCH?NAr-2′-OH), were synthesized. The size of AgNPs was characterized by transmission electron microscopy (TEM), and the UV absorption spectra of AgNPs, XBAYs, and MC-AgNPs mixed solutions were measured, respectively. The results show that (1) the size of AgNPs is larger in MC-AgNPs solutions than that in AgNPs solution due to the distribution of MC molecules on the surface of AgNPs; (2) the UV absorption wavelength of XBAYs changes in the action of AgNPs and their wavelength shift exists limitation between XBAY and MC-AgNPs solutions; and (3) the wavelength shift limit of MC-AgNPs (λWSL) is influenced by the substituents X and Y and the position of hydroxyl OH. The wavenumber ΔνWSL of λWSL can be quantified by employing the excited-state substituent constant σexCC and Hammett constant σ of substituents X and Y. Comparing with the 4-OH, the 4′-OH makes the ΔνWSL a red shift, whereas the 2′-OH, comparing with the 2-OH, makes the ΔνWSL a blue shift.
- Cao, Chao-Tun,Cheng, Shimao,Zhang, Jingyuan,Cao, Chenzhong
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- Production method of Ezetimibe intermediate
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The invention discloses a two-stage three-step method for preparing an Ezetimibe intermediate. The method comprises the following steps: stage one, using common commodities such as p-hydroxy benzaldehyde and p-fluoro aniline as reactants and using water as a reagent, and carrying out heating condensation to generate Schiff base, wherein the yield can reach 97.0%; and stage two, the stage comprising two steps, firstly using a chiral reducing reagent R-CBS and borane dimethyl sulfide to reduce a starting material 1 and obtain an in situ intermediate; enabling the in situ intermediate to directly react with the Schiff base obtained in the stage one, so as to obtain the final product Ezetimibe intermediate, wherein the yield can reach more than 75.0%. In the first step of the second stage, a sulfuric acid solution, a 5% sodium sulfite solution and a 10% sodium chloride solution are used in sequence for washing an organic phase, and finally the organic phase is washed with water and is dried by using sodium sulfate, so that various organic and inorganic impurities are sufficiently removed, and the in situ intermediate is not separated, but the purity is high. The prepared in situ intermediate reacts with the Schiff base, so that the Ezetimibe intermediate is high in yield and high in purity.
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Paragraph 0029; 0030; 0031
(2017/08/29)
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- METHOD FOR PREPARING AZETIDINONE COMPOUND AND INTERMEDIATE OF AZETIDINONE COMPOUND
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Disclosed is a new method for preparing an azetidinone compound represented by formula (I). The carboxylic ketoester represented by formula (II) serves as the raw material and is subjected to Grignard addition, stereoselective dehydration, ester group reduction, hydroxyl group protection, addition with imine after condensation with a chiral auxiliary, cyclization and deprotection to obtain the compound represented by formula (I). The present invention has advantages of easily available raw material, a few synthetic steps, simple operation, high yield, good stereoselectivity and low cost, and can be used for industrial production.
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Paragraph 0054-0056
(2017/05/31)
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- according to folds Mai Bu and its intermediate synthesis method
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The invention provides an Ezetimibe synthesis method comprising the following steps: (a) a compound (5) is subjected to asymmetric reduction reaction to obtain a compound (6), and the compound (6) and tert-butyldimethylsilyl chloride react in an organic solution under the action of alkali to obtain a compound (7); (b) the compound (7) and diisopropylethylamine are dissolved in the organic solution, titanium tetrachloride is added in the organic solution to react at 20-50 DEG C, and a compound (3) is added in the organic solution at minus 20 to minus 60 DEG C to react to obtain a compound (8); (c) the compound (8) and N,O-bis(trimethylsilyl) acetamide react in the organic solution at 20-80 DEG C, tetrabutylammonium fluoride trihydrate is added into the organic solution to react at 20-80 DEG C to obtain a compound (9); (d) the compound (9) is subjected to off-protection reaction to obtain Ezetimibe, wherein R is equal to TBS, Ac or COOCH2CCl3. The invention further provides an Ezetimibe intermediate and a preparation method thereof.
