- Synthesis, biological evaluation, and molecular modeling studies of chiral chloroquine analogues as antimalarial agents
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In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum. Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.
- Kondaparla, Srinivasarao,Debnath, Utsab,Dola, Vasantha Rao,Sinha, Manish,Katti, Seturam B.,Soni, Awakash,Srivastava, Kumkum,Puri, Sunil K.
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- Aqueous MW eco-friendly protocol for amino group protection
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In this paper a new catalyst-free and on-water method for protection of amines and amino acids with di-tert-butyl dicarbonate, 9-fluorenylmethoxycarbonyl chloride, acetyl chloride and tosyl chloride is presented. The protection can be realized in a few minutes under microwave-assistance. The reaction proved to be chemoselective in presence of ambident nucleophiles and water solution of di-tert-butyl carboxylic acid or chloride acid are the only wastes produced.
- Nardi,Cano, N. Herrera,Costanzo,Oliverio,Sindona,Procopio
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p. 18751 - 18760
(2015/06/15)
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- Design, synthesis and evaluation of novel indole derivatives as AKT inhibitors
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Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line.
- Yang, Dezhi,Wang, Peng,Liu, Jianzhen,Xing, Hualu,Liu, Yang,Xie, Wencheng,Zhao, Guisen
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p. 366 - 373
(2014/01/17)
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- Lipopeptides from the tropical marine cyanobacterium symploca sp.
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A collection of the tropical marine cyanobacterium Symploca sp., collected near Kimbe Bay, Papua New Guinea, previously yielded several new metabolites including kimbeamides A-C, kimbelactone A, and tasihalide C. Investigations into a more polar cytotoxic fraction yielded three new lipopeptides, tasiamides C-E (1-3). The planar structures were deduced by 2D NMR spectroscopy and tandem mass spectrometry, and their absolute configurations were determined by a combination of Marfeys and chiral-phase GC-MS analysis. These new metabolites are similar to several previously isolated compounds, including tasiamide (4), grassystatins (5, 6), and symplocin A, all of which were isolated from similar filamentous marine cyanobacteria.
- Mevers, Emily,Haeckl, F. P. Jake,Boudreau, Paul D.,Byrum, Tara,Dorrestein, Pieter C.,Valeriote, Frederick A.,Gerwick, William H.
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p. 969 - 975
(2014/05/20)
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- Catalytic methyl transfer from dimethylcarbonate to carboxylic acids
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Although methylation reactions are commonplace, currently used reagents are hazardous, toxic, and/or unstable. Dimethylcarbonate has been put forth as an inexpensive, nontoxic, and green potential methylating reagent. Herein we report a general, base-catalyzed methyl transfer from dimethylcarbonate to carboxylic acids. High selectivity for esterification is observed even in the presence of unprotected phenols, and the mild reaction conditions enable conservation of stereochemistry at epimerizable stereocenters. Isotope-labeling studies suggest a mechanism proceeding by direct methyl transfer from dimethylcarbonate to the substrate.
- Ji, Yuan,Sweeney, Jessica,Zoglio, Jillian,Gorin, David J.
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p. 11606 - 11611
(2013/12/04)
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- Design, synthesis, and applications of potential substitutes of t-Bu-phosphinooxazoline in Pd-catalyzed asymmetric transformations and their use for the improvement of the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates
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The design, synthesis, and applications of potential substitutes of t-Bu-PHOX in asymmetric catalysis is reported. The design relies on the incorporation of geminal substituents at C5 in combination with a substituent at C4 other than t-butyl (i-Pr, i-Bu, or s-Bu). Most of these new members of the PHOX ligand family behave similarly in terms of stereoinduction to t-Bu-PHOX in three palladium-catalyzed asymmetric transformations. Electronically modified ligands were also prepared and used to improve the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates.
