- CYTISINE-LINKED ISOFLAVONOID ANTINEOPLASTIC AGENTS FOR THE TREATMENT OF CANCER
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Cytisine-linked isoflavonoids, or pharmaceutically acceptable salts thereof or pharmaceutically acceptable compositions thereof, are useful for the treatment of conditions in which cells have a reliance on peroxisomal HSD17B4 to degrade very long chain fatty acids and provide necessary energy for cell proliferation, such as is seen in colorectal cancer and prostate cancer, for example.
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Paragraph 0089
(2019/01/04)
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- Developing antineoplastic agents that target peroxisomal enzymes: Cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4)
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Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.
- Frasinyuk, Mykhaylo S.,Zhang, Wen,Wyrebek, Przemyslaw,Yu, Tianxin,Xu, Xuehe,Sviripa, Vitaliy M.,Bondarenko, Svitlana P.,Xie, Yanqi,Ngo, Huy X.,Morris, Andrew J.,Mohler, James L.,Fiandalo, Michael V.,Watt, David S.,Liu, Chunming
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supporting information
p. 7623 - 7629
(2017/09/27)
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- Regioselective Alkoxycarbonylation of Allyl Phenyl Ethers Catalyzed by Pd/dppb under Syngas Conditions
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A simple and regioselective synthesis of phenoxy esters and phenylthio esters is reported. The products are obtained by selective alkoxycarbonylation catalyzed by Pd2(dba)3, 1,4-bis(diphenylphisphino)butane (dppb), and syngas (CO/H2) in chloroform/alcohol. This methodology affords bifunctional products in good yield with excellent n-selectivity and without the need to use additives.
- Amézquita-Valencia, Manuel,Alper, Howard
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p. 3860 - 3867
(2016/05/24)
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- Copper-Catalyzed Cross-Coupling Reaction of Allyl Boron Ester with 1°/2°/3°-Halogenated Alkanes
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The cross-coupling reaction of allyl boron ester with 1°/2°/3°-halogenated alkanes in the presence of copper has been developed for the first time, which provides a mild and efficient method for the construction of saturated C(sp3)-C(sp3) bonds. This protocol shows excellent compatibility with the nonactivated primary, secondary, and even tertiary halogenated alkanes under mild conditions.
- Wang, Guang-Zu,Jiang, Jian,Bu, Xiao-Song,Dai, Jian-Jun,Xu, Jun,Fu, Yao,Xu, Hua-Jian
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supporting information
p. 3682 - 3685
(2015/08/18)
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- Engaging unactivated alkyl, alkenyl and aryl iodides in visible-light-mediated free radical reactions
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Radical reactions are a powerful class of chemical transformations. However, the formation of radical species to initiate these reactions has often required the use of stoichiometric amounts of toxic reagents, such as tributyltin hydride. Recently, the use of visible-light-mediated photoredox catalysis to generate radical species has become popular, but the scope of these radical precursors has been limited. Here, we describe the identification of reaction conditions under which photocatalysts such as fac-Ir(ppy) 3 can be utilized to form radicals from unactivated alkyl, alkenyl and aryl iodides. The generated radicals undergo reduction via hydrogen atom abstraction or reductive cyclization. The reaction protocol utilizes only inexpensive reagents, occurs under mild reaction conditions, and shows exceptional functional group tolerance. Reaction efficiency is maintained upon scale-up and decreased catalyst loading, and the reaction time can be significantly shortened when the reaction is performed in a flow reactor.
- Nguyen, John D.,D'Amato, Erica M.,Narayanam, Jagan M. R.,Stephenson, Corey R. J.
