The peroxidation of linoleic acid (LA) in the absence and presence of either Cu(II) ions alone or Cu(II)‐ascorbate combination was investigated in aerated and incubated emulsions at 37°C and pH 7. LA peroxidation induced by either copper(II) or copper(II)‐ascorbic acid system followed pseudo‐first order kinetics with respect to primary (hydroperoxides) and secondary (aldehydes‐ and ketones‐like) oxidation products, detected by ferric‐thiocyanate and TBARS tests, respectively. α‐Tocopherol showed both antioxidant and prooxidant effects depending on concentration and also on the simultaneous presence of Cu(II) and ascorbate. Copper(II)‐ascorbate combinations generally led to distinct antioxidant behavior at low concentrations of α‐tocopherol and slight prooxidant behavior at high concentrations of α‐tocopherol, probably associated with the recycling of tocopherol by ascorbate through reaction with tocopheroxyl radical, while the scavenging effect of α‐tocopherol on lipid peroxidation was maintained as long as ascorbate was present. On the other hand, in Cu(II) solutions without ascorbate, the antioxidant behavior of tocopherol required higher concentrations of this compound because there was no ascorbate to regenerate it. Practical applications: Linoleic acid (LA) peroxidation induced by either copper(II) or copper(II)‐ascorbic acid system followed pseudo‐first order kinetics with respect to primary (hydroperoxides) and secondary (e.g., aldehydes and ketones) oxidation products. α‐Tocopherol showed both antioxidant and prooxidant effects depending on concentration and also on the simultaneous presence of Cu(II) and ascorbate. The findings of this study are believed to be useful to better understand the actual role of α‐tocopherol in the preservation of heterogenous food samples such as lipid emulsions. Since α‐tocopherol (vitamin E) is considered to be physiologically the most important lipid‐soluble chain‐breaking antioxidant of human cell membranes, the results can be extended to in vivo protection of lipid oxidation. 相似文献
Poly(2,2′‐imidazole‐5,5′‐bibenzimidazole) (PBI‐imi) was synthesized via the polycondensation between 3,3′,4,4′‐tetraaminobiphenyl and 4,5‐imidazole‐dicarboxylic acid. Effects of the reaction conditions on the intrinsic viscosity of the synthesized polymers were studied. The results show that the molecular weight of the polymers increases with increasing monomer concentration and reaction time, and then levels off. With higher reaction temperature, the molecular weight of the polymer is higher. With the additional imidazole group in the backbone, PBI‐imi shows improved phosphoric acid doping ability, as well as a little higher proton conductivity when compared with widely used poly[2,2′‐(m‐phenylene)‐5,5′‐bibenzimidazole] (PBI‐ph).Whereas, PBI‐imi and PBI‐ph have the similar chemical oxidation stability. PBI‐imi/3.0 H3PO4 composite membranes exhibit a proton conductivity as high as 10–4 S cm–1 at 150 °C under anhydrous condition. The temperature dependence of proton conductivity of acid doped PBI‐imi can be modeled by an Arrhenius equation. 相似文献
Copolymers of poly(2,5‐benzimidazole) (ABPBI) and poly[2,2′‐(p‐phenylene)‐5,5′‐bibenzimidazole] (pPBI) were synthesized for use as fuel cell membranes to take advantage of the properties of both constituents. The composition of the copolymers were controlled by changing the feed ratio of 3,4‐diaminobenzoic acid and terephthalic acid with 3,3′‐diaminobenzidine in the polycondensation reaction. The copolymer membranes showed higher conductivities, better mechanical properties, and larger acid absorbing abilities than commercial poly[2,2′‐(m‐phenylene)‐5,5′‐bibenzimidazole] membranes.
