- Design and synthesis of 3,5-substituted 1,2,4-oxadiazoles as catalytic inhibitors of human DNA topoisomerase IIα
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Cancer constitutes a group of diseases linked to abnormal cell growth that can potentially spread to other parts of the body and is one of the most common causes of death. The molecular motors - DNA topoisomerases - that enable topological changes of the DNA molecule are one of the most established targets of cancer therapies. Due to known limitations of established topo II poisons such as cardiotoxicity, induction of secondary malignancies and recognized cancer cell resistance, an emerging group of catalytic topo II inhibitors attempts to circumvent these challenges. Currently, this approach comprises several subgroups of mechanistically diverse inhibitors, one of which are compounds that act by binding to their ATPase domain. In this study we have designed, synthesized and characterized a new series of 3,5-substituted 1,2,4-oxadiazoles that act as catalytic inhibitors of human topo IIα. The introduction of the substituted rigid substitutions on the oxadiazole backbone was intended to enhance the interactions with the ATP binding site. In the inhibition assays selected compounds revealed a new class of catalytic inhibitors targeting this molecular motor and showed binding to the isolated topo IIα ATPase domain. The predicted inhibitor binding geometries were evaluated in molecular dynamics simulations and subsequently dynophore models were derived, which provided a deeper insight into molecular recognition with its macromolecular target. Selected compounds also displayed in vitro cytotoxicity on the investigated MCF-7 cancer cell line and did not induce double-strand breaks (DSB), thus displaying a mechanism of action diverse from the topo II poisons also on the cellular level. The substituted oxadiazoles thus comprise a chemical class of interesting compounds that are synthetically fully amenable for further optimization to anticancer drugs.
- Dolenc, Marija Sollner,Loboda, Kaja Bergant,Perdih, Andrej,Valjavec, Katja,Wolber, Gerhard,?tampar, Martina,?egura, Bojana,Filipi?, Metka
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- Fragmentation of Protonated N-(3-Aminophenyl)Benzamide and Its Derivatives in Gas Phase
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An ion of m/z 110.06036 (ion formula [C6H8NO]+; error: 0.32 mDa) was observed in the collision induced dissociation tandem mass spectrometry experiments of protonated N-(3-aminophenyl)benzamide, which is a rearrangement product ion purportedly through nitrogen-oxygen (N–O) exchange. The N–O exchange rearrangement was confirmed by the MS/MS spectrum of protonated N-(3-aminophenyl)-O18-benzamide, where the rearranged ion, [C6H8NO18]+ of m/z 112 was available because of the presence of O18. Theoretical calculations using Density Functional Theory (DFT) at B3LYP/6-31?g(d) level suggest that an ion-neutral complex containing a water molecule and a nitrilium ion was formed via a transition state (TS-1), followed by the water molecule migrating to the anilide ring, eventually leading to the formation of the rearranged ion of m/z 110. The rearrangement can be generalized to other protonated amide compounds with electron-donating groups at the meta position, such as, –OH, –CH3, –OCH3, –NH(CH3)2, –NH-Ph, and –NHCOCH3, all of which show the corresponding rearranged ions in MS/MS spectra. However, the protonated amide compounds containing electron-withdrawing groups, including –Cl, –Br, –CN, –NO2, and –CF3, at the meta position did not display this type of rearrangement during dissociation. Additionally, effects of various acyl groups on the rearrangement were investigated. It was found that the rearrangement can be enhanced by substitution on the ring of the benzoyl with electron-withdrawing groups. [Figure not available: see fulltext.]
- Zu, Chengli,Mukhopadhyay, Sukrit,Hanley, Patrick S.,Xia, Shijing,Bell, Bruce M.,Grigg, David,Gilbert, Jeffrey R.,O’Brien, John P.
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p. 917 - 926
(2016/05/02)
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- Solvatochromic probes for detecting hydrogen-bond-donating solvents
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Hydrogen bonding heavily influences conformations, rate of reactions, and chemical equilibria. The development of a method to monitor hydrogen bonding interactions independent of polarity is challenging as both are linked. We have developed two solvatochr
- Landis, Ryan F.,Yazdani, Mahdieh,Creran, Brian,Yu, Xi,Nandwana, Vikas,Cooke, Graeme,Rotello, Vincent M.