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Paragraph 0047; 0048; 0049
(2017/07/26)
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- Abnormal effect of hydroxyl on the longest wavelength maximum in ultraviolet absorption spectra for bis-aryl Schiff bases
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Two sets of bis-aryl Schiff bases that contain 4(or 4′)-OH and 2(or 2′)-OH were synthesized. The first set consists of 4-HOArCH=NArY and XArCH=NArOH-4′, and the second set consists of 2-HOArCH=NArY and XArCH=NArOH-2′. Their ultraviolet absorption spectra were measured and investigated. A very interesting phenomenon was observed by analyzing their wave number νmax (cm?1) of longest wavelength maximum λmax (nm) of ultraviolet. Compared with the change regularity of the νmax of XArCH=NArY (where the X and Y excluded OH), the 4′-position hydroxyl (4′-OH) and 2′-position hydroxyl (2′-OH) have abnormal performance. The details are the following: the 4′-OH contributes an additional red shift to the νmax of XArCH=NArOH-4′ (λmax increase), whereas the 2′-OH contributes an additional blue shift to the νmax of XArCH=NArOH-2′ (λmax decrease). In addition, there are ortho steric effects of all 2-OH and 2′-OH on the νmax for 2-HOArCH=NArY and XArCH=NArOH-2′, and the ortho steric effect contributes a red shift to their νmax. These experimental facts can provide an important theoretical reference for us using aryl Schiff base compounds as optical materials and performing the molecular design.
- Cao, Chao-Tun,Zhou, Wei,Cao, Chenzhong
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- The evaluation of the role of C-H?F hydrogen bonds in crystal altering the packing modes in the presence of strong hydrogen bond
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Interactions involving fluorine is an area of contemporary research. To unravel the importance of weak C-H?F hydrogen bonds and C-H?π interactions in organic compounds in the presence of strong hydrogen bond, a series of N-benzylideneanilines with simultaneously hydroxyl (-OH) and fluorine substitutions were synthesized for structural analysis. These compounds have been studied through experimental single crystal X-ray diffraction analysis and computational methods (Gaussian09 and AIM2000). The hydroxyl group present in all the molecules were found to form strong O-H?N hydrogen bond, but the spatial arrangement of the molecules connected by this hydrogen bond have been found to be controlled by the weak C-H?F and C-H?O hydrogen bonds, weak C-H?π and π?π interactions. This manuscript illustrates the importance of several weaker interactions in altering the packing modes in the presence of strong hydrogen bonds.
- Kaur, Gurpreet,Singh, Sandhya,Sreekumar, Amritha,Choudhury, Angshuman Roy
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p. 154 - 169
(2015/11/18)
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- Efficient and scalable process for the synthesis of antihypercholesterolemic drug ezetimibe
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An efficient and scalable process for the synthesis of antihypercholesterolemic drug ezetimibe through chiral Evans auxiliary (S)-4-phenyl-2-oxazolidinone is described. The key steps in this process are the condensation of (S)-3-(5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one and N-(4-((tert-butyldimethylsilyl)oxy)benzylidene)-4-fluoroaniline, and the stereoselective reduction of ezetimibe-ketone with NaBH4/I2, which is first applied in the synthesis of ezetimibe. The process is concise, mild, easy to operate, and highly stereoselective (99.6% of de value of ezetimibe). In addition, three diastereomers of ezetimibe are synthesized and served as the references in quality control of the product.
- Zhu, Yijun,Pan, Jing,Zhang, Shunli,Liu, Zhenren,Ye, Deyong,Zhou, Weicheng
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supporting information
p. 1687 - 1693
(2016/10/21)
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- Development of the β-lactam type molecular scaffold for selective estrogen receptor α modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells
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The estrogen receptors (ERα and ERβ) which are ligand inducible nuclear receptors are recognized as pharmaceutical targets for diseases such as osteoporosis and breast cancer. There is an increasing interest in the discovery of subtype Selective Estrogen Receptor Modulators (SERMs). A series of novel β-lactam compounds with estrogen receptor modulator properties have been synthesized. The antiproliferative effects of these compounds on human MCF-7 breast tumor cells are reported, together with binding affinity for the ERα and ERβ receptors. The most potent compound 15g demonstrated antiproliferative effects on MCF-7 breast tumor cells (IC50=186 nM) and ERα binding (IC50=4.3 nM) with 75-fold ERα/β receptor binding selectivity. The effect of positioning of the characteristic amine containing substituted aryl ring (on C-4 or N-1 of the β-lactam scaffold) on the antiproliferative activity and ER-binding properties of the β-lactam compounds is rationalized in a molecular modeling study.
- Carr, Miriam,Knox, Andrew J. S.,Lloyd, David G.,Zisterer, Daniela M.,Meegan, Mary J.
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p. 117 - 130
(2016/12/16)
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- BETA-LACTAM CHOLESTEROL ABSORPTION INHIBITORS
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The present invention relates to the novel compounds represented by Formula (la) or (lb) and to their pharmaceutical preparations for the treatment of atherosclerosis and cholesterol level reduction.
