- Novel tdp1 inhibitors based on adamantane connected with monoterpene moieties via heterocyclic fragments
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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35–0.57 μM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (μM) values were seen from the mid-teens to no effect at 100 μM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.
- Chepanova, Arina A.,Dyrkheeva, Nadezhda S.,Ilina, Ekaterina S.,Korchagina, Dina V.,Lavrik, Olga I.,Mozhaitsev, Evgenii S.,Munkuev, Aldar A.,Reynisson, Jóhannes,Salakhutdinov, Nariman F.,Suslov, Evgeniy V.,Volcho, Konstantin P.,Zakharenko, Alexandra L.,Zakharova, Olga D.
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- Replacement of an Indole Scaffold Targeting Human 15-Lipoxygenase-1 Using Combinatorial Chemistry
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Human 15-lipoxygenase-1 (15-LOX-1) belongs to the class of lipoxygenases, which catalyze oxygenation of polyunsaturated fatty acids, such as arachidonic and linoleic acid. Recent studies have shown that 15-LOX-1 plays an important role in physiological processes linked to several diseases such as airway inflammation disease, coronary artery disease, and several types of cancer such as rectal, colon, breast and prostate cancer. In this study, we aimed to extend the structural diversity of 15-LOX-1 inhibitors, starting from the recently identified indolyl core. In order to find new scaffolds, we employed a combinatorial approach using various aromatic aldehydes and an aliphatic hydrazide tail. This scaffold-hopping study resulted in the identification of the 3-pyridylring as a suitable replacement of the indolyl core with an inhibitory activity in the micromolar range (IC50=16±6 μm) and a rapid and efficient structure–activity relationship investigation.
- Prismawan, Deka,van der Vlag, Ramon,Guo, Hao,Dekker, Frank J.,Hirsch, Anna K. H.
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- Amide linked redox-active naphthoquinones for the treatment of mitochondrial dysfunction
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Naphthoquinones have been investigated as potential therapeutic molecules for neurodegenerative disorders, which is largely based on their anti-oxidative potential. However, a theoretical framework for the pleiotropic protective effects of naphthoquinone derivatives is largely missing. We synthesized a library of novel short chain 2,3-disubstituted naphthoquinone derivatives and measured their redox characteristics to identify a potential connection with their biological activity. Using two cell lines with different reducing potential, the compounds were tested for their inherent toxicity, acute rescue of ATP levels and cytoprotective activity. For the first time, a structure-activity-relationship for naphthoquinones has been established. Our results clearly demonstrate that it is the group on the alkyl side chain and not solely the redox characteristics of the naphthoquinone unit or lipophilicity that determines the extent of cytoprotection by individual compounds. From this, we developed a number of amide containing naphthoquinones with superior activity in ATP rescue and cell viability models compared to the clinically used benzoquinone idebenone.
- Woolley, Krystel L.,Nadikudi, Monila,Koupaei, Mitra N.,Corban, Monika,McCartney, Paul,Bissember, Alex C.,Lewis, Trevor W.,Gueven, Nuri,Smith, Jason A.
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supporting information
p. 399 - 412
(2019/03/28)
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- IMINIUM SALT ORGANOCATALYSTS, METHODS OF MAKING, AND METHODS OF USING
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Aspects of the present disclosure include compositions comprising iminium catalyst, methods of making, methods of using, and the like.
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Page/Page column 37-38
(2018/04/11)
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- Oxidative Transformations of Biosourced Alcohols Catalyzed by Earth-Abundant Transition Metals
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The catalytic acceptorless dehydrogenative oxidation of biosourced alcohols into carboxylic acid salts was achieved using earth-abundant Fe and Mn complexes that feature aliphatic PNP pincer ligands in good to excellent yields. The Fe derivatives were characterized by using 57Fe NMR spectroscopy. Mn pincer catalysts are catalytically more efficient than their Fe counterparts thanks to their robustness under basic conditions. Attempts to generate aldehydes from alcohols were not successful using the Fe and Mn species, but a commercially available Ru analogue achieves this transformation selectively under very mild conditions in the presence of a large excess of acetone as a hydrogen acceptor.