- Belanger, Etienne,Pouliot, Marie-France,Courtemanche, Marc-Andre,Paquin, Jean-Francois
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scheme or table
p. 317 - 331
(2012/02/15)
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- Universal peptidomimetics
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This paper concerns peptidomimetic scaffolds that can present side chains in conformations resembling those of amino acids in secondary structures without incurring excessive entropic or enthalpic penalties. Compounds of this type are referred to here as minimalist mimics. The core hypothesis of this paper is that small sets of such scaffolds can be designed to analogue local pairs of amino acids (including noncontiguous ones) in any secondary structure; i.e., they are universal peptidomimetics. To illustrate this concept, we designed a set of four peptidomimetic scaffolds. Libraries based on them were made bearing side chains corresponding to many of the protein-derived amino acids. Modeling experiments were performed to give an indication of kinetic and thermodynamic accessibilities of conformations that can mimic secondary structures. Together, peptidomimetics based on these four scaffolds can adopt conformations that resemble almost any combination of local amino acid side chains in any secondary structure. Universal peptidomimetics of this kind are likely to be most useful in the design of libraries for high-throughput screening against diverse targets. Consequently, data arising from submission of these molecules to the NIH Molecular Libraries Small Molecule Repository (MLSMR) are outlined.
- Ko, Eunhwa,Liu, Jing,Perez, Lisa M.,Lu, Genliang,Schaefer, Amber,Burgess, Kevin
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supporting information; scheme or table
p. 462 - 477
(2011/04/16)
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- Efficient and selective cleavage of the t-butoxycarbonyl group from di-t-butylimidodicarbonate using catalytic bismuth(III) bromide in acetonitrile
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Di-t-butylimidodicarbonates can be chemoselectively and efficiently deprotected to the corresponding mono-BOC-protected amines in high yields using a catalytic amount of bismuth(III) bromide in acetonitrile at room temperature. This method is mild and compatible with the presence of a wide range of functional and other protecting groups in the substrates, such as TBDMS, MOM and mono-BOC or Cbz-protected amines, etc. The method has advantages of ease of operation and use of nontoxic and inexpensive catalyst.
- Zheng, Jianlong,Yin, Biaolin,Huang, Wenming,Li, Xiaopeng,Yao, Hequan,Liu, Zhaogui,Zhang, Jiancun,Jiang, Sheng
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scheme or table
p. 5094 - 5097
(2009/12/01)
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- Development of a temporary marker for peptides
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3-[(N,N-Dimethylaminophenyl)-4′-diazenyl]benzoic acid was coupled with several amino acid esters and the product acylated further with Boc. The material thus obtained was then submitted to cleavage by electrolysis and nucleophilic attack in order to evaluate the possibility of using this chromophore as a temporary marker.
- Sameiro,Goncalves,Maia, Hernani L.S.
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p. 1480 - 1485
(2007/10/03)
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- Efficient and selective cleavage of t-butoxycarbonyl group from carbamates and amides by CeCl3·7H2O-NaI
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A highly selective cleavage of the t-butoxycarbonyl group has been achieved in high yields using CeCl3·7H2O-NaI in acetonitrile at ambient temperature under neutral conditions. This method is mild and compatible with a wide range of
- Yadav,Subba Reddy,Reddy, K. Srinivasa
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p. 468 - 470
(2007/10/03)
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- Indium-mediated facile cleavage of the t-butoxycarbonyl group from di-t-butylimidodicarbonate
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Di-t-butylimidodicarbonates are selectively and efficiently deprotected to the corresponding mono-BOC protected amines in high yields using indium or zinc metal in refluxing methanol. Simple BOC and CBz protected amines are unaffected by these conditions.
- Yadav,Reddy,Reddy, K.Srinivasa,Reddy, K.Bhaskar
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p. 1549 - 1551
(2007/10/03)
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- A temporary marker for biological applications
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Having in mind the development of new colour labelled amino acid derivatives, a carboxyl azo dye was coupled to amino acid esters to give the corresponding orange N-acyl derivatives, which were in turn further acylated at their N-terminus with Boc for investigation of the conditions of possible cleavage of the chromophore by electrolysis or with nucleophiles. While difficulties were met with electrolysis owing to competitive reduction of the azo group, cleavage with N,N-diethylaminoethylamine (DEAEA) gave satisfactory results. This allows the use of the chromophore as a temporary marker.