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p. 854 - 859
(2012/11/07)
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- Intramolecular triplet energy transfer in flexible molecules: Electronic, dynamic, and structural aspects
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Exothermic intramolecular triplet energy transfer (TET) rate constants in various flexible bichromophoric systems D-(CH2)n-O-A (D = benzoyl, 4-methylbenzoyl; A = 2-naphthyl, 4-, 3-, 2-biphenyl; n = 3-14) have been determined from steady-state quenching and quantum yield measurements. The magnitude of the rate constants in molecules where n = 3 is comparable to those in molecules with a rigid spacer between chromophores, so that a through-bond mechanism is presumed to remain important. A very gradual drop in TET rate constants as the connecting polymethylene chain becomes longer indicates that through-space interactions compete and apparently provide the only mechanism responsible for transfer when n ≥ 5. Rate constants in long molecules (n = 11-14) remain remarkably high (~108 s-1) - lower than in those with four-atom tethers by only 1 order of magnitude. This effect is explained on the basis of rapid conformational equilibria always keeping a sufficient fraction of the molecules coiled so that the two chromophores are close enough to interact within 10 ns, the time required for the competing γ-hydrogen abstraction used to monitor triplet lifetimes. Energy transfer accounts for 40-75% of triplet decay for the longer molecules. This high efficiency indicates that only a small fraction involves static quenching in ground-state conformers with the two ends within 4 A. The majority must represent a combination of rate-determining bond rotations to such geometries and equilibrated conformations with their ends farther apart but still able to undergo energy transfer within 10 ns. Thus, the measured rate constants are, in fact, a weighted average of three different conformational mechanisms. The decrease in rate constant with tether length is not monotonic: a relative increase in rate for medium-chain-length molecules is explained by a larger number of favorable conformers and further, in biphenyl derivatives, by a rotation along the terminal O-C bond between the tether and the aromatic ring. As was expected, replacement of the polymethylene tether with poly(ethylene oxide) promotes better flexibility and thus higher transfer rates. Rate constants were found to be lower by a factor of ~2 when biphenyl rather than naphthyl is the acceptor, in agreement with earlier bimolecular measurements. With the 4-methylbenzoyl group (π,π* lowest triplet) as donor instead of benzoyl (n,π* lowest triplet), a small (~1.5x) but consistent rate increase occurred for all tether lengths.
- Wagner, Peter J.,Klan, Petr
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p. 9626 - 9635
(2007/10/03)
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- The action of sodium hydrogen telluride on olefins
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The action of sodium hydrogen telluride, NaTeH, on non electrophilic carbon-arbon double bonds has been investigated.The reaction is found to be very sensitive to the substituents on the ethylenic linkage. Whereas phenyl conjugated olefins are reduced to alkylbenzenes,the reagent adds to isolated mono and disubstituted double bonds leading to organotellurium derivatives and with gem-disubstituted ones it leads to a mixture of reduction and addition products. These results are interpreted in terms of a radical pair mechanism involving hydrogen atom transfer from hydrogen telluride,HTe- to the double bond.
- Barton, Derek H. R.,Bohe, Luis,Lusinchi, Xavier
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p. 5273 - 5284
(2007/10/02)
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- REGIOSELECTIVITY OF OLEFIN OXIDATION BY IODOSOBENZENE CATALYZED BY METALLOPORPHYRINS: CONTROL BY THE CATALYST
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The regioselectivity of the oxidation of three monosubstituted olefins, 6-phenoxyhex-1-ene, hex-1-ene and styrene, by iodosobenzene in the presence of various Fe-, Mn- or Cr-tetraaryl-porphyrins, was studied.It was found that, besides epoxides, known products from such systems, allylic alcohols and aldehydes were formed, the latter not being derived from the corresponding epoxides.The relative importance of these reactions greatly depends upon both the metal and porphyrin constituents of the catalyst.More particularly, the competition between epoxidation and allylic hydroxylation can be efficiently controlled by non bonded interactions between the olefin and porphyrin substituents.No hydroxylation of the aromatic rings and no oxidative dealkylation of the ether function was detected.
- Mansuy, Daniel,Leclaire, Jacques,Fontecave, Marc,Dansette, Patrick
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p. 2847 - 2857
(2007/10/02)
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