- Nguyen, Duc Hanh,Morin, Yohann,Zhang, Lei,Trivelli, Xavier,Capet, Frédéric,Paul, Sébastien,Desset, Simon,Dumeignil, Franck,Gauvin, Régis M.
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p. 2652 - 2660
(2017/07/28)
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- An Iminium Salt Organocatalyst for Selective Aliphatic C-H Hydroxylation
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The first examples of catalysis of aliphatic C-H hydroxylation by an iminium salt are presented. The method allows the selective organocatalytic hydroxylation of unactivated 3° C-H bonds at room temperature using hydrogen peroxide as the terminal oxidant. Hydroxylation of an unactivated 2° C-H bond is also demonstrated. Furthermore, improved functional group compatibility over other catalytic methods is reported in the form of selectivity for aliphatic C-H hydroxylation over alcohol oxidation. On the basis of initial mechanistic studies, an oxaziridinium species is proposed as the active oxidant.
- Wang, Daoyong,Shuler, William G.,Pierce, Conor J.,Hilinski, Michael K.
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supporting information
p. 3826 - 3829
(2016/08/16)
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- Metal-free, hydroacylation of CC and NN bonds via aerobic C-H activation of aldehydes, and reaction of the products thereof
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In this report, a thorough evaluation of the use of aerobically initiated, metal-free hydroacylation of various CC and NN acceptor molecules with a wide range of aldehydes is presented. The aerobic-activation conditions that have been developed are in sharp contrast to previous conditions for hydroacylation, which tend to use transition metals, peroxides that require thermal or photochemical degradation, or N-heterocyclic carbenes. The mildness of the conditions enables a number of reactions involving sensitive reaction partners and, perhaps most significantly, allows for α-functionalised chiral aldehydes to undergo radical-based hydroacylation with complete retention of optical purity. We also demonstrate how the resulting hydroacylation products can be transformed into other useful intermediates, such as γ-keto- sulfonamides, sultams, sultones, cyclic N-sulfonyl imines and amides.
- Chudasama, Vijay,Akhbar, Ahmed R.,Bahou, Karim A.,Fitzmaurice, Richard J.,Caddick, Stephen
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p. 7301 - 7317
(2013/10/22)
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- Chemoselective hydrogenation of the olefinic bonds using a palladium/magnesium-lanthanum mixed oxide catalyst
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A palladium/magnesium-lanthanum mixed oxide catalyst is found to be an efficient heterogeneous catalyst for the chemoselective hydrogenation of olefinic double bonds in the presence of various functional groups. The catalyst was recovered by centrifugation and reused for several cycles with consistent activity and selectivity. Copyright
- Kantam, Mannepalli Lakshmi,Kishore, Ramineni,Yadav, Jagjit,Sudhakar, Medak,Venugopal, Akula
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supporting information; experimental part
p. 663 - 669
(2012/04/23)
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- Nonsteroidal benzophenone-containing analogues of cholesterol
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The four benzophenones, 10-13, containing the natural side chain of cholesterol (1) have been synthesized to explore whether the tetracyclic nucleus of 1 is essential for its biochemical properties. The syntheses of analogues 10, 11, and 13 feature efficient introduction of the alkyl side chain by Suzuki coupling. Preliminary biochemical evaluation of 10 and 12 suggests that the sterol tetracyclic nucleus is not required for biological compatibility with 1.
- Gan, Yonghong,Blank, David H.,Ney, Joshua E.,Spencer, Thomas A.
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p. 5864 - 5869
(2007/10/03)
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- Oxidation of alcohols with catalytic amounts of IBX
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Herein we present a catalytic IBX-based method for the oxidation of alcohols. Using this system a variety of benzylic alcohols were transformed to aldehydes in good yields whereas secondary alcohols were easily converted to ketones. Primary aliphatic alcohols were oxidised to the corresponding carboxylic acids. 2-lodobenzoic acid can also be used instead of IBX. Georg Thieme Verlag Stuttgart.
