19812-64-7Relevant articles and documents
Discovery and Pharmacological Studies of 4-Hydroxyphenyl-Derived Phosphonium Salts Active in a Mouse Model of Visceral Leishmaniasis
Manzano, José Ignacio,Cueto-Díaz, Eduardo J.,Olías-Molero, Ana Isabel,Perea, Ana,Herraiz, Tomás,Torrado, Juan J.,Alunda, José María,Gamarro, Francisco,Dardonville, Christophe
, p. 10664 - 10675 (2019)
We report the discovery of new 4-hydroxyphenyl phosphonium salt derivatives active in the submicromolar range (EC50 from 0.04 to 0.28 μM, SI > 10) against the protozoan parasite Leishmania donovani. The pharmacokinetics and in vivo oral efficacy of compound 1 [(16-(2,4-dihydroxyphenyl)-16-oxohexadecyl)triphenylphosphonium bromide] in a mouse model of visceral leishmaniasis were established. Compound 1 reduced the parasite load in spleen (98.9%) and liver (95.3%) of infected mice after an oral dosage of four daily doses of 1.5 mg/kg. Mode of action studies showed that compound 1 diffuses across the plasma membrane, as designed, and targets the mitochondrion of Leishmania parasites. Disruption of the energetic metabolism, with a decrease of intracellular ATP levels as well as mitochondrial depolarization together with a significant reactive oxygen species production, contributes to the leishmanicidal effect of 1. Importantly, this compound was equally effective against antimonials and miltefosine-resistant clinical isolates of Leishmania infantum, indicating its potential as antileishmanial lead.
Electrostatic Control of Macrocyclization Reactions within Nanospaces
Wang, Kaiya,Cai, Xiaoyang,Yao, Wei,Tang, Du,Kataria, Rhea,Ashbaugh, Henry S.,Byers, Larry D,Gibb, Bruce C.
, p. 6740 - 6747 (2019)
The intrinsic structural complexity of proteins makes it hard to identify the contributions of each noncovalent interaction behind the remarkable rate accelerations of enzymes. Coulombic forces are evidently primary, but despite developments in artificial nanoreactor design, a picture of the extent to which these can contribute has not been forthcoming. Here we report on two supramolecular capsules that possess structurally identical inner-spaces that differ in the electrostatic potential (EP) field that envelops them: one positive and one negative. This architecture means that only changes in the EP field influence the chemical properties of encapsulated species. We quantify these influences via acidity and rates of cyclization measurements for encapsulated guests, and we confirm the primary role of Coulombic forces with a simple mathematical model approximating the capsules as Born spheres within a continuum dielectric. These results reveal the reaction rate accelerations possible under Coulombic control and highlight important design criteria for nanoreactors.
Interaction between Disodium 1,14-tetradecanediyl Disulfate and Sodium Dodecyl Sulfate or Poly(oxyethylene) Nonyl Phenyl Ether on Alumina
Esumi, Kunio,Asano, Yuki,Sakamoto, Yuichi,Meguro, Kenjiro
, p. 1037 - 1041 (1989)
The interactions between disodium 1,14-tetradecanediyl disulfate (α,ωC14) and sodium dodecyl sulfate (SDS) or poly(oxyethylene) nonyl phenyl ether (NP 7.5) on α-alumina have been studied by measuring the zeta potential, the mean particle size, the amounts of surfactants adsorbed, and the fluorescence spectra of pyrene.When α,ωC14, SDS, or NP 7.5 as a second additive is added to alumina previously flocculated by the addition of SDS or α,ωC14, as a first additive, the flocculated alumina redisperses in the α,ωC14-SDS and α,ωC14-SDS and α,ωC14-NP 7.5 systems.For the α,ωC14-SDS and αωC14-NP 7.5 systems, the redispersion of alumina proceeds in such a manner that the hydophobic parts of SDS or NP 7.5 are in contact with the α,ωC14-coated alumina and the hydrophilic polar groups direct out to aqueous solution, resulting in the formation of mixed bilayers on the alumina, while for the α,ωC14-SDS system the adsorption of SDS on the α,ωC14-coated alumina is not enough to attain the redispersion of alumina.The measurement of the ratio I1/I3 of intensities of the first and third vibrionic bands of the pyrene monomer fluorescence spectra indicates that pyrene is solubilized in a much lower polar site for the αωC14-SDS mixed bilayer than for the mixed bilayer of α,ωC14-NP7.5.
