- Design, synthesis and biological evaluation of novel plumbagin derivatives as potent antitumor agents with STAT3 inhibition
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Based on the structure of signal transducer and activator of transcription 3 (STAT3), a series of 1,4-naphthoquinones derived from plumbagin (PL) with STAT3 inhibition potential were designed, synthesized, and biologically evaluated in vitro against several human cancer cell lines (MDA-MB-231, HepG2 and A549 cells) and three normal cells. The structure–activity relationship (SAR) and molecular docking result showed that the presence of hydroxyl group at C-5 of PL might interact with STAT3 in the form of hydrogen bonds, which is conducive to the binding of this kind structures with STAT3. Among the target compounds, 7a displayed the most potent inhibition against cancer cells and weaker cytotoxicity on normal cells than PL. The western bolting analysis showed that 7a could suppress the phosphorylation of STAT3 as well as the downstream genes instead of affecting its upstream tyrosine kinases (Src and JAK2) levels and p-STAT1 expression. Furthermore, molecular docking indicated that 7a bound to STAT3 more tightly than PL, and it could significantly induce the apoptosis of cancer cells in vitro. All these results may provide reference for the discovery of effective STAT3 inhibitors.
- Li, Na,Ou, Jinfeng,Bao, Na,Chen, Cheng,Shi, Zhixian,Chen, Li,Sun, Jianbo
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- A detailed study of antibacterial 3-acyltetramic acids and 3-acylpiperidine-2,4-diones
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Inspired by the core fragment of antibacterial natural products such as streptolydigin, 3-acyltetramic acids and 3-acylpiperidine-2,4-diones have been synthesised from the core heterocycle by direct acylation with the substituted carboxylic acids using a strategy which permits ready access to a structurally diverse compound library. The antibacterial activity of these systems has been established against a panel of Gram-positive and Gram-negative bacteria, with activity mostly against the former, which in some cases is very potent. Data consistent with modes of action against undecaprenylpyrophosphate synthase (UPPS) and/or RNA polymerase (RNAP) for a small subset of the library has been obtained. The most active compounds have been shown to exhibit binding at known binding sites of streptolydigin and myxopyronin at UPPS and RNAP. These systems offer potential for their antibacterial activity, and further demonstrate the use of natural products as biologically validated starting points for drug discovery.
- Jeong, Yong-Chul,Bikadi, Zsolt,Hazai, Eszter,Moloney, Mark G.
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p. 1826 - 1837
(2014/08/18)
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- Studies of 2-substituted 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones as precursors for the synthesis of N-alkyl-β-amino acids
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1,3-Oxazolidin-5-ones and 1,3-oxazinan-6-ones have been shown to be useful precursors for the synthesis of N-methyl α- and β-amino acids, respectively. The methodology has now been expanded to allow for the synthesis of N-alkyl-β-amino acids. Copyright Ta
- Hughes, Andrew B.,Sleebs, Brad E.
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experimental part
p. 48 - 60
(2009/04/06)
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- 1-Acyldeoxyvasicinone salts as effective intermediate C- and N-acylating agents for alkaloids and amino acids
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The reaction of deoxyvasicinone with acid chlorides of aliphatic (acetylbromide) and aromatic (benzoyl-, o-, p-methoxy-, p-nitrobenzoylchlorides) acids was studied. It was shown that 1-deoxyvasicinone salts were formed at room temperature; α-aroyloxymethylidenedeoxyvasicinones, in the presence of triethylamine at 80-85°C. It was found that acid chlorides cause 1-acyldeoxyvasicinone salts to transform into α-hydroxy-or α-aroyloxyarylidenedeoxyvasicinones, which indirectly confirmed their acylating properties. It was found that 1-acyldeoxyvasicinone salts were effective acylating agents for alkaloids (cytisine, 1,2-dihydrodeoxyvasicinone) and amino acids (glycine, β-alanine, α-aminobutyric acid) and can be used to acylate primary and secondary aliphatic and heterocyclic amines.
