- Bioinspired honokiol analogs and their evaluation for activity on the norepinephrine transporter
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In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of Magnolia bark extracts. In the central nervous system, Magnolia bark preparations that contain honokiol are thought to primarily interact with -aminobutyric acid A (GABAA) receptors. However, stress responses inherently involve the noradrenergic system, which has not been investigated in the pharmacological mechanism of honokiol. We present here interactions of honokiol and other synthesized biphenyl-type neolignans and diphenylmethane analogs with the norepinephrine transporter (NET), which is responsible for the synaptic clearance of norepinephrine and the target of many anxiolytics. Of the synthesized compounds, 16 are new chemical entities, which are fully characterized. The 52 compounds tested show mild, non-potent interactions with NET (IC50 > 100 μM). It is thus likely that the observed anxiolytic effects of, e.g., Magnolia preparations, are not due to direct interaction with the noradrenergic system.
- Stout, Kristen,Bernaskova, Marketa,Miller, Gary W.,Hufner, Antje,Schuehly, Wolfgang
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Read Online
- A novel pH "off-on" fluorescent probe for lysosome imaging
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In the present paper, a new pH sensitive fluorescent probe based on a 4-acylated naphthalimide fluorophore was well designed and synthesized. It has a high specificity for lysosomes over other cell organelles. The intrinsic high signal to noise ratio in cell imaging, broad Stokes shift and practical fluorescence quantum yield of this probe will ensure its prominent position in the intracellular lysosome targeting and imaging toolbox.
- Chen, Laizhong,Li, Jing,Liu, Zhenzhen,Ma, Zhao,Zhang, Wei,Du, Lupei,Xu, Wenfang,Fang, Hao,Li, Minyong
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Read Online
- Enantiopure 5-CF3-Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry
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The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.
- Sanchez, Clément A.,Gadais, Charlène,Chaume, Grégory,Girard, Sylvaine,Chelain, Evelyne,Brigaud, Thierry
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supporting information
p. 382 - 387
(2021/01/13)
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- Eco-friendly synthesis of peptides using fmoc-amino acid chlorides as coupling agent under biphasic condition
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Background: Agro-waste derived solvent media act as a greener process for the peptide bond formation using Nα-Fmoc-amino acid chloride and amino acid ester salt with in situ neutralization and coupling under biphasic condition. The Fmoc-amino acid chlorides are prepared by the reported procedure of freshly distilled SOCl2 with dry CH2Cl2. The protocol found many added ad-vantages such as neutralization of amino acid ester salt and not required additional base for the neu-tralization, and directly coupling take place with Fmoc-amino acid chloride gave final product dipeptide ester in good to excellent yields. The protocol occurs with complete stereo chemical integrity of the configuration of substrates. Here, we revisited Schotten-Baumann condition, instead of using inorganic base. Objective: To develop green protocol for the synthesis of peptide bond using Fmoc-amino acid chloride with amino acid esters salt. Methods: The final product isolated is analyzed in several spectroscopic and analytical techniques such as FT-IR,1H-,13C-NMR, Mass spectrometry and RP-HPLC to check stereo integrity and puri-ty of the product. Conclusion: The present method developed greener using natural agro-waste (lemon fruit shell ash) derived solvent medium for the reaction and not required chemical entity.
- Kantharaju, Kamanna,Khatavi, Santosh Y.
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p. 699 - 707
(2021/08/23)
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- One-pot synthesis of Weinreb amides employing 3,3-dichloro-1,2-diphenylcyclopropene (CPI-Cl) as a chlorinating agent
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The synthesis of Nα-protected amino alkyl Weinreb amides starting from the corresponding α-amino acids as well as carboxylic acids has been delineated through the in situ generation of acid chlorides using CPI-Cl as a chlorinating agent. The protocol is simple; the reaction conditions employed were mild, and compatible with all the three commonly used urethane protecting groups namely, Boc, Cbz and Fmoc groups. The resulting Weinreb amides are obtained in good yields as optically pure products.