- Sameiro, M,Gon?alves, T,Maia, Hernani L.S
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p. 7775 - 7777
(2007/10/03)
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- Cyclopeptide alkaloids from Paliurus ramossisimus
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Seven zizyphine A-type cyclopeptide alkaloids were isolated from the roots of Paliurus ramossisimus by the combination of centrifugal partition chromatography and conventional separation methods. The novel structures of paliurines A-F (1-6) were characterized and established on the basis of MS and elaborate NMR spectral analyses. Terminal dipeptide stereochemistry was confirmed by correlation with the synthetic dipeptides via comparison of their 13C NMR data.
- Lin,Chen,You,Chen Liu,Lee
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p. 1338 - 1343
(2007/10/03)
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- 1,3-Diastereocontrol with Bromoallenes. Synthesis of Enantiomerically Pure β-Branched α-Amino Acids
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Bromoallenes 3a and 3b derived from (D)-Serine undergo SN2' alkylation with organo copper reagents to give alkynyl amino alcohol derivatives.These compounds can be further transformed into branched enantiomerically enriched α-amino acids as, for example (L)-Isoleucine and (L)-Alloisoleucine.
- D'Aniello, Fabiana,Mann, Andre,Taddei, Maurizio,Wermuth, Camille-Georges
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p. 7775 - 7778
(2007/10/02)
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- One-Pot Conversion of Fluorenylmethyl Carbamates into tert-Butyl Carbamates
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N-Fluorenylmethoxycarbonyl groups may be efficiently converted into N-tert-butoxycarbonyl groups by potassium fluoride/Et3N in the presence of Boc2O.
- Li, Wen-Ren,Jiang, Jianjun,Joullie, Madelaine M.
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p. 1413 - 1414
(2007/10/02)
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- The role of hydroxymethyl function on the biological activity of the antitumor antibiotic sparsomycin
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The synthesis is described of the sparsomycin analogues 11-14 from the L-amino acids valine, isoleucine, phenylalanine and proline, respectively. The sparsomycin derivative 21 was not prepared in a similar way from glycine, but from cystamine following a different reaction route. These analogues, as well as the O-methylated and O-acetylated derivatives 15 and 16, respectively, were tested in vitro for their protein synthesis inhibitory activity and for their inhibition of colony formation of murine leukemia L1210 cells. The results of these assays indicate that the hydroxymethyl function of 1 is not essential for its biological activity, and that increase of lipophilicity in this 'northern' region of 1 does not noticeably affect the activity of the drug.
- Van den Broek,Fennis,Arevalo,Lazaro,Ballesta,Lelieveld,Ottenheijm
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p. 503 - 510
(2007/10/02)
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- New Methods and Reagents in Organic Synthesis. 67. A General Synthesis of Derivatives of Optically Pure 2-(1-Aminoalkyl)thiazole-4-carboxylic Acids
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Preparations of 2-(1-aminoalkyl)thiazole-4-carboxylic acids (thiazole amino acids), important constituents of a series of cytotoxic cyclic peptides from marine organisms, have been conveniently and efficiently achieved as their N- and C-protected derivatives 6 from N-Boc or N-Z α-amino acids 1 in five steps.Esterification of 1 with methyl iodide followed by reduction with lithium chloride-sodium borohydride afforded N-protected amino alcohols 3.Selective reduction of the α-ester functions of the glutamic acid derivatives (Z-D- and Z-L-Glu(O-t-Bu)-OMe and O-t-Bu) was also achieved under the above reduction conditions.Dimethyl sulfoxide oxidation, followed by condensation with cysteine methyl ester afforded the thiazolidine derivatives 5, which were conveniently dehydrogenated with manganese dioxide, called chemical manganese dioxide (CMD) and produced for batteries, to give the desired thiazole amino acid derivetives 6.The glutamine derivatives (Z-D- and Z-L-(gln)Thz-OMe) were prepared from the corresponding glutamic acid derivatives (Z-D- and Z-L-6f).No appreciable racemization was observed in the above conversion, which was proven by HPLC of the 3,5-dinitrobenzoyl derivatives of thiazole amino acids 6 using a chiral column.
- Hamada, Yasumasa,Shibata, Makoto,Sugiura, Tsuneyuki,Kato, Shinji,Shioiri, Takayuki
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p. 1252 - 1255
(2007/10/02)
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