The Thermodynamics of the Micelle Formation of Sodium α,ω-Alkanediyl Disulfate
Ikeda, Kenji,Nakasima, Tomoko,Esumi, Kunio,Meguro, Kenjiro
, p. 578 - 580 (1989)
The critical micelle concentrations of a α,ω-type surfactant: (sodium α,ω-alkanediyl disulfate: n=12, 14, 16) in an aqueous solution have been determined by studying the electrical conductivity, and the free energies of the micelle formation have then been estimated from these data.The free energy of micelle formation of a α,ω-type surfactant was smaller than that of a normal-type surfactant with the same alkyl chain length as the α,ω-type one.The free-energy changes per -(CH2)-segment was also calculated from these data.It is found that the free-energy change per -(CH2)-segment of the α,ω-type surfactant is -11.1 -1>.
Total synthesis of (3R,16E,20E,23R)-(-)-eushearilide and structural determination of naturally occurring eushearilide
Tonoi, Takayuki,Kawahara, Ryo,Yoshinaga, Yutaka,Inohana, Takehiko,Fujimori, Keiko,Shiina, Isamu
, p. 1356 - 1359 (2015)
An asymmetric total synthesis of the proposed structure of (16Z,20E)-eushearilide, a novel 24-membered macrolide, was achieved via an enantioselective aldol reaction and 2-methyl-6-nitrobenzoic anhydride-mediated macrolactonization. The obtained synthetic compounds were not identical to the natural product. The newly proposed most likely structure of eushearilide, (±)-(16E,20E)-eushearilide, was determined on the basis of detailed NMR analysis, and (3R,16E,20E,23R)-(-)-eushearilide was successfully synthesized. A comparison of the optical rotation of (3R,16E,20E,23R)-(-)-eushearilide with that of the natural product confirmed that the true structure of naturally occurring eushearilide is the (3S,16E,20E,23S)-(+)-form.
Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis
Fiedler, Tobias,Barbasiewicz, Micha?,Stollenz, Michael,Gladysz, John A.
, p. 2354 - 2365 (2018)
Two routes to the title compounds are evaluated. First, a ca. 0.01 M CH2Cl2 solution of H3B·P((CH2)6CH=CH2)3 (1·BH3) is treated with 5 mol % of Grubbs' first generation catalyst (0 °C to reflux), followed by H2 (5 bar) and Wilkinson's catalyst (55 °C). Column chromatography affords H3B·P(n-C8H17)3 (1%), H3B·P((CH2)13CH2)(n-C8H17) (8%; see text for tie bars that indicate additional phosphorus–carbon linkages, which are coded in the abstract with italics), H3B·P((CH2)13CH2)((CH2)14)P((CH2)13CH2)·BH3 (6·2BH3, 10%), in,out-H3B·P((CH2)14)3P·BH3 (in,out-2·2BH3, 4%) and the stereoisomer (in,in/out,out)-2·2BH3 (2%). Four of these structures are verified by independent syntheses. Second, 1,14-tetradecanedioic acid is converted (reduction, bromination, Arbuzov reaction, LiAlH4) to H2P((CH2)14)PH2 (10; 76% overall yield). The reaction with H3B·SMe2 gives 10·2BH3, which is treated with n-BuLi (4.4 equiv) and Br(CH2)6CH=CH2 (4.0 equiv) to afford the tetraalkenyl precursor (H2C=CH(CH2)6)2(H3B)P((CH2)14)P(BH3)((CH2)6CH=CH2)2 (11·2BH3; 18%). Alternative approaches to 11·2BH3 (e.g., via 11) were unsuccessful. An analogous metathesis/hydrogenation/chromatography sequence with 11·2BH3 (0.0010 M in CH2Cl2) gives 6·2BH3 (5%), in,out-2·2BH3 (6%), and (in,in/out,out)-2·2BH3 (7%). Despite the doubled yield of 2·2BH3, the longer synthesis of 11·2BH3 vs 1·BH3 renders the two routes a toss-up; neither compares favorably with precious metal templated syntheses.
