Chemically modified nucleoside triphosphates (NTPs) are widely exploited as unnatural metabolites in chemical biology and medicinal chemistry. Because anionic NTPs do not permeate cell membranes, their corresponding neutral precursors are employed in cell-based assays. These precursors become active metabolites after enzymatic conversion, which often proceeds insufficiently. Here we show that metabolically-active NTPs can be directly transported into eukaryotic cells and bacteria by the action of designed synthetic nucleoside triphosphate transporters (SNTTs). The transporter is composed of a receptor, which forms a non-covalent complex with a triphosphate anion, and a cell-penetrating agent, which translocates the complex across the plasma membrane. NTP is then released from the complex in the intracellular milieu and accumulates in nuclei and nucleoli in high concentration. The transport of NTPs proceeds rapidly (seconds to minutes) and selectively even in the presence of other organic anions. We demonstrate that this operationally simple and efficient means of transport of fluorescently labelled NTPs into cells can be used for metabolic labeling of DNA in live cells.
Recently, naphthalenoide derivatives of Troger's base (TB) have become important as structural compartments of molecular tweezers and compounds with high specific rotation. The formation of TB derivatives and byproducts from naphthalen-2-amine, methyl 6-aminonaphthalene-2-carboxylate, and anthracen-2-amine was studied. It was discovered that the formation of a naphthalenoide TB derivative is followed by the formation of a unique structural isomer of TB: spiroTB.
Chemically modified nucleoside triphosphates (NTPs) are widely exploited as unnatural metabolites in chemical biology and medicinal chemistry.B ecause anionic NTPs do not permeate cell membranes,t heir corresponding neutral precursors are employed in cell-based assays.T hese precursors become active metabolites after enzymatic conversion, whicho ften proceeds insufficiently.H ere we show that metabolically-active NTPs can be directly transported into eukaryotic cells and bacteria by the action of designed synthetic nucleoside triphosphate transporters (SNTTs). The transporter is composed of ar eceptor,w hich forms an on-covalent complex with at riphosphate anion, and ac ell-penetrating agent, whicht ranslocates the complex across the plasma membrane.N TP is then released from the complex in the intracellular milieu and accumulates in nuclei and nucleoli in high concentration. The transport of NTPs proceeds rapidly (seconds to minutes) and selectively even in the presence of other organic anions.W ed emonstrate that this operationally simple and efficient means of transport of fluorescently labelled NTPs into cells can be used for metabolic labeling of DNAinl ive cells.Control over the transport of ions across the plasma membrane is avital function of viable cells.The permeability of ac ell membrane to ions,w hich are not recognized by membrane-incorporated transporting proteins,i st herefore significantly limited. In particular,t he transport of anionic compounds into cells represents agreat challenge in scientific fields ranging from fundamental research in chemical biology to medicinal applications. [1] Nucleoside triphosphates (NTPs) are important metabolites that are involved in numerous cellular processes.T heir chemically modified analogues have long been exploited as antimetabolites in chemical biology and medicinal chemistry. Due to their anionic nature,N TPs do not permeate cell membranes and, therefore,t heir corresponding neutral and more readily transportable precursors (nucleosides or monophosphate prodrug derivatives) are most commonly employed in cell-based assays as well as in clinical use. However,n ucleosides become active metabolites upon sequential phosphorylation to NTPs by intracellular kinases, which often proceeds with low efficiency for unnatural analogues. [2] Thei mpermeability of the plasma membrane to anionic NTPs,t ogether with the specificity of nucleoside/ nucleotide-phosphorylating kinases,seem to constitute avery efficient cellular barrier preventing the interference of unnatural NTPs with the cell metabolism. Nevertheless,t he interest in using unnatural NTP analogues in chemical biology and medicinal chemistry has fuelled efforts to develop methods that would allow the delivery of NTPs to cells. Most approaches described for eukaryotic cells to date are based on 1) transient disruption of the plasma membrane by physical and mechanical means, [3] 2) uptake of nanoparticulate assemblies of NTPs with positively charged polymers [4] or highly concentrated DNAt ransfection reagent...
A simple and highly efficient one-pot route to b-selenocarbonyl compounds and nitriles has been developed by Zn/RuCl 3 -catalyzed cleavage of diselenides and subsequent Michael addition of zinc selenolates to conjugated alkenes in aqueous media.Over the last three decades, many investigators have described important chemical transformations that were efficiently achieved using organoselenium reagents. Organoselenium compounds are of considerable interest because of their involvement as key intermediates in organic synthesis and use as a food supplement. 1 These compounds are no longer systematically classified as toxic and, thus, much effort is being devoted to accomplishing the synthesis of organic selenides. Although numerous reports on the synthesis of organoselenium compounds have already been published, 1,2 most of them, with the exception of three recent reports, 3 usually require the handling of unstable reagents, strongly acidic or basic reaction conditions, and two-step procedures. Hence, the development of a one-pot synthetic method using stable reagents under neutral conditions is in demand.Reductive cleavage of Se-Se bonds, especially cleavage of diphenyl or other diaryl diselenides, has attracted considerable attention due to the fact that selenide anion formed can be used for preparation of wide variety of compounds. Several reducing agents, including LiAlH 4 , NaBH 4 , Bu 3 SnH, and Na/NH 3 , have been introduced for Se-Se bond cleavage. 4Organometallic reactions in aqueous media have attracted considerable attention in organic synthesis. 5 Recently, transition-metal selenolates or complexes have been widely used in synthesis of organoselenium compounds, 6 but reports exploring zinc selenolates are rare. 3a,7 As a part of our interest in zinc chemistry, 7,8 we are in constant search for novel applications of zinc selenolates and zinc thiolates in chemical reactions. In the present paper we describe the use of zinc metal-ruthenium(III) chloride (Zn/ RuCl 3 ) 3a system for the cleavage of diselenides and in situ Michael addition of selenolate anion to a,b-unsaturated carbonyl compounds and nitriles to give the corresponding b-selenocarbonyl compounds and nitriles (Scheme 1).Simple stirring of diselenides 1 with metallic zinc dust in the presence of ruthenium(III) chloride (10 mol%) in MeCN-H 2 O (4:1) mixed solvent at 80 °C produced the zinc selenolate 2. This was followed by addition of a,bunsaturated carbonyl compounds and nitriles 3 which gave, after workup, the desired product 4 with yields ranging from 55-98% (Table 1). 9 Both diaryl and dialkyl (dibenzyl) diselenides react with a variety of conjugated alkenes by this procedure to produce the corresponding adducts. The conjugated alkenes include a,b-unsaturated ketones, aldehydes, carboxylic esters, and nitriles. The reaction of diaryl diselenides with methyl vinyl ketone (Table 1