Functionalized α‐arylamino‐α′‐chloro ketones are obtained in high yield via a straightforward homologation reaction of Weinreb amides derived from N‐arylglycines using in situ generated chloromethyllithium. The use of the Weinreb amides is essential and allows the chemoselective homologation of N‐aryl‐N‐substituted glycine analogues, a transformation which is not possible using similar glycine esters. The procedure is promising for the large‐scale preparation of α‐amino‐α′‐chloropropanones, which are valuable precursors for a variety of bioactive compounds. 相似文献
The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1R and OX2R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1R or OX2R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models. 相似文献
The ramipril derivative N,N′‐dioxide 3g ‐indium(III) complex was found to be an efficient catalyst for the allylation of the aromatic α‐keto phosphonates. The corresponding α‐hydroxy phosphonates were obtained with high yields (up to 98 %) and high enantioselectivities (up to 91 % ee). A bifunctional catalyst system was described with an N‐oxide as Lewis base activating tetraallyltin and indium as Lewis acid activating aromatic α‐keto phosphonates. A possible catalytic cycle has been proposed to explain the mechanism of the reaction. 相似文献
CTP synthase (CTPS) catalyzes the conversion of UTP to CTP and is a target for the development of antiviral, anticancer, antiprotozoal, and immunosuppressive agents. Exposure of cell lines to the antineoplastic cytidine analogue gemcitabine causes depletion of intracellular CTP levels, but the direct inhibition of CTPS by its metabolite gemcitabine‐5′‐triphosphate (dF‐dCTP) has not been demonstrated. We show that dF‐dCTP is a potent competitive inhibitor of Escherichia coli CTPS with respect to UTP [Ki=(3.0±0.1) μm ], and that its binding affinity exceeds that of CTP ≈75‐fold. Site‐directed mutagenesis studies indicated that Glu149 is an important binding determinant for both CTP and dF‐dCTP. Comparison of the binding affinities of the 5′‐triphosphates of 2′‐fluoro‐2′‐deoxycytidine and 2′‐fluoro‐2′‐deoxyarabinocytidine revealed that the 2′‐F‐arabino group contributes markedly to the strong binding of dF‐dCTP. Geminal 2′‐F substitution on UTP (dF‐dUTP) did not result in an increase in binding affinity with CTPS. Remarkably, CTPS catalyzed the conversion of dF‐dUTP into dF‐dCTP, thus suggesting that dF‐dCTP might be regenerated in vivo from its catabolite dF‐dUTP. 相似文献
The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)2] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time. 相似文献
The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off‐target‐related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA‐approved proteasome inhibitors bortezomib ( 1 ) or carfilzomib ( 2 ). A systematic comparison of electrophilic headgroups recently identified the class of α‐keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure–activity relationship (SAR)‐based approach for rational ligand design using an electronic parameter (Hammett’s σ) and in silico molecular modeling. This resulted in the tripeptidic α‐keto phenylamide BSc4999 [(S)‐3‐(benzyloxycarbonyl‐(S)‐leucyl‐(S)‐leucylamino)‐5‐methyl‐2‐oxo‐N‐(2,4‐dimethylphenyl)hexanamide, 6 a ], a highly potent (IC50=38 nM ), cell‐permeable, and slowly reversible covalent inhibitor which targets both the primed and non‐primed sites of the proteasome’s substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new α‐keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies. 相似文献
A series of sugar‐modified derivatives of cytostatic 7‐heteroaryl‐7‐deazaadenosines (2′‐deoxy‐2′‐fluororibo‐ and 2′‐deoxy‐2′,2′‐difluororibonucleosides) bearing an aryl or heteroaryl group at position 7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non‐ stereoselective glycosidation of 6‐chloro‐7‐deazapurine with benzoyl‐protected 2‐deoxy‐2,2‐difluoro‐D ‐erythro‐pentofuranosyl‐1‐mesylate, followed by amination and aqueous Suzuki cross‐couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium‐catalyzed cross‐coupling reactions of the corresponding 7‐iodo‐7‐deazaadenine 2′‐deoxy‐2′‐fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six‐step sequence from the corresponding arabinonucleoside by selective protection of 3′‐ and 5′‐hydroxy groups with acid‐labile groups, followed by stereoselective SN2 fluorination and deprotection. Some of the title nucleosides and 7‐iodo‐7‐deazaadenine intermediates showed micromolar cytostatic or anti‐HCV activity. The most active were 7‐iodo and 7‐ethynyl derivatives. The corresponding 2′‐deoxy‐2′,2′‐difluororibonucleoside 5′‐O‐triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase α. 相似文献
A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers. 相似文献
Bis(monoacylglycero)phosphate (BMP) is a structural isomer of phosphatidylglycerol (PtdGro) with an unusual sn‐1:sn‐1′ fatty acyl configuration and is found almost exclusively in late endosomes/lysosomes. BMP comprises only about 1–2 % of the total phospholipids in most mammalian cells, but accumulates in tissues of humans and animals with lysosomal storage disorders including the gangliosidoses. Total BMP content was significantly greater in cells of macrophage/microglial origin than in cells of macroglial origin. BMP composition was similar in tumorigenic/metastatic macrophages and non‐tumorigenic macrophages/microglia. Finally, BMP fatty acid composition differed between cells grown in culture and obtained in vivo suggesting an influence from growth environment. 相似文献
The diammonium ( 1 ) and bishydrazinium ( 2 ) salts of 4,4′,5,5′‐tetranitro‐2,2′‐biimidazolate (TNBI) were synthesized and their physical properties as well as predicted explosive performance characteristics are described. These dianionic salts are easily formed in good yields by reaction of TNBI with aqueous solutions of the cationic species. TNBI is synthesized from 2,2′‐biimidazole, which is ultimately synthesized by the condensation of aqueous glyoxal with ammonium acetate. The compounds were characterized by NMR spectroscopy, vibrational (FT‐IR and Raman) spectroscopy, elemental analysis, thermal analysis (DSC, VTS and calorimetry), and small scale safety testing (impact, friction, ESD). The measured densities and heats of formation are reported. The materials show promise for use in IM explosive and propellant formulations due to the combination of their calculated performances, thermal stability and insensitivity to stimuli. 相似文献