- Design and Catalyzed Activation of Tak-242 Prodrugs for Localized Inhibition of TLR4-Induced Inflammation
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Tak-242 (resatorvid), a Toll-like Receptor 4 (TLR4) inhibitor, has been identified as a potent suppressor of innate inflammation. As a strategy to target Tak-242 to select tissue, four TLR4-inactive prodrugs were synthesized for activation via two different release mechanisms. Two nitrobenzyl Tak-242 prodrugs released the parent drug upon exposure to the exogenous enzyme nitroreductase, while the two propargyl prodrugs were converted to Tak-242 in the presence of Pd0.
- Plunk, Michael A.,Alaniz, Alyssa,Olademehin, Olatunde P.,Ellington, Thomas L.,Shuford, Kevin L.,Kane, Robert R.
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supporting information
p. 141 - 146
(2020/01/31)
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- Benzimidazolinone-Free Peptide o-Aminoanilides for Chemical Protein Synthesis
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The thioester surrogate 3,4-diaminobenzoic acid (Dbz) facilitates the efficient synthesis of peptide thioesters by Fmoc chemistry solid phase peptide synthesis and the optional attachment of a solubility tag at the C-terminus. The protection of the partially deactivated ortho-amine of Dbz is necessary to obtain contamination-free peptide synthesis. The reported carbamate protecting groups promote a serious side reaction, benzimidazolinone formation. Herein we introduce the Boc-protected Dbz that prevents the benzimidazolinone formation, leading to clean peptide o-aminoanilides suitable for the total chemical synthesis of proteins.
- Mannuthodikayil, Jamsad,Singh, Sameer,Biswas, Anamika,Kar, Abhisek,Tabassum, Wahida,Vydyam, Pratap,Bhattacharyya, Mrinal Kanti,Mandal, Kalyaneswar
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supporting information
p. 9040 - 9044
(2019/11/14)
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- Synthesis of Supramolecular Iridium Catalysts and Their Use in Enantioselective Visible-Light-Induced Reactions
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Iridium complexes were prepared which are covalently linked via a bipyridine ligand to a chiral octahydro-1H-4,7-methanoisoindol-1-one skeleton. The skeleton allows for two-point hydrogen bonding to prochiral lactams, which can be processed in iridium-catalyzed photochemical reactions. Attempts to use the iridium complexes in reactions, which typically involve photoinduced electron transfer, failed to provide the desired enantioselectivity. If employed as triplet sensitizers the complexes showed an improved performance and moderate enantioselectivities (up to 29% ee) were achieved in a photochemical epoxide rearrangement.
- B?hm, Alexander,Bach, Thorsten
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supporting information
p. 1056 - 1060
(2016/05/19)
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- A Turn-On Fluorescent Probe for Highly Selective and Sensitive Detection of Palladium
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A novel turn-on fluorescent probe for the detection of palladium has been designed. The probe can selectively and sensitively detect palladium in solution, and the limit of detection was calculated to be 11.4 nmol·L?1. Furthermore, the probe was successfully used for fluorescence imaging of palladium in living cells.
- Zhou, Junliang,Zhang, Jian,Ren, Hang,Dong, Xiaochun,Zheng, Xing,Zhao, Weili
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supporting information
p. 715 - 719
(2016/07/22)
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- Thiol-yne radical reaction mediated site-specific protein labeling via genetic incorporation of an alkynyl-l-lysine analogue
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Three alkyne-containing pyrrolysine derivatives were synthesized and genetically encoded into proteins by a mutant PylRS-tRNA pair with high efficiencies. With these alkyne handles, site-specific dual labeling of proteins can be achieved via a bioorthogonal thiol-yne ligation reaction.
- Li, Yiming,Pan, Man,Li, Yitong,Huang, Yichao,Guo, Qingxiang
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p. 2624 - 2629
(2013/06/05)
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- Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity
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Sirtuins are NAD+ dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on Nε-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodium falciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD+ supporting the formation of EI2 and E·NAD+·I2 complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket accommodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P. falciparum with 50% inhibitory concentration in the micromolar range.
- Chakrabarty, Subhra Prakash,Ramapanicker, Ramesh,Mishra, Roli,Chandrasekaran, Srinivasan,Balaram, Hemalatha
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experimental part
p. 8060 - 8072
(2010/03/24)
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- Base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates to 4-alkylidene-2-oxazolidinones
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The base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates is studied in detail. The effect of various bases and solvents on the efficacy of this cyclization reaction is analyzed and a new base-solvent system (LiOH in DMF) for effective cyclization of these carbamates is reported. A number of differentially substituted O-propargyl carbamates were cyclized to the corresponding 2-oxazolidinones under these conditions. The reaction conditions reported here are mild and no side reactions were observed in any of the substrates studied. A propargyl carbonate group was unaffected during the course of the cyclization of the O-propargyl carbamate group. The propargyl carbamates were prepared from the corresponding alkyl or aryl amines and the corresponding propargyl chloroformate, resulting in oxazolidinones diversely substituted at the nitrogen atom. N-Aryl-O-propargyl carbamates cyclized readily to the corresponding oxazolidinones with LiOH in DMF, whereas N-alkyl-O-propargyl carbamates reacted slowly under the same conditions. O-Propargyl carbamates substituted at the 1-position tend to cyclize faster whereas those substituted at 3-position cyclize considerably slower than the unsubstituted carbamates.