- Shakhidoyatov,Genjemuratova,Oripov
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p. 718 - 723
(2008/02/08)
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- Different transition-state structures for the reactions of β-lactams and analogous β-sultams with serine β-lactamases
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β-Sultams are the sulfonyl analogues of β-lactams, and N-acyl β-sultams are novel inactivators of the class C β-lactamase of Enterobacter cloacae P99. They sulfonylate the active site serine residue to form a sulfonate ester which subsequently undergoes C-O bond fission and formation of a dehydroalanine residue by elimination of the sulfonate anion as shown by electrospray ionization mass spectroscopy. The analogous N-acyl β-lactams are substrates for β-lactamase and undergo enzyme-catalyzed hydrolysis presumably by the normal acylation-deacylation process. The rates of acylation of the enzyme by the β-lactams, measured by the second-order rate constant for hydrolysis, kcat/Km, and those of sulfonylation by the β-sultams, measured by the second-order rate constant for inactivation, ki, both show a similar pH dependence to that exhibited by the β-lactamase-catalyzed hydrolysis of β-lactam antibiotics. Electron-withdrawing groups in the aryl residue of the leaving group of N-aroyl β-lactams increase the rate of alkaline hydrolysis and give a Bronsted βIg of -0.55, indicative of a late transition state for rate-limiting formation of the tetrahedral intermediate. Interestingly, the corresponding Bronsted βIg for the β-lactamase-catalyzed hydrolysis of the same substrates is -0.06, indicative of an earlier transition state for the enzyme-catalyzed reaction. By contrast, although the Bronsted βIg for the alkaline hydrolysis of N-aroyl β-sultams is -0.73, similar to that for the β-lactams, that for the sulfonylation of β-lactamase by these compounds is -1.46, compatible with significant amide anion expulsion/S-N fission in the transition state. In this case, the enzyme reaction displays a later transition state compared with hydroxide-ion-catalyzed hydrolysis of the β-sultam.
- Tsang, Wing Y.,Ahmed, Naveed,Hinchliffe, Paul S.,Wood, J. Matthew,Harding, Lindsay P.,Laws, Andrew P.,Page, Michael I.
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p. 17556 - 17564
(2007/10/03)
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- The use of cellulose (chromatography paper) as a cheap, versatile and non-covalent support for organic molecules during multi-step synthesis
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Cellulose chromatography paper provides a novel non-covalent support for synthesis and in-situ purification of multi-dimensional arrays.
- Shanahan, Stephen E.,Byrne, Douglas D.,Inglis, Graham G. A.,Alam, Mahbub,Macdonald, Simon J. F.
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p. 2554 - 2555
(2007/10/03)
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- Structural and mechanistic studies of the copper(II)-assisted ortho-hydroxylation of benzoates by trimethylamine N-oxide
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N-benzoyl-2-methylalanine (H2L1) is ortho-hydroxylated stereoselectively by trimethylamine N-oxide (TMAO) in the presence of copper(II). The experimental structure of [Cu(L1)(TMAO)2] suggests that the oxygen transfer agent TMAO transfers the oxygen atom to copper(II), and (L1)2-, coordinated to copper(II) by a carboxylate oxygen and the amide nitrogen donor, is well pre-organized for an oxygen transfer from copper to the ortho carbon atom of the benzene ring. Product analyses as a function of reaction time of the copper(II)-mediated ortho-hydroxylation reaction with H2L1 and various derivatives support the suggestion of a reactive copper-oxo or copper-hydroxo intermediate, stabilized by a five-membered chelate with hard carboxylate and N-amide donors. The analysis also suggests that there is a pre-equilibrium with a Cu:L=1:1 ratio, and this might involve Cu/L2-/TMAO or dicopper complexes. Depending on the ligand H2L, complexation with the salicylate product may inhibit the ortho-hydroxylation reaction.
- Buijs, Wim,Comba, Peter,Corneli, Danny,Pritzkow, Hans
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- ERYTHROMYCIN A 9-0-OXIME DERIVATIVES ENDOWED WITH ANTIBIOTIC ACTIVITY
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PCT No. PCT/EP95/04815 Sec. 371 Date May 16, 1997 Sec. 102(e) Date May 16, 1997 PCT Filed Dec. 7, 1995 PCT Pub. No. WO96/18633 PCT Pub. Date Jun. 20, 1996Erythromycin 9-oxime derivatives wherein a phenyl or heterocylic group is attached indirectly to the 9-position of erythromycin A through an alkylene diamine bridging member. These compounds exhibit broad spectrum antibiotic activity.
