- Overcoming imatinib resistance in chronic myelogenous leukemia cells using non-cytotoxic cell death modulators
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Recent studies examined the possibility to overcome imatinib resistance in chronic myeloid leukemia (CML) patients by combination therapy with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Pioglitazone, a full PPARγ agonist, improved the survival of patients by the gradual elimination of the residual CML stem cell pool. To evaluate the importance of the pharmacological profile of PPARγ agonists on the ability to circumvent resistance, the partial PPARγ agonist 4‘-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid, derived from telmisartan, and other related derivatives were investigated. The 4-substituted benzimidazole derivatives bearing a [1,1′-biphenyl]-2-carboxamide moiety sensitized K562-resistant cells to imatinib treatment. Especially the derivatives 18a-f, which did not activate PPARγ to more than 40% at 10 μM, retrieved the cytotoxicity of imatinib in these cells. The cell death modulating properties were higher than that of pioglitazone. It is of interest to note that all novel compounds were not cytotoxic neither on non-resistant nor on resistant cells. They exerted antitumor potency only in combination with imatinib.
- Schoepf, Anna M.,Salcher, Stefan,Obexer, Petra,Gust, Ronald
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supporting information
(2019/10/22)
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- Preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-one
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The invention provides a preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-one, which comprises the following steps: Q1, preparation of 2, 6-dinitrochlorobenzene, Q2, preparation of 2, 6-dinitroaniline, Q3, preparation of 3-nitro-o-phenylenediamine, Q4, preparation of 4-nitro-1H-benzo[d]imidazole-2(3H)-one and Q5, preparation of 4-amino-1, 3-dihydro-benzimidazole-2-one. According to the preparation method, 3, 5-dinitro-4-chlorobenzoic acid which is low in price is used as a raw material, and the high-yield 4-amino-1, 3-dihydro-benzimidazole-2-one is obtained through reactions such asdecarboxylation and ammoniation. The whole reaction process is easy to control, the product yield is high, good social benefits and economic benefits can be brought, and the economic value potential is large.
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Paragraph 0041
(2020/07/15)
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- Synthesis and evaluation of analogs of 5′-(((Z)-4-amino-2-butenyl)methylamino)-5′-deoxyadenosine (MDL 73811, or AbeAdo) – An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity
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We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5′-(((Z)-4-amino-2-butenyl)methylamino)-5′-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood–brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5′-amine, the ribose, and the purine fragments. Although we gained valuable structure–activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1.
- Brockway, Anthony J.,Volkov, Oleg A.,Cosner, Casey C.,MacMillan, Karen S.,Wring, Stephen A.,Richardson, Thomas E.,Peel, Michael,Phillips, Margaret A.,De Brabander, Jef K.
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supporting information
p. 5433 - 5440
(2017/10/06)
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- Atom-Specific Mutagenesis Reveals Structural and Catalytic Roles for an Active-Site Adenosine and Hydrated Mg2+ in Pistol Ribozymes
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The pistol RNA motif represents a new class of self-cleaving ribozymes of yet unknown biological function. Our recent crystal structure of a pre-catalytic state of this RNA shows guanosine G40 and adenosine A32 close to the G53–U54 cleavage site. While the N1 of G40 is within 3.4 ? of the modeled G53 2′-OH group that attacks the scissile phosphate, thus suggesting a direct role in general acid–base catalysis, the function of A32 is less clear. We present evidence from atom-specific mutagenesis that neither the N1 nor N3 base positions of A32 are involved in catalysis. By contrast, the ribose 2′-OH of A32 seems crucial for the proper positioning of G40 through a H-bond network that involves G42 as a bridging unit between A32 and G40. We also found that disruption of the inner-sphere coordination of the active-site Mg2+ cation to N7 of G33 makes the ribozyme drastically slower. A mechanistic proposal is suggested, with A32 playing a structural role and hydrated Mg2+ playing a catalytic role in cleavage.
- Neuner, Sandro,Falschlunger, Christoph,Fuchs, Elisabeth,Himmelstoss, Maximilian,Ren, Aiming,Patel, Dinshaw J.,Micura, Ronald
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supporting information
p. 15954 - 15958
(2017/11/21)
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- Gold supported on titania for specific monohydrogenation of dinitroaromatics in the liquid phase
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Liquid-phase selective monohydrogenation of various substituted dinitroaromatics to the corresponding valuable nitroanilines was investigated on gold-based catalysts. Special attention was paid to the effect of Au particle size on this monoreduction reaction. Interestingly, TiO2 supported gold catalysts containing a relatively larger mean Au particle size (>5 nm) showed far superior chemoselectivity for specific mono-hydrogenation of dinitroaromatics, with the highest performance attainable for the catalyst bearing Au particles of ca. 7.5 nm. Results in the intermolecular competitive hydrogenation showed that the intrinsic higher accumulation rates of the desired nitroanilines associated with the catalyst possessing larger Au particles were responsible for the high chemoselectivity observed. the Partner Organisations 2014.