- Ramesh, Ramapanicker,Chandrasekaran, Yogesh,Megha, Rajendran,Chandrasekaran, Srinivasan
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p. 9153 - 9162
(2008/02/10)
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- Simultaneous protection and activation of amino acids using propargyl pentafluorophenyl carbonate
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A very efficient method for the simultaneous protection of the amino group and activation of the carboxyl group of amino acids is reported using propargyl pentafluorophenyl carbonate (PocOPfp). The amino group is protected as a propargyloxycarbonyl (Poc) derivative, and the carboxyl group is activated as a pentafluorophenyl ester. The yields obtained are good to excellent ranging from 60 to 87%.
- Ramesh, Ramapanicker,Rajasekaran, Sakthidevi,Gupta, Rohit,Chandrasekaran, Srinivasan
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p. 1933 - 1936
(2007/10/03)
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- Method for the preparation of aliphatic chloroformates
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A method for preparing an aliphatic chloroformate comprising, introducing a mixture of at least one aliphatic hydroxyl compound, phosgene, at least one solvent, and optionally at least one organic base into a flow reactor to obtain a unidirectional flowing reaction mixture. The at least one aliphatic hydroxyl compound comprises at least one aliphatic hydroxyl group. The unidirectional flowing reaction mixture is maintained at a temperature between about 0° C. and about 60° C. to produce a single product stream comprising an aliphatic chloroformate.
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Page/Page column 7-8
(2008/06/13)
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- Highly selective deblocking of propargyl carbonates in the presence of propargyl carbamates with tetrathiomolybdate
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(Chemical Equation Presented) Propargyloxycarbonyl chloride, 1, has been used to protect the hydroxyl and amino functionalities of amino alcohols and aminophenols in one pot using triethylamine or pyridine as a base. The increased reactivity of benzyltriethylammonium tetrathiomolybdate, 2, toward propargyl carbonates over propargyl carbamates is studied in detail and has been exploited further to develop an orthogonal protection strategy for the hydroxyl and amino functionalities. For example, 2-amino-1-butanol, 6a, was treated with 1 to get the N,O-diPoc compound 7a in 90% yield, which when treated with 1.1 equiv of 2 at room temperature removes the Poc group attached to oxygen while leaving the one attached to nitrogen intact to yield compound 8a in 85% yield. This particular observation offers a new protecting strategy where an amine and an alcohol group can be protected simultaneously in one pot, and in a later synthetic step, if the alcohol group has to be deprotected selectively, it can be achieved with 1 equiv of 2.
- Ramesh,Bhat, Ramakrishna G.,Chandrasekaran, Srinivasan
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p. 837 - 840
(2007/10/03)
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- A mild and selective method for N-dealkylation of tertiary amines
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Alkyl groups can be cleaved efficiently and selectively from tertiary alkyl amines using propargyl chloroformate. The propargyloxycarbonyl (Poc) protected secondary amines thus obtained can be deblocked under neutral and mild conditions using benzyltriethylammonium tetrathiomolybdate. The generality and compatibility of the method have been studied with a wide range of functionalities. Alkyl groups can be cleaved efficiently and selectively from tertiary alkyl amines using propargyl chloroformate. The propargyloxycarbonyl (Poc) protected secondary amines thus obtained can be deblocked under neutral and mild conditions using benzyltriethylammonium tetrathiomolybdate. The generality and compatibility of the method have been studied with a wide range of functionalities.
- Bhat, Ramakrishna G.,Ghosh, Yagnaseni,Chandrasekaran, Srinivasan
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p. 7983 - 7985
(2007/10/03)
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- Synthesis and applications of propargyl pentafluorophenyl carbonate for peptide synthesis
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Propargyl pentafluorophenyl carbonate was synthesised in quantitative yield by the reaction of propargyl chloroformate and pentafluorophenol. All the N-propargyloxycarbonyl (N-Poc) amino acids were obtained in good yield. The use of Poc-OPfp in peptide synthesis has been explored.
- Bhat, Ramakrishna G,Kérourédan, Erwan,Porhiel, Emmanuel,Chandrasekaran, Srinivasan
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p. 2467 - 2469
(2007/10/03)
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- Synthesis of potentially β-blocking practolol derivatives: (E + Z)-3- [4-(3-iodoprop-2-enyloxycarbonylamino)phenoxy]-1-(isopropylamino)propan-2-ol
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The iodinatied carbamates 3 (E + Z), with potential β-blocking properties, were synthesized. The first route chosen, from 4-aminophenol and the chloroformate 7, had to be abandoned because of the formation of the oxazolidinone 10 during the epoxidation step. The aminoalcohol 17 prepared from the practolol 1 finally gave the target compounds by condensation with the iodoallylic chloroformates 8 (E + Z). The secondary Boc-protected amine function was regenerated without removing the carbamate function situated in the p-postion, by using mild reaction conditions (1 N HCl).
- Apparu, Marcel,Ben Tiba, Younes,Leo, Pierre-Marc,Fagret, Daniel
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p. 1007 - 1012
(2007/10/03)
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- Propargyloxycarbonyl and propargyl groups for novel protection of amino, hydroxy, and carboxy functions
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The propargyloxycarbonyl group readily introduced to both amino and hydroxy groups by using propargyl chloroformate is stable to neat TFA but is readily cleaved at ambient temperature by treatment with Co2(CO)8 and TFA in CH2Cl2 via formation of an alkyne-Co complex. The propargyl ester similarly serves as a good protecting group for carboxy functions.
- Kukase,Fukase,Kusumoto
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p. 1169 - 1170
(2007/10/03)
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- Cyclization-Activated Prodrugs: N-(Substituted 2-hydroxyphenyl and 2-hydroxypropyl)carbamates Based on Ring-Opened Derivatives of Active Benzoxazolones and Oxazolidinones as Mutual Prodrugs of Acetaminophen
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N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates based on masked active benzoxazolones (model A) and oxazolidinones (model B), respectively, were synthesized and evaluated as potential drug delivery systems.A series of alkyl and aryl N-(5-chloro-2-hydroxyphenyl)carbamates 1 related to model A was prepared.These are open drugs of the skeletal muscle relaxant chlorzoxazone.The corresponding 4-acetamidophenyl ester named chloracetamol is a mutual prodrug of chloroxazone and acetaminophen.Chlorzacetamol and two other mutual prodrugs of active bezoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetrachloroethyl carbonate with the appropiate anilines.Based on model B, two mutual prodrugs of acetaminophen and active oxazolidinones (metaxalone and mephenoxalone) were similarly obtained using the appropiate amines.All the carbamate prodrugs prepared were found to release the parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media.The detailed mechanistic study of prodrugs 1 carried out in aqueous medium at 37 deg C shows a change in the Broensted-type relationship log t1/2 vs pKa of the leaving groups ROH: log t1/2 = 0.46pKa - 3.55 for aryl and trihalogenoethyl esters and log t1/2 = 1.46pKa - 16.03 for alkyl esters.This change is consistent with a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (step k1) to departure of the leaving group ROH (step k2) when the leaving group ability decreases.This mechanism occurs for all the prodrugs related to model A.Regeneration of the parent drugs from mutual prodrugs related to model B takes place by means of a rate-limiting elimination-addition reaction (E1cB mechanism).This affords acetaminophen and the corresponding 2-hydroxypropyl isocyanate intermediates which cyclize at any pH to the corresponding oxazolidinone drugs.As opposed to model A, the rates of hydrolysis of mutual prodrugs of model B clearly exhibit a catalytic role of the plasma.It is concluded from the plasma studies that the carbamate substrates can be enzymatically transformed into potent electrophiles, i.e., isocyanates.In the case of the present study, the prodrugs are 2-hydroxycarbamates for which the propinquity of the hydroxyl residue and the isocyanate group enforces a cyclization reaction.This mechanistic particularity precludes their potential toxicity in terms of potent electrophiles capable of modifying critical macromolecules.
- Vigroux, Alain,Bergon, Michel,Zedde, Chantal
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p. 3983 - 3994
(2007/10/03)
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- Carbamate series of juvenoids: Variation of the O-alkyl substituent
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By changing the O-alkyl substituents of the carbamate moiety of alkyl N-{2-{4-[(2-oxocyclohexyl)methyl]phenoxy}ethyl}carbamates and subsequent transformation of the oxo group in the cyclohexyl substituent, the juvenoids 1-20 were synthesized (Scheme). The methyl (1-4), propyl (9-12), isopropyl (13-16), and prop-2-ynylcarbamates (17-20) were subjected to biological screening on several non-related insect species (Tenebrio molitor, Galleria mellonella, Dysdercus cingulatus, and Pyrrhocoris apterus). Some of the juvenoids showed high biological activity and excellent selectivity with respect to target insect species (Table 2).
- Wimmer,Saman,Nemec,Francke
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p. 561 - 568
(2007/10/02)
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- 3-amino-3-carbamoyloxyalkylacrylic acid intermediates to dihydropyridines
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A process for preparing a 2-carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by the general formula: STR1 which comprises: (a) reacting a 3-amino-3-carbamoyloxyalkylacrylic acid derivative represented by the general formula: STR2 with a benzylidene compound represented by the general formula: STR3 (b) reacting the 3-amino-3-carbamoyloxyalkylacrylic acid derivative of the general formula II with an aldehyde compound represented by the general formula: STR4 and a β-keto-ester compound represented by the general formula: (c) reacting a 3-carbamoyloxyalkylpropiolic acid derivative represented by the general formula: STR5 with the benzylidene compound of the general formula III and ammonia or its salt; or (d) reacting the 3-carbamoyloyalkylpropiolic acid derivative of the general formula VI with the aldehyde compound of the general formula IV, the β-keto-ester compound of the general formula V and ammonia or its salt.
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