5‐Trideuteromethyl‐α‐tocotrienol and 5‐14CH3‐α‐tocotrienol as biological tracers of tocotrienols

The tocotrienols have attracted increased attention recently as evidence has accrued that their biological activities are significantly different from tocopherols. The biokinetics and metabolic fate of tocopherols have long been studied using deuteromethylated forms of α‐tocopherol prepared by a stannous chloride catalysed paraformaldehyde methylation of γ‐ and δ‐tocopherols. We show here that his methodology is not an efficient route to deuterated α‐tocotrienol because of low yields and extensive exchange of allylic hydrogens under the prolonged acidic conditions of the deuteromethylation. Instead, we have prepared deuteromethylated and ¹⁴C‐radiolabelled α‐tocotrienol by aminomethylation at C‐5 of γ‐tocotrienol (available from palm oil), followed by reduction with NaCNBD₃ in refluxing iso‐butanol. The deuteromethylation procedure is amenable to multi‐gram scale reactions. Copyright © 2006 John Wiley & Sons, Ltd.     

Deuterated drugs: where are we now?

Introduction: Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium– carbon bond modifying their metabolism. There is great interest in the current state of development of this approach.

Areas covered: This review covers recent US patent applications and prosecutions in this area that are based on beneficial modifications in metabolism of deuterated versions of existing drugs. The current state of 35 U.S.C. §103 ‘obviousness’ rejections are emphasized, as is the development of strategies to overcome such rejections. Current trials and market considerations are also discussed.

Expert opinion: Deuterated drugs collectively are worth at least US$1 billion. It would seem that the likelihood of obviousness rejections is increasing in this area. However, careful elucidation of metabolic outcomes from deuteration that would not be anticipated from the prior art, and are instead unexpected and unobvious, has enabled allowance. Showing that drug deuteration alters pharmacokinetics by mechanisms not currently part of the prior art surrounding deuterated drugs has also been successful. Development of these and other strategies, combined with developing the extensive base of issued patents will enable the field to remain commercially attractive for some time.     

Stereoselective synthesis of L‐[2,3,4,5‐D4] ornithine

Synthesis of L ‐[2,3,4,5‐D₄]ornithine in which all of the diastereotopic hydrogens were stereoselectively labeled with deuterium was investigated. The chirally deuterated 3‐aminopropanal derivative, a key intermediate in this synthesis, was prepared by a catalytic deuteration of an unsaturated γ‐lactone derived for L ‐glutamic acid followed by several functional group interconversions. Condensation of the obtained deuterium‐labeled 3‐aminopropanal derivative with a chiral glycine template afforded unsaturated ornithine. The dehydroornithine was then subjected to a catalytic deuteration followed by deprotection to give the L ‐[2,3,4,5‐D₄]ornithine. Copyright © 2002 John Wiley & Sons, Ltd.     

2,2’-二氟-6,6’-双(二苯基膦)联苯的合成

2,2’-二氟-6,6’-双(二苯基膦)联苯是一种极具吸引力的、缺电子的过渡金属催化剂的配体。本文用三步反应合成了这个配体(总收率为53%)。比原文献报道的四步反应及49%总收率的方法有了改进。其结构为IR,MS及NMRI所证实。     

Base metal-catalyzed hydrogen isotope exchange

Hydrogen isotope exchange (HIE) has played an increasingly important role in deuteration and tritiation of compounds in the pharmaceutical industry. Transition metal-catalyzed HIE methods have gained considerable attention in the past decades, and most of these methods were comprehensively reviewed in 2010 in a special JLCR issue. It covered a wide variety of HIE catalysis systems involving precious metal catalysts, and a relatively small percentage of base metal catalysts, with a major focus on heterogeneous nickel. While base metal catalysts have remained underdeveloped for HIE chemistry relative to second and third row transition metal catalysts, in recent years, the first examples of homogeneous iron, nickel, and cobalt catalysts have been introduced to the field. Hence, in this review, we describe the recent development of base metal catalysts for HIE and their applications in isotopic labeling of pharmaceutical compounds. These research efforts have resulted in the development of labeling approaches that complement traditional methods in terms of activity and selectivity, thus diversifying the methodologies available for isotope chemists.     