Tocopherol long chain fatty alcohols decrease the production of TNF-α and NO radicals by activated microglial cells
Muller, Thierry,Grandbarbe, Luc,Morga, Eleonora,Heuschling, Paul,Luu, Bang
, p. 6023 - 6026 (2004)
Tocopherol derivatives were found to strongly modulate microglial activation induced by lipopolysaccharide. The synthesis of a series of Tocopherol long chain Fatty Alcohols (TFA) and their biological activities on the modulation of microglial activation are described. Specifically, the 2-(12-hydroxy-dodecyl)-2,5,7,8-tetramethyl-chroman-6-ol, the TFA bearing 12 carbon atoms on the side chain (n = 12), shows the most potent inhibition of secretion on nitric oxide (NO) and tumour necrosis factor-α (TNF-α) by lipopolysaccharide (LPS)-activated microglia.
Synthesis of 13C-labelled cutin and suberin monomeric dicarboxylic acids of the general formula HO213C-(CH2)n-13CO2H (n = 10, 12, 14, 16, 18, 20, 22, 24, 26, 28)
Schink, Carina,Spielvogel, Sandra,Imhof, Wolfgang
, p. 14 - 29 (2020/11/30)
13C-labeled dicarboxylic acids HO213C-(CH2)n-13CO2H (n = 10, 12, 14, 16, 18, 20, 22, 24, 26, 28) have been synthesized as internal standards for LC-MS and GC-MS analysis of cutin and suberin monomer degradation by soil-based microorganisms. Different synthetic strategies had to be applied depending on the chain length of the respective synthetic target and because of economic considerations. 13C-labels were introduced by nucleophilic substitution of a suitable leaving group with labelled potassium cyanide and subsequent hydrolysis of the nitriles to produce the corresponding dicarboxylic acids. All new compounds are characterized by GC/MS, IR, and NMR methods as well as by elemental analysis.
Novel insights into oxidation of fatty acids and fatty alcohols by cytochrome P450 monooxygenase CYP4B1
Thesseling, Florian A.,Hutter, Michael C.,Wiek, Constanze,Kowalski, John P.,Rettie, Allan E.,Girhard, Marco
, (2019/12/12)
CYP4B1 is an enigmatic mammalian cytochrome P450 monooxygenase acting at the interface between xenobiotic and endobiotic metabolism. A prominent CYP4B1 substrate is the furan pro-toxin 4-ipomeanol (IPO). Our recent investigation on metabolism of IPO related compounds that maintain the furan functionality of IPO while replacing its alcohol group with alkyl chains of varying structure and length revealed that, in addition to cytotoxic reactive metabolite formation (resulting from furan activation) non-cytotoxic ω-hydroxylation at the alkyl chain can also occur. We hypothesized that substrate reorientations may happen in the active site of CYP4B1. These findings prompted us to re-investigate oxidation of unsaturated fatty acids and fatty alcohols with C9–C16 carbon chain length by CYP4B1. Strikingly, we found that besides the previously reported ω- and ω-1-hydroxylations, CYP4B1 is also capable of α-, β-, γ-, and δ-fatty acid hydroxylation. In contrast, fatty alcohols of the same chain length are exclusively hydroxylated at ω, ω-1, and ω-2 positions. Docking results for the corresponding CYP4B1-substrate complexes revealed that fatty acids can adopt U-shaped bonding conformations, such that carbon atoms in both arms may approach the heme-iron. Quantum chemical estimates of activation energies of the hydrogen radical abstraction by the reactive compound 1 as well as electron densities of the substrate orbitals led to the conclusion that fatty acid and fatty alcohol oxidations by CYP4B1 are kinetically controlled reactions.
METHOD FOR PRODUCING EUSHEARILIDES
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Paragraph 0064; 0079; 0080, (2017/09/12)
Provided are: eushearilides; a method for producing eushearilides; a production intermediate; and a pharmaceutical composition containing eushearilides. By having the Wittig reaction process, Mukaiyama Aldol reaction process and Macrolactonizaion process serve as key processes, eushearilides represented by formula (I) are efficiently produced.