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Page/Page column 20
(2015/07/07)
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- Synthesis of N-benzyl-N-phenylthiophene-2-carboxamide analogues as a novel class of enterovirus 71 inhibitors
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A series of novel human enterovirus 71 inhibitors, N-benzyl-N-phenylthiophene-2-carboxamide analogues, were synthesized and their antiviral activities were evaluated in vitro. Most derivatives of this structure against EV71 had a low micromolar range in the RD (rhabdomyosarcoma) cell lines. The most potent compound 5a, N-(4-bromobenzyl)-N-(4-fluorophenyl)thiophene-2-carboxamide, showed low micromolar activity against EV71 (EC50 = 1.42 μM) compared to the reference anti-EV71 drug enviroxime (EC50 = 0.15 μM). Preliminary SAR studies revealed that the thiophene-2-carboxamide core is crucial for maintaining antiviral activity, and N-substituent phenyl groups largely influenced the anti-EV71 efficacy of this new class of potent antiviral agents.
- Pan, Jiawei,Han, Xin,Sun, Ningyuan,Wu, Haoming,Lin, Dandan,Tien, Po,Zhou, Hai-Bing,Wu, Shuwen
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p. 55100 - 55108
(2015/07/07)
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- Synthesis and antitubercular activity of some 2-(4-substituted phenyl)-3-(4-substituted phenyl)-5-methylthiazolidin-4-ones
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The compounds 2-(4-substituted phenyl)-3-(4-substituted phenyl)-5-methylthiazolidin-4-ones were synthesized by condensing 4-substituted anilines with 4-substituted benzaldehydes by using ethanol as solvent. The synthesized compounds were heated with 2-mercaptopropionic acid in excess of benzene. The chemical nature of synthesized compounds have been confirmed by means of IR, NMR and mass data. The synthesized compounds were screened for antitubercular activity. The compounds were subjected to in vitro screening by the tube dilution technique employing the human virulent H37R V strain of M. tuberculosis using isoniazid as a reference standard. The results revealed that the test compounds IIa, IIc, IId, IIe, exhibits remarkable antitubercular activity against H37RV strain of Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC) values were found in the range of 25 to 42 μg/mL.
- Patil, Sunila T.,Bhatt, Parloop A.
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experimental part
p. 1405 - 1406
(2011/12/16)
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- GREEN SYNTHESIS OF ARYL ALDIMINES USING ETHYL LACTATE
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The present invention relates to a method for preparing aryl aldimines. In particular, the present invention relates to methods of preparing aryl aldimines that uses environmentally friendly solvent systems.
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Page/Page column 5-6
(2011/08/22)
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- METHOD OF PREPARING EZETIMIBE AND INTERMEDIATES USED THEREIN
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Disclosed is a method for preparing ezetimibe which is effective for preventing or treating arteriosclerosis, and novel intermediates used therein. In accordance with the method which does not use expensive reagents, unwanted diastereoisomers can be easily removed by a step-by-step crystallization procedure, and the ezetimibe of formula 1 can be prepared in a high yield without the use of a hydrogenation procedure under a high pressure.
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Page/Page column 16
(2010/08/05)
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- PROCESS FOR THE PREPARATION OF AZETIDINONES
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A process for preparing an azetidinone such as ezetimibe of formula (I) is disclosed using an alcohol of formula (III) as starting material.
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Page/Page column 12-13
(2010/11/25)
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- Process for the synthesis of azetidinones
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A process is provided for preparing azetidinones useful as intermediates in the synthesis of penems and as hypocholesterolemic agents, comprising reacting a β-(substituted-amino)amide, a β-(substituted-amino)acid ester, or a β-(substituted-amino)thiolcarbonic acid ester with a silylating agent and a cyclizing agent selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof, or the reaction product of: (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl.
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Page/Page column 15-16
(2008/06/13)
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- PROCESS FOR THE SYNTHESIS OF AZETIDINONES
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This invention provides a process for preparing the hypocholesterolemic compound (I) comprising: (a) reacting p-fluorobenzoylbutyric acid with pivaloyl chloride and acylating the product with a chiral auxiliary to obtain a ketone of formula (IV); (b) reducing the ketone of formula (IV) in the presence of a chiral catalyst to an alcohol; (c) reacting the chiral alcohol of step (b), an imine and a silyl protecting agent, then condensing the protected compounds to obtain a beta -(substituted-amino)amide of formula (VII); (d) cyclizing the beta -(substituted-amino)amide of formula (VII) with a silylating agent and a fluoride ion catalyst to obtain a protected lactam of formula (VIII); and removing the protecting groups. The intermediates of formulas (VII and VIII) are also claimed.
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Page/Page column 9
(2010/02/11)
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