- Liu, Shuang-Shuang,Liu, Xiang,Yu, Lei,Liu, Yong-Mei,He, He-Yong,Cao, Yong
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p. 4162 - 4169
(2014/09/29)
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- Base substituted 5′-O-(N-isoleucyl)sulfamoyl nucleoside analogues as potential antibacterial agents
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Aminoacyl-sulfamoyl adenosines are well-known nanomolar inhibitors of the corresponding prokaryotic and eukaryotic tRNA synthetases in vitro. Inspired by the aryl-tetrazole containing compounds of Cubist Pharmaceuticals and the modified base as found in the natural antibiotic albomycin, the selectivity issue of the sulfamoylated adenosines prompted us to investigate the pharmacophoric importance of the adenine base. We therefore synthesized and evaluated several isoleucyl-sulfamoyl nucleoside analogues with either uracil, cytosine, hypoxanthine, guanine, 1,3-dideaza-adenine (benzimidazole) or 4-nitro-benzimidazole as the heterocyclic base. Based on the structure and antibacterial activity of microcin C, we also prepared their hexapeptidyl conjugates in an effort to improve their uptake potential. We further compared their antibacterial activity with the parent isoleucyl-sulfamoyl adenosine (Ile-SA), both in in vitro and in cellular assays. Surprisingly, the strongest in vitro inhibition was found for the uracil containing analogue 16f. Unfortunately, only very weak growth inhibitory properties were found as of low uptake. The results are discussed in the light of previous literature findings.
- Gadakh, Bharat,Vondenhoff, Gaston,Lescrinier, Eveline,Rozenski, Jef,Froeyen, Mathy,Van Aerschot, Arthur
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p. 2875 - 2886
(2014/05/06)
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- Contiguous metal-mediated base pairs comprising two AgI ions
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The incorporation of transition-metal ions into nucleic acids by using metal-mediated base pairs has proved to be a promising strategy for the site-specific functionalization of these biomolecules. We report herein the formation of Ag+-mediated Hoogsteen-type base pairs comprising 1,3-dideaza-2′-deoxyadenosine and thymidine. By defunctionalizing the Watson-Crick edge of adenine, the formation of regular base pairs is prohibited. The additional substitution of the N3 nitrogen atom of adenine by a methine moiety increases the basicity of the exocyclic amino group. Hence, 1,3-dideazaadenine and thymine are able to incorporate two Ag+ ions into their Hoogsteen-type base pair (as compared with one Ag+ ion in base pairs with 1-deazaadenine and thymine). We show by using a combination of experimental techniques (UV and circular dichroism (CD) spectroscopies, dynamic light scattering, and mass spectrometry) that this type of base pair is compatible with different sequence contexts and can be used contiguously in DNA double helices. The most stable duplexes were observed when using a sequence containing alternating purine and pyrimidine nucleosides. Dispersion-corrected density functional theory calculations have been performed to provide insight into the structure, formation and stabilization of the twofold metalated base pair. They revealed that the metal ions within a base pair are separated by an Ag...Ag distance of about 2.88 A. The Ag-Ag interaction contributes some 16 kcal mol-1 to the overall stability of the doubly metal-mediated base pair, with the dominant contribution to the Ag-Ag bonding resulting from a donor-acceptor interaction between silver 4d-type and 4s orbitals. These Hoogsteen-type base pairs enable a higher functionalization of nucleic acids with metal ions than previously reported metal-mediated base pairs, thereby increasing the potential of DNA-based nanotechnology. Copyright
- Megger, Dominik A.,Fonseca Guerra, Celia,Hoffmann, Jan,Brutschy, Bernhard,Bickelhaupt, F. Matthias,Mueller, Jens
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scheme or table
p. 6533 - 6544
(2011/08/07)
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- Silver(I)-mediated cytosine self-pairing is preferred over hoogsteen-type base pairs with the artificial nucleobase 1,3-dideaza-6-nitropurine
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A 2′-deoxyribonucleoside containing 1,3-dideaza-6-nitropurine was synthesized and incorporated into oligonucleotides. The acid-base properties of this nucleoside and the corresponding N9-methylated derivative were investigated by pD-dependent 1H NMR spectroscopy. A possible formation of Hoogsteen-type base pairs with cytosine was studied by ultraviolet (UV) and circular dichroism (CD) spectroscopy in the presence and absence of Ag(I) and under neutral and acidic conditions, respectively. In each case, no indication for the formation of Hoogsteen-type base pairs was obtained, which is attributed to the higher affinity of cytosine to form self-complementary hemi-protonated base pairs under acidic conditions and metal-mediated homo base pairs in presence of Ag(I), respectively.