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p. 4579 - 4581
(2014/05/06)
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- Thioacids mediated selective and mild N-acylation of amines
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N-Acylated amines are ubiquitous in nature. Selective N-acylation at neutral conditions remains a key area of interest. Here we are reporting the copper sulfate-mediated highly selective, mild, and rapid N-acylation of various aliphatic and aromatic amines using thioacids in methanol at neutral conditions. All N-acylated products of primary and secondary amines were isolated in good to excellent yields. This method is found to be highly selective for the amines and not sensitive to other functional groups such as phenols, alcohols, and thiols. The simple workup, high yields, and high selectivity of this reaction can be an attractive alternative to those of the existing acyl halide- and acid anhydride-mediated N-acylation reactions.
- Mali, Sachitanand M.,Bhaisare, Rupal D.,Gopi, Hosahudya N.
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p. 5550 - 5555
(2013/07/25)
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- APO AI EXPRESSION ACCELERATING AGENT
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Pharmaceutical compositions for enhancing the expression of apoAI are provided.Pharmaceutical compositions for enhancing the expression of apoAI which comprises a compound of formula (I): in which Y1 is O, S or NR1; Y2, Y
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- Amide conformational switching induced by protonation of aromatic substituent
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(Matrix presented) Introduction of an electron-withdrawing group on the aromatic ring of N-methylacetanilide decreased the ratio of the cis conformer, and the ratio correlates well with the Hammett σ values of the substituents. These steric properties can be applied to achieve amide conformational swiching by protonation at the aromatic substituent of 4-[bis(dimethylamino)]-N-methylacetanilide or N-[p-(dimethylamino)phenyl]-N-phenylacetamide.
- Yamasaki, Ryu,Tanatani, Aya,Azumaya, Isao,Saito, Shoichi,Yamaguchi, Kentaro,Kagechika, Hiroyuki
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p. 1265 - 1267
(2007/10/03)
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- Indium-mediated one-pot reductive conversion of nitroarenes to N-arylacetamides
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N-Arylacetamides were prepared in excellent yields from nitroarenes in the presence of acetic anhydride, acetic acid and indium by a one-pot procedure.
- Kim, Byeong Hyo,Han, Rongbi,Piao, Fengyu,Jun, Young Moo,Baik, Woonphil,Lee, Byung Min
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- SUBSTITUTED THIAZOLE DERIVATIVES BEARING 3-PYRIDYL GROUPS, PROCESS FOR PREPARING THE SAME AND USE THEREOF
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The present invention provides a pharmaceutical composition having a steroid C17,20-lyase inhibitory activity, which is useful as a prophylactic or therapeutic agent of prostatism, tumor such as breast cancer and the like, more particularly, a steroid C17,20-lyase inhibitor containing a compound represented by the formula: wherein A1 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, one of A2 and A3 is a hydrogen atom, a halogen atom, a C1-4 aliphatic hydrocarbon group optionally having substituents or an optionally esterified carboxyl group, the other of A2 and A3 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and at least one of A1, A2 and A3 is a 3-pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof.
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Page/Page column 59
(2008/06/13)
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- SOLVOLYSIS KINETICS AND MECHANISM OF SUBSTITUTED 3-ACETYL-1,3-DIPHENYLTRIAZENES IN ACID MEDIUM; KINETIC ACIDITY FUNCTION
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The decomposition kinetics has been measured of fourteen 3-acetyl-1,3-bis(subst.phenyl)triazines in 40percent (v/v) ethanol and sulphuric acid.The kinetic acidity function and catalytic rate constants have been determined from the rate constants observed.Mechanism has been suggested for the general acid-catalyzed solvolysis from comparison of the course of the kinetic acidity function and H0 function and from the reaction constant of the Hammett equation.
- Pytela, Oldrich,Kaska, Martin,Ludwig, Miroslav,Vecera, Miroslav
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p. 2212 - 2216
(2007/10/02)
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