- Shekharappa,Roopesh Kumar,Sureshbabu, Vommina V.
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supporting information
p. 790 - 798
(2019/03/26)
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- The synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing versatile chlorinating agent CPI-Cl
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Racemization free synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing the versatile chlorinating reagent CPI-Cl has been described in one-pot. The present protocol has shown compability towards urethane protecting groups like Boc, Cbz and Fmoc, and side chain protections of amino acids showed complete tolerance.
- Vathsala,Srinivasulu,Santhosh,Sureshbabu, Vommina V.
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p. 449 - 457
(2019/03/08)
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- Synthetic procedure for N-Fmoc amino acyl-N-sulfanylethylaniline linker as crypto-peptide thioester precursor with application to native chemical ligation
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N-Sulfanylethylanilide (SEAlide) peptides 1, obtainable using Fmoc-based solid-phase peptide synthesis (Fmoc SPPS), function as crypto-thioesters in native chemical ligation (NCL), yielding a wide variety of peptides/proteins. Their acylating potential with N-terminal cysteinyl peptides 2 can be tuned by the presence or absence of phosphate salts, leading to one-pot/multifragment ligation, operating under kinetically controlled conditions. SEAlide peptides have already been shown to be promising for use in protein synthesis; however, a widely applicable method for the synthesis of N-Fmoc amino acyl-N- sulfanylethylaniline linkers 4, required for the preparation of SEAlide peptides, is unavailable. The present study addresses the development of efficient condensation protocols of 20 naturally occurring amino acid derivatives to the N-sulfanylethylaniline linker 5. N-Fmoc amino acyl aniline linkers 4 of practical use in NCL chemistry, except in the case of the proline- or aspartic acid-containing linker, were successfully synthesized by coupling of POCl3- or SOCl2-activated Fmoc amino acid derivatives with sodium anilide species 6, without accompanying racemization and loss of side-chain protection. Furthermore, SEAlide peptides 7 possessing various C-terminal amino acids (Gly, His, Phe, Ala, Asn, Ser, Glu, and Val) were shown to be of practical use in NCL chemistry.
- Sakamoto, Ken,Sato, Kohei,Shigenaga, Akira,Tsuji, Kohei,Tsuda, Shugo,Hibino, Hajime,Nishiuchi, Yuji,Otaka, Akira
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experimental part
p. 6948 - 6958
(2012/10/07)
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- Characterization of Nα-Fmoc-protected dipeptide isomers by electrospray ionization tandem mass spectrometry (ESI-MSn): Effect of protecting group on fragmentation of dipeptides
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A series of positional isomeric pairs of Fmoc-protected dipeptides, Fmoc-Gly-Xxx-OY/Fmoc-Xxx-Gly-OY (Xxx = Ala, Val, Leu, Phe) and Fmoc-Ala-Xxx-OY/Fmoc-Xxx-Ala-OY (Xxx = Leu, Phe) (Fmoc = [(9-fluorenylmethyl) oxy]carbonyl) and Y = CH3/H), have been characterized and differentiated by both positive and negative ion electrospray ionization ion-trap tandem mass spectrometry (ESI-IT-MSn). In contrast to the behavior of reported unprotected dipeptide isomers which mainly produce y 1+ and/or a1+ ions, the protonated Fmoc-Xxx-Gly-OY, Fmoc-Ala-Xxx-OY and Fmoc-Xxx-Ala-OY yield significant b 1+ ions. These ions are formed, presumably with stable protonated aziridinone structures. However, the peptides with Gly- at the N-terminus do not form b1+ ions. The [M + H]+ ions of all the peptides undergo a McLafferty-type rearrangement followed by loss of CO2 to form [M + H-Fmoc + H]+. The MS3 collision-induced dissociation (CID) of these ions helps distinguish the pairs of isomeric dipeptides studied in this work. Further, negative ion MS 3 CID has also been found to be useful for differentiating these isomeric peptide acids. The MS3 of [M-H-Fmoc + H]- of isomeric peptide acids produce c1-, z1 - and y1- ions. Thus the present study of Fmoc-protected peptides provides additional information on mass spectral characterization of the dipeptides and distinguishes the positional isomers. Copyright
- Ramesh,Raju,Srinivas,Sureshbabu,Vishwanatha,Hemantha
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experimental part
p. 1949 - 1958
(2012/05/20)
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- Discovery of a potent tubulin polymerization inhibitor: Synthesis and evaluation of water-soluble prodrugs of benzophenone analog
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Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3·HCl (l-valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3·HCl intravenously, with rapid clearance of 3·HCl indicating the effective cleavage of prodrug. Compound 3·HCl (CKD-516) has now been progressed to phase 1 clinical trial.