- Schulze, Agnes,Giannis, Athanassios
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p. 257 - 260
(2007/10/03)
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- Oxone/sodium chloride: A simple and efficient catalytic system for the oxidation of alcohols to symmetric esters and ketones
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An efficient method for the oxidation of alcohols is presented. The use of catalytic amounts of sodium chloride in combination with oxone allows the conversion primary aliphatic alcohols to symmetric esters. Secondary alcohols can be easily oxidized to ketones, and benzylic alcohols are converted to the corresponding aldehydes. The method is cost effective and enviromentally benign. Copyright Taylor & Francis Group, LLC.
- Schulze, Agnes,Pagona, Georgia,Giannis, Athanassios
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p. 1147 - 1156
(2007/10/03)
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- Substituent effects on regioselective intramolecular oxidation of unactivated C-H bonds: Stereoselective synthesis of substituted tetrahydropyrans
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Our previously reported intramolecular δ-selective C-H bond oxidation by dioxiranes, generated in situ from activated ketones, offers a novel approach to the synthesis of tetrahydropyrans. To synthesize substituted tetrahydropyrans in a stereoselective manner, we examined the effects of alkyl, nitrogen, and oxygen substituents at the α-,β-, and γ-sites of ketones on the stereoselectivities of intramolecular C-H bond oxidation reactions. Ketones 1-4 with a methyl group at the α-, β-, or γ-site showed the diastereo-selectivities that agreed with the trans/cis ratio predicted by considering steric interactions in the transition states. Furthermore, ketones 5 and 6 carrying a bulky phthalimido group at the α- and the β-sites, respectively, exhibited excellent stereoselectivity, each affording only one diastereomer. However, ketones 9 and 10 bearing β-oxygen substituents gave reversed stereoselectivity as compared to those with β-alkyl or nitrogen substituents, possibly because of the hydrogen bonding interaction in the transition state. For ketones 12 and 13, both bearing methyl and silyloxy groups, the hydrogen bonding interaction was probably more important than the steric effect on the diastereoselectivity of intramolecular oxidation of C-H bonds.
- Wong, Man-Kin,Chung, Nga-Wai,He, Lan,Yang, Dan
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p. 158 - 162
(2007/10/03)
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- Configurations of polyunsaturated sesterterpenoids from the diatom, Haslea ostrearia
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The partial configurations of C25 isoprenoid alkenes isolated from the diatom Haslea ostrearia Gaillon (Simonsen) have been established. A combination of NMR spectroscopy studies of the alkenes with chiral shift reagents in conjunction with soluble silver β-diketonate complexes and enantioselective gas chromatography of oxidation products of the alkenes was used. Unexpected differences in highly branched isoprenoid isomer configurations were observed between different laboratory cultures of the alga. (C) 2000 Elsevier Science Ltd.
- Johns, Lesley,Belt, Simon,Lewis, C. Anthony,Rowland, Steven,Masse, Guillaume,Robert, Jean-Michel,Koenig, Wilfried A.
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p. 607 - 611
(2007/10/03)
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- Intramolecular Nucleophilic Acyl Substitution Reactions Mediated by Samarium(II) Iodide: A Convergent Approach to the Preparation of Enantiomerically Enriched 4-Hydroxy Ketones from 3-Iodopropyl Carboxylates
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Intramolecular nucleophilic acyl substitution (I NAS) reactions of substituted δ-iodopropylcarboxylates have been achieved using samarium(II) iodide (SmI2) in the presence of an iron(III) catalyst.Diverse ester starting materials containing stereogenic centers placed in varying postions on the substrates have been converted to acyclic 4-hydroxy ketone derivatives in good yields using this method.No racemization of stereogenic centers α to the carbonyl was observed in any of the reactions examined.Consequently, the method serves as a convenient, high-yield synthesis of functionalized, enantiomerically enriched acyclic ketones possesing stereogenic centers far removed from one another.
- Molander, Gary A.,Shakya, Sagar R.
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p. 3445 - 3452
(2007/10/02)
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