Iridium‐mediated β‐deuteration of enones

Exposure of captodative enone systems to deuterium in the presence of Crabtree's catalyst ( 1 ) results in deuteration at the vinylic site β‐ to the ketone carbonyl, as well as at any accessible ortho‐position. β‐exchange is also observed during the reduction of ethyl cinnamate ( 3 ) catalyzed by 1 . Copyright © 2003 John Wiley & Sons, Ltd.     

An improvement to the synthesis of deuterated meso‐tetraphenylporphyrins

An improved method for the synthesis of deuterated tetraphenylporphyrins (TPPs) is reported. In this method, deuterium labelling at the pyrrole–β‐position is increased to more than 95 at%. TPP is the most widely used synthetic porphyrin and high deuterium incorporation is essential for spectroscopic studies and kinetic studies involving relaxation processes. Copyright © 2006 John Wiley & Sons, Ltd.     

金属细菌叶绿素的合成及其对肿瘤细胞的抑制作用金属细菌叶绿素的合成及其对肿瘤细胞的抑制作用

目的寻找一种新型光动力学疗法光敏剂。方法采用从光合细菌中分离纯化的脱镁细菌叶绿素为配体，与金属盐在有机溶剂中反应，合成了Cu，Zn，Co，Ni 4种金属细菌叶绿素，并对其紫外可见光谱和荧光光谱进行研究。此外还研究了4种金属细菌叶绿素对K562和HL60两种白血病细胞生长的影响。结果4种金属细菌叶绿素的光谱图都有可预见的漂移，证明金属已配位到细菌叶绿素的卟啉大环上。同时，4种金属细菌叶绿素都有很强的抑瘤作用，光照可以明显提高其抑瘤率。结论金属细菌叶绿素作为一种新型光敏剂具有优良的性质，是新一代光敏剂发展的一个方向。     

Convenient synthesis of deuterated glutamic acid,proline and leucine via catalytic deuteration of unsaturated pyroglutamate derivatives

Novel 3,4‐didehydropyroglutamate derivatives, the key intermediates in this synthesis, were obtained from a protected pyroglutamate by the well‐known selenenylation‐oxidative deselenenylation method and were catalytically deuterated using a slow‐addition technique. The obtained deuterated pyroglutamates were converted to [3,4‐²H₂]glutamic acid, [3,4,5‐²H₃]proline, and [3,4,5,5,5‐²H₅]leucine via an appropriate functional group interconversions followed by the standard deprotection procedure. Copyright © 2006 John Wiley & Sons, Ltd.     

Significance of physicochemical forms of storage in microalgae in predicting copper transfer to filter-feeding oysters (Crassostrea gigas)

Copper distribution has been examined in two microalgae (Haslea ostrearia, Diatom; Tetraselmis suecica, Prasinophyceae) exposed to Cu at 30 microg/L(-1). Exchangeable copper linked at the cell surface was desorbed using 8-hydroxyquinoline-5-sulfonate as complexing agent. Then, incorporated copper was separated between soluble and insoluble fractions. In addition, algae were resuspended in acid solutions, the pHs of which covered the range existing in the digestive tract of bivalves. Considering that the soluble fraction is the most easily transferred in the food chain and that exchangeable Cu is easily desorbed, the percentages of Cu potentially available in microalgae have been assessed. These percentages have been compared with those retained in oysters Crassostrea gigas fed with contaminated microalgae in previous studies. In H. ostrearia, the potentially available fraction of Cu (90%) was very similar to the percentage retained by oysters (93%) when the bivalves were acclimated to this food for 3 weeks. Only half (21%) of the potentially available Cu of T. suecica (42%) was readily assimilated in oysters after 3 weeks. This is in agreement with the results of the desorption tests at physiological pHs which showed that only 15-25% of Cu was lost, despite solubilization of other constituents of T. suecica as demonstrated by the decrease in their dry weight. Bioavailability determined from metal speciation in food allows a relevant prediction of the trophic transfer in the case of H. ostrearia, but caution is recommended in generalizing this mode of assessment as shown in the case of T. suecica.     