- Lee, Jaekwang,Bae, Suyeal,Lee, Seo-Hee,Choi, Hojin,Kim, Young Hoon,Kim, Soo Jin,Park, Gyu Tae,Moon, Seung Kee,Kim, Dal-Hyun,Lee, Sungsook,Ahn, Soon Kil,Choi, Nam Song,Lee, Kyung Joo
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scheme or table
p. 6327 - 6330
(2010/12/18)
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- Benzotriazole-assisted solid-phase assembly of Leu-Enkephalin, amyloid β segment 34-42, and other "difficult" peptide sequences
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Microwave-assisted solid-phase syntheses of six "difficult" peptides, H-VVSVV-NH2 (3), H-VVVSVV-NH2(4), H-VIVIG-OH (5), H-TVTVTV-NH2 (6), H-VKDGYI-NH2 (7), and H-VKDVYI-NH2 (8), were achieved utilizing N-(Fmoc-α-aminoacyl) benzotriazoles. Extension to the syntheses of Leu-enkephalin (9) and amyloid-β (34-42) (10) demonstrates that this strategy comprises an efficient route to new and known "difficult" peptides.
- Katritzky, Alan R.,Haase, Danniebelle N.,Johnsons, Jodie V.,Chung, Alfred
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body text
p. 2028 - 2032
(2009/08/07)
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- Asymmetric transfer hydrogenation of ketimines with trichlorosilane: Structural studies
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We report structural and mechanistic studies on the organocatalytic asymmetric transfer hydrogenation of ketimines with trichlorosilane. Amines were obtained in good yields and moderate enantioselectivities. Both experiment and computation were utilized to provide an improved understanding of the mechanism. Georg Thieme Verlag Stuttgart.
- Zhang, Zhiguo,Rooshenas, Parham,Hausmann, Heike,Schreiner, Peter R.
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experimental part
p. 1531 - 1544
(2009/12/09)
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- HOAt.DCHA as co-coupling agent in the synthesis of peptides employing Fmoc-amino acid chlorides as coupling agents: Application to the synthesis of ss-casomorphin
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A simple, efficient and racemization free method for the synthesis of peptides employing Fmoc-amino acid chlorides mediated by HOAtDCHA as a co-coupling agent has been described. This protocol is successfully employed in the synthesis of the pentapeptide H-Pro-Gly-VaI-GIy-VaI-OH (PGVGV), and ss-casomorphin (H-Tyr-Pro-Phe-Pro-Gly-OH) in 85 and 80% yields, respectively.
- Sureshbabu, Vommina V.,Chennakrishnareddy, Gundala
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experimental part
p. 981 - 988
(2009/12/28)
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- Diastereoselective Pictet - Spengler approach for the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-one peptide turn mimics
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(Chemical Equation Presented) Sixteen pyrrolo[3,2-e][1,4]diazepin-2-ones 1 were synthesized in 4-5 steps and 5-48% overall yields from 4-oxoproline 8 by a route featuring a diastereoselective Pictet-Spengler reaction to close the seven-membered diazepinon
- Deaudelin, Philippe,Lubell, William D.
