- Iron(II) and Copper(I) Control the Total Regioselectivity in the Hydrobromination of Alkenes
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A new method that allows the complete control of the regioselectivity of the hydrobromination reaction of alkenes is described. Herein, we report a radical procedure with TMSBr and oxygen as common reagents, where the formation of the anti-Markovnikov product occurs in the presence of parts per million amounts of the Cu(I) species and the formation of the Markovnikov product occurs in the presence of 30 mol % iron(II) bromide. Density functional theory calculations combined with Fukui's radical susceptibilities support the obtained results.
- Cruz, Daniel A.,Sinka, Victoria,De Armas, Pedro,Steingruber, Hugo Sebastian,Fernández, Israel,Martín, Víctor S.,Miranda, Pedro O.,Padrón, Juan I.
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p. 6105 - 6109
(2021/08/18)
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- The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH
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Based on the SAR of both α1-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [C6min]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α1-AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined.
- Chen, Kaixuan,Jiang, Zhenzhou,Liu, Shuwen,Xi, Baomin,Yang, Fubiao,Zeng, Li-Yan,Zeng, Yunong
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- Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX
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Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in?vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2?h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in?vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.
- Chambers, Janice E.,Chambers, Howard W.,Funck, Kristen E.,Meek, Edward C.,Pringle, Ronald B.,Ross, Matthew K.
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p. 154 - 159
(2016/12/06)
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- Synthesis and biological evaluation of vinyl ether-containing azole derivatives as inhibitors of Trichophyton rubrum
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In an attempt to search for many target compounds with excellent activities, a series of vinyl ether-containing azole derivatives were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against Trichophyton rubrum in vitro indicated that most of the synthesized compounds showed excellent activities. In comparison with fluconazole, itraconazole, voriconazole, omoconazole and amphotericin B, several compounds (such as 7d, 7g and 7h) exhibited more potent inhibitory activities, suggesting that they were promising leads for the development of novel antifungal agents.
- Wang, Lulu,Yang, Wenge,Wang, Kai,Zhu, Jing,Shen, Fei,Hu, Yonghong
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scheme or table
p. 4887 - 4890
(2012/08/07)
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- Fragmentations observed in the reactions of α-methoxy-γ- alkoxyalkyl iodide substrates with super-electron-donors derived from 4-DMAP and N-methylbenzimidazole
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Reactions of super-electron-donors (SEDs) derived from 4- dimethylaminopyridine and from N-methylbenzimidazole with α-methoxy- γ-alkoxyalkyl iodides lead to liberation of the γ-alkoxy groups as their alcohols. This is consistent with generation of alkyl radicals from the alkyl halide precursors, and trapping of these radicals by the radical-cation of the SED, followed by a heterolytic fragmentation.
- Sword, Ryan,Baldwin, Luke A.,Murphy, John A.
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experimental part
p. 3560 - 3570
(2011/06/20)
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- Discovery of highly potent novel antifungal azoles by structure-based rational design
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On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of new azoles were designed and synthesized. All the new azoles show excellent in vitro activity against most of the tested pathogenic fungi, which represent a class of promising leads for the development of novel antifungal agents. The MIC80 value of compounds 8c, 8i and 8n against C. albicans is 0.001 μg/mL, indicating that these compounds are more potent than fluconazole, itraconazole and voriconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions.
- Wang, Wenya,Sheng, Chunquan,Che, Xiaoying,Ji, Haitao,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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supporting information; experimental part
p. 5965 - 5969
(2010/07/04)
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- Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory t cells in autoimmune diseases
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The lymphocyte K+ channel Kv1.3 constitutes an attractive pharmacological target for the selective suppression of terminally differentiated effector memory T (TEM) cells in T cell mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Unfortunately, none of the existing small molecule Kv1.3 blockers is selective, and many of them, such as correolide, 4-phenyl-4-[3-(methoxyphenyl)-3-oxo-2- azapropyl] cyclohexanone, and our own compound Psora-4 inhibit the cardiac K+ channel Kv1.5. By further exploring the structure activity relationship around Psora-4 through a combination of traditional medicinal chemistry and whole-cell patch-clamp, we identified a series of new phenoxyalkoxypsoralens that exhibit 2- to 50-fold selectivity for Kv1.3 over Kv1.5, depending on their exact substitution pattern. The most potent and "druglike" compound of this series, 5-(4-phenoxybutoxy)psoralen (PAP-1), blocks Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 of 2 nM, by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33- to 125-fold selective over other Kv1-family channels, and 500- to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+, Ca2+, and Cl- channels. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, and affects cytochrome P450-dependent enzymes only at micromolar concentrations. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a TEM cell-mediated reaction, in rats. PAP-1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulators. Copyright
- Schmitz, Alexander,Sankaranarayanan, Ananthakrishnan,Azam, Philippe,Schmidt-Lassen, Kristina,Homerick, Daniel,Haensel, Wolfram,Wulff, Heike
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p. 1254 - 1270
(2007/10/03)
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- Effect of chromophore-charge distance on the energy transfer properties of water-soluble conjugated oligomers
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The synthesis of 1,4-bis(9,9′-bis(3″-(N,N,N-trimethylammonium)-propyl)-2 ′-fluorenyl)benzene tetrabromide (C3), 1,4-bis(9,9′-bis(4″-(N,N,N-trimethylammonium)-butyl)-2 ′-fluorenyl)benzene tetrabromide (C4), 1,4-bis(9,9′-bis(6″-(N,N,N-
- Liu, Bin,Gaylord, Brent S.,Wang, Shu,Bazan, Guillermo C.
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p. 6705 - 6714
(2007/10/03)
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- New, Easily Removable Poly(ethylene glycol) Supports for the Liquid-Phase Method of Peptide Synthesis
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Poly(ethylene glycol) (PEG) was derivatized with a number of acid-cleavable and photocleavable anchoring groups in order to test the applicability of these derivatives as supports in liquid-phase peptide synthesis.PEG was subjected to rapid and quantitati
- Pillai, V. N. Rajasekharan,Mutter, Manfred,Bayer, Ernst,Gatfield, Ian
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p. 5364 - 5370
(2007/10/02)
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