Detection of Low Levels of Amorphous Lactose using H/D Exchange and FT-Raman Spectroscopy

Purpose  To demonstrate the potential of monitoring H/D exchange by FT-Raman spectroscopy as a tool for the detection and quantification of low levels of amorphous lactose in formulations. Methods  Samples containing different proportions of amorphous and crystalline lactose were prepared. H/D exchange was carried out by exposing the samples to a flow of D₂O vapour. A calibration curve was constructed from the FT-Raman spectra of the deuterated samples by integrating the ν(OD) band and normalizing to an internal standard. This method was benchmarked against a conventional approach using Raman spectroscopy where the ratio of Raman bands associated with crystalline and amorphous lactose is used to estimate the amorphous content. Results  The H/D exchange method revealed a linear response over the entire composite range with an excellent correlation coefficient (R ² = 0.999). The sensitivity of this approach in detecting the amount of amorphous lactose present in a blend is significantly greater than that offered by conventional FT-Raman in the 0–10% level of amorphous material. Conclusions  A non-destructive method that is capable of providing reproducible measurements of low levels of amorphous material in lactose has been demonstrated and this method has enhanced sensitivity relative to approaches using Raman spectroscopy without deuteration.     

Preparation of α‐labeled aldehydes by base‐catalyzed exchange reactions

A simple, efficient protocol for the preparation of α‐labeled aldehydes based on H/D exchange catalyzed by 4‐(N,N‐dimethylamino)pyridine or Et₃N is described. High chemical yields and ratios of isotope incorporation were obtained even when small amounts (～1 mmol) of aldehyde were used. Copyright © 2010 John Wiley & Sons, Ltd.     

半乳糖胺-过渡金属配合物的合成,结构表征和活性研究Δ

目的半乳糖糖胺-过渡金属配合物的合成及其水解酶活性的研究。方法以半乳糖为原料,经三(2-氨乙基)胺连接修饰后再分别与过渡金属Cu(II)、Ni(II)反应合成两个配合物。以对硝基苯酚吡啶甲酸酯(PNPP)为水解模拟酶模型,研究了在两个不同pH值下所合成糖胺-过渡金属配合物的水解活性。结果通过元素分析、金属含量测定、光谱分析及摩尔电导等表征手段,确定了两个配合物化学结构为[C24H48N4O15CuCl]Cl·3H2O]和[C24H48N4O15Ni·2H2O]Cl2·H2O],而且两个配合物的水解速率远大于自发水解的速率。结论三角双锥构型的Cu(II)配合物和具有八面体构型的Ni(II)配合物都具有较好的金属水解酶活性。     

Synthesis of deuterated isoflavone disulfates

Efficient synthesis of polydeuterated di‐O‐sulfates of three isoflavones, daidzein ( 1 ), genistein ( 2 ), glycitein ( 3 ), is described. The isoflavones were first deuterated with CF₃COOD under microwave irradiation to yield daidzein‐d₆ ( 4 ), genistein‐d₄ ( 5 ) and glycitein‐d₆ ( 6 ) in 90% yield and in a high isotopic purity. The deuterated isoflavones were then sulfated with chlorosulfonic acid and pyridine to give the title compounds, again in high yield and isotopic purity (>90%). The compounds are useful as internal standards in LC‐MS quantitation of isoflavones. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of sequentially deuterated 1‐n‐Butyl‐3‐methylimidazolium ionic liquids

Deuterium isotopologues of the ionic liquid (IL) 1–n‐butyl‐3‐methylimidazolium chloride ([C₄mim]Cl) sequentially labeled on the C‐1″, C‐1′, C‐2′, C‐3′, and C‐4′ positions of the N‐alkyl groups were prepared following a strategy that minimizes the number of distinct reactions through the use of analogous synthetic routes. In several cases, good yields after the initial deuterium incorporation reaction were achieved by combining well‐established chemical transformations into efficient single‐step processes. Copyright © 2011 John Wiley & Sons, Ltd.     

Chirally deuterated benzyl chlorides from benzyl alcohols via hexachloroacetone/polymer‐supported triphenylphosphine: synthesis of protected (2S, 3S)‐[3‐2H, 15N]‐tyrosine

Chirally deuterated benzyl chlorides were prepared using novel, general hexachloroacetone/polymer‐supported triphenylphosphine treatment of chirally deuterated benzyl alcohols. Doubly labeled protected tyrosine was obtained in 62% yield with 86% de at the α‐carbon and 82% de at the β‐carbon. Key in the synthesis was the alkylation of ¹⁵N‐labeled (?)‐8‐phenylmenthylhippurate with R‐(?)‐4‐triisopropylsilyloxybenzyl‐α‐d chloride.     