- Megger, Dominik A.,Mueller, Jens
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scheme or table
p. 27 - 38
(2010/07/06)
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- Bakers' yeast-catalyzed ring opening of benzofuroxans: An efficient green synthesis of aryl-1,2-diamines
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A simple and inexpensive method for the reductive cleavage of N-O bond of benzofuroxans with bakers' yeast under nonfermenting condition in aqueous media was achieved. The procedure gives excellent yields of aryl-1,2-diamines. Copyright Taylor & Francis Group, LLC.
- Borah, Harsha N.,Prajapati, Dipak,Boruah, Romesh C.
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scheme or table
p. 267 - 272
(2009/04/07)
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- AMINOQUINOXALINE COMPOUND, POLYAMINOQUINOXALINE COMPOUND, AND USE THEREOF
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An aminoquinoxaline compound represented by the following formula (1a), and a polyaminoquinoxaline compound obtained by polymerizing the aminoquinoxaline compound, wherein R1 and R2 independently represent a hydrogen atom, a hydroxyl group, a C1-C10 alkyl group, a C1-C10 alkoxy group, or the like, R3 and R4 independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a C1-C10 alkyl group, a C1-C10 alkoxy group or the like, and X1 represents -NH-R5-NH2 or -NH-R6.
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Page/Page column 21
(2008/06/13)
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- DIAMINE HAVING QUINOXALINE UNIT, POLYIMIDE PRECURSOR, POLYIMIDE AND USE THEREOF
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A diaminobenzene compound is disclosed which is represented by the formula (1). By reacting this compound with a tetracarboxylic acid (derivative), there can be obtained a polyimide which has charge carrier transport properties and is excellent in heat resistance, film strength and thin-film properties.
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- A Convenient, Efficient, and Environmentally Benign Method for Preparing Nitroanilines
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An efficient method for the catalytic monoreduction of aromatic dinitro compounds to nitroanilines is reported. In the presence of selenium catalyst, the dinitroaromatic compounds are selectively reduced by CO/H2O to the corresponding nitroanilines under atmospheric pressure. The mono-reduction occurs in high selectivity regardless of the substitution groups on the aromatic ring without affecting other reducible functional groups.
- Liu, Xiao-Zhi,Lu, Shi-Wei
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p. 1142 - 1143
(2007/10/03)
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- Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base
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A series of dialkyl esters of purine and pyrimidine N-[2- (phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2- chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07-2 μg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1- 0.4 μg/mL) against herpes simplex viruses and (EC50 = 0.006-0.3 μg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 ~0.01-0.02 μg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 ~7.5 μg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2- chloroadenine analogue of PMEA showed substantially (10-100x) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.
- Holy, Antonín,Günter, Jaroslav,Dvo?áková, Hana,Masojídková, Milena,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,De Clercq, Erik
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p. 2064 - 2086
(2007/10/03)
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- An improved procedure for the synthesis of 1,3-dideazaadenosine
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The preparation of the titled compound has been conveniently achieved in five steps, and in 43% overall yield. The large scale monoreduction of 2,6-dinitroaniline, and the stannic chloride catalyzed glycosylation of 4 to obtain 6 as the only product (86%) are two important reactions in this five step synthesis.
- Devlin,Jebaratnam
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p. 711 - 718
(2007/10/02)
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- Convenient Synthesis of 4-Methoxy-3-nitro-1,2-benzenediamine and its Conversion into 6-Methoxy-5-nitroquinoxalines
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4-Methoxy-3-nitro-1,2-benzenediamine (6) has been prepared through nitration of 5-methoxy-2,1,3-benzoselenadiazole, followed by reductive removal of the selenium.Cyclocondensation of 6 with α-dicarbonyl compounds afforded the title quinoxalines, some of them novel and not easily obtainable by direct nitration.Methyl- or phenylglyoxal gave mixtures of quinoxalines in proportions strongly influenced by the acidity of the reaction medium.
- Grivas, Spiros,Tian, Wei
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p. 1109 - 1113
(2007/10/02)
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