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- N-LITHIO-N-(2-LITHIOETHYL)- AND N-LITHIO-N-(3-LITHIOPROPYL)-BENZAMIDE: DIRECT PREPARATION AND SYNTHETIC APPLICATIONS OF 2-LITHIOETHYL- AND 3-LITHIOPROPYL-AMINE EQUIVALENTS
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The successive reaction of 2-chloroethyl and 3-chloropropyl-benzamide with n-butyl-lithium and lithium naphthalenide at temperatures ranging between -78 and -50 deg C leads to N-lithio-N-(2-lithioethyl)- and N-lithio-N-(3-lithiopropyl)benzamide , which by treatment with different electrophiles (H2O, D2O, Me2S2, CO2, PriCHO, PhCHO, Me2CO, Ph2CO, and O2) yields the expected functionalized benzamides .The acidic and basic hydrolysis of compounds (10) and (11) gives different results depending on the structure of the substrate and the reaction conditions.
- Barluenga, Jose,Foubelo, Francisco,Fananas, Francisco J.,Yus, Miguel
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p. 2183 - 2192
(2007/10/02)
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- Composition containing a penem or carbapenem antibiotic and the use of the same
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Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially.
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- N-LITHIO-N-(2-LITHIOETHYL)BENZAMIDE: DIRECT PREPARATION OF A 2-LITHIOETHYLAMINE EQUIVALENT
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The successive reaction of 2-chloroethylbenzamide with n-butyl-lithium and lithium naphthalenide at -78 deg C leads to N-lithio-N-(2-lithioethyl)benzamide, which reacts with different electrophiles (H2O, D2O, Me2S2, CO2, i-PrCHO, PhCHO, Me2CO, Ph2CO) to afford the expected 2-functionalized benzamides.
- Barluenga, Jose,Foubelo, Francisco,Fananas, Francisco J.,Yus, Miguel
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p. 2859 - 2860
(2007/10/02)
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- A Mechanism for bitter Taste Sensibility in Peptides
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To estimate the steric distance between the bitter taste determinant sites in peptides, some cyclic dipeptides, amino acid anilides, amino acid cyclohexylamides, and benzoyl amino acids were synthesized and their tastes were evaluated.The diketopiperazine ring of cyclic dipeptides acted as a bitter taste determinant site due to its hydrophobicity.The steric distance between 2 sites was estimated as 4.1 Angstroem from the molecule models of cyclic dipeptides composed of typical amino acids in the bitter peptides.Due to the hypothesis of two bitter taste determinant sites, which bind with the bitter taste receptor via a "binding unit" and a "stimulating unit," a mechanism for the bitterness in peptides was postulated.
- Ishibashi, Norio,Kouge, Katsushige,Shinoda,Ichizo,Kanehisa, Hidenori,Okai, Hideo
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p. 819 - 828
(2007/10/02)
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- Composition containing a penem or carbapenem antibiotic
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Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially. The composition may be prepared by simple mixing.
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- Studies on Potential Antibacterial and Chelating Agents: Part I - Synthesis, Physicochemical Properties and Antibacterial Screening of Some Benzimidazoles
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Six properly substituted benzimidazoles (I-VI) suitable for chelation have been synthesised from benzoylamino acids by condensation with o-phenylenediamine following Phillips and fusion methods.Dissociation constants of the benzoyl derivatives of glycine, (dl)-α-alanine, β-alanine, L-(-)-aspartic acid, L-(+)-glutamic acid and the six protonated benzamidobenzimidazoles (I-VI) in water-dioxane (1:1) at constant ionic strength (μ=0.5) at 20 deg C +/- 0.1 deg C have been determined by potentiometric titration.Structures of I-VI have been established on the basis of their elemental analysis, synthetic route, IR and PMR spectra and pK* values.Some of the compounds show significant antibacterial activity against gram + ve organisms only whereas corresponding sulphonamidobenzimidazoles are active against the gram - ve organism E. coli.
- Nandi, M. M.,Ray, Ruma
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p. 222 - 224
(2007/10/02)
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