Transition Metal-Mediated Liposomal Encapsulation of Irinotecan (CPT-11) Stabilizes the Drug in the Therapeutically Active Lactone Conformation

Purpose To determine whether entrapped transition metals could mediate the active encapsulation of the anticancer drug irinotecan into preformed liposomes. Further, to establish that metal complexation could stabilize liposomal irinotecan in the therapeutically active lactone conformation. Materials and Methods Irinotecan was added to preformed 1,2-distearoyl-sn-glycero-phosphocholine/cholesterol (DSPC/chol) liposomes prepared in CuSO₄, ZnSO₄, MnSO₄, or CoSO₄ solutions, and drug encapsulation was determined over time. The roles of the transmembrane pH gradient and internal pH were evaluated. TLC and HPLC were used to monitor drug stability and liposome morphology was assessed by cryo-TEM. Results Irinotecan was rapidly and efficiently loaded into preformed liposomes prepared in unbuffered (∼pH 3.5) 300 mM CuSO₄ or ZnSO₄. For Cu-containing liposomes, results suggested that irinotecan loading occurred when the interior pH and the exterior pH were matched; however, addition of nigericin to collapse any residual transmembrane pH gradient inhibited irinotecan loading. Greater than 90% of the encapsulated drug was in its active lactone form and cryo-TEM analysis indicated dark intravesicular electron-dense spots. Conclusion Irinotecan is stably entrapped in the active lactone conformation within preformed copper-containing liposomes as a result of metal–drug complexation.     

Copper‐mediated reduction of 2‐[18F]fluoroethyl azide to 2‐[18F]fluoroethylamine

¹⁸F‐labelled fluoroalkylamines are attractive reagents for the preparation of positron emission tomography tracers containing amine, amide, and N‐heterocyclic moieties. Herein, we report that 2‐[¹⁸F]fluoroethylamine can be obtained from 2‐[¹⁸F]fluoroethyl azide by reduction with elemental copper under acidic conditions. Azide to amine reduction was achieved in near quantitative analytical yields within 30 min by heating a solution of 2‐[¹⁸F]fluoroethyl azide in the presence of copper wire and aqueous trifluoroacetic acid. Subsequent reaction of 2‐[¹⁸F]fluoroethylamine with benzoyl chloride in the presence of triethylamine provided N‐[¹⁸F]fluoroethyl benzamide in 63% decay‐corrected radiochemical yield from 2‐[¹⁸F]fluoroethyl azide. The utility of the Cu(0)/H⁺ azide reduction method was further exemplified by preparation of the potential GABA_A tracer 9H‐β‐carboline N‐2‐[¹⁸F]fluoroethylamide, which was obtained in 46% decay‐corrected radiochemical yield by reaction of 2‐[¹⁸F]fluoroethylamine with the corresponding 9H‐β‐carboline pentafluorophenyl ester. Copyright © 2012 John Wiley & Sons, Ltd.     

A behavioural bioassay for impaired sea-water quality using the plantigrades of the common mussel Mytilus edulis L.: the response to copper

A bioassay has been developed, using the crawling and attachment behaviour of plantigrades of the common mussel, Mytilus edulis, for copper-impaired sea water. Potentiometric stripping analysis has been used to quantify the total and electrochemically labile species of copper. The threshold of sensitivity for the bioresponse lies between 13 ppb total, 8 ppb labile and 25 ppb total, 15 ppb labile copper, for a bioassay of 1 h duration. There is an example of hormesis for the bioresponse of the number of plantigrades that crawl for levels of copper at and below 13 ppb total, 8 ppb labile metal. The effects of light and gravity as directional cues and the effect of animal size and density in the bioassay have also been considered.     

葡萄糖胺和麦芽糖胺-过渡金属配合物的合成和结构表征Δ

摘要：目的研究葡萄糖胺和麦芽糖胺-过渡金属配合物的结构,为其应用奠定基础,合成及表征了4个葡萄糖胺和麦芽糖胺-过渡金属配合物。方法以葡萄糖和麦芽糖为原料,将合成的双葡萄糖丙二胺配体及双麦芽糖丙二胺配体分别与过渡金属Cu(II)、Ni(II)形成配合物。结果以33.9 %~73.8 % 的产率制备了4个葡萄糖胺和麦芽糖胺-过渡金属配合物,并通过紫外、红外、元素分析、摩尔电导等数据推测出了配合物的结构式。结论过渡离子与配体的摩尔比为1 : 2,Cu(II)配合物含有两种配位构型分别为不规则四边形和三角双锥,而Ni(II)配合物的构型为2分子水参与的八面体构型。