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supporting information; experimental part
p. 2841 - 2844
(2009/05/27)
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- Microwave-assisted, zinc-mediated peptide coupling of N-benzyl-α,α-disubstituted amino acids
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Incorporation of the extremely hindered amino acid N-benzylaminoisobutyric acid into dipeptides under microwave irradiation with commercial zinc dust is described. A comparative survey of various methodologies for hindered peptide couplings was undertaken
- Cianci, Julia,Baell, Jonathan B.,Harvey, Andrew J.
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p. 5973 - 5975
(2008/02/10)
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- BENZOTHIOPHENE DERIVATIVES: PREPARATION AND PHARMACEUTICAL APPLICATIONS
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The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to benzothiophene containing compounds and methods for their preparation. These compounds may be useful as
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Page/Page column 49-50
(2008/06/13)
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- Novel compounds and compositions as protease inhibitors
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The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.
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- Asymmetric Organocatalytic Diels-Alder Reactions on Solid Support
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Asymmetric organocatalysis on solid support combines the environmental advantages of metal-free catalysts and the ease of operation of solid-supported reagents. Enantioselective organo-catalytic Diels-Alder reactions have been demonstrated by two differen
- Selkaelae, Sami A.,Tois, Jan,Pihko, Petri M.,Koskinen, Ari M. P.
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p. 941 - 945
(2007/10/03)
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- (Fluoren-9-ylmethoxy)carbonyl (Fmoc) amino acid azides: Synthesis, isolation, characterisation, stability and application to synthesis of peptides
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The synthesis of Fmoc amino acid azides starting from the corresponding protected amino acid and sodium azide (NaN3) by the mixed anhydride method using isobutoxycarbonyl chloride (IBC-Cl) or by the acid chloride method is described. Isolated as crystalli
- Babu, Vommina V. Suresh,Ananda, Kuppanna,Vasanthakumar, Ganga-Ramu
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p. 4328 - 4331
(2007/10/03)
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- Synthesis of peptides mediated by potassium salt of 1-hydroxy-7-azabenzotriazole
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The potassium salt of 1-hydroxy-7-azabenzotriazole can be used along with acid chlorides of 9-fluorenylmethyloxycarbonylamino acids as coupling agents in peptide bond formation.The acylation reactions are rapid and efficient and can be carried out in an organic medium.The yields as well as purity of the peptides are satisfactory.
- Gopi, H. N.,Babu, V. V. Suresh
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p. 394 - 396
(2007/10/03)
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- A new facile one-pot preparation of pentafluorophenyl (Pfp) and 3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl (Dhbt) esters of Fmoc amino acids
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A new one-pot procedure for the preparation of pentafluorophenyl and 3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl esters of Nα-9-fluorenylmethyloxycarbonyl amino acids bearing no side chain protecting groups is described. The method gives the desired activated esters in high yield and purity without use of the highly allergenic DCC.
- Jacobsen, Mogens Havsteen,Buchardt, Ole,Engdahl, Tom,Holm, Arne
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p. 6199 - 6202
(2007/10/02)
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- Rapid Continous Peptide Synthesis via FMOC Amino Acid Chloride Coupling and 4-(Aminomethyl)piperidine Deblocking
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The recently described FMOC/4-AMP technique for rapid continous solution synthesis of peptides involving coupling by crystalline FMOC amino acid chlorides and deblocking via 4-(aminomethyl)piperidine (4-AMP) has been extended to the synthesis of a varied
- Beyermann, Michael,Bienert, Michael,Niedrich, Hartmut,Carpino, Louis A.,Sadat-Aalaee, Dean
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p. 721 - 728
(2007/10/02)
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- ((9-Fluorenylmethyl)oxy)carbonyl (Fmoc) Amino Acid Chlorides. Synthesis, Characterization, and Application to the Rapid Synthesis of Short Peptide Segments
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Fmoc amino acid chlorides are described as stable, easily synthesized coupling agents and shown to be useful in a novel method of rapid, repetitive peptide synthesis
- Carpino, Louis A.,Cohen, Beri J.,Stephens, Kenton E.,Sadat-Aalaee, S. Yahya,Tien, Jien-Heh,Langridge, Denton C.
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p. 3732 - 3734
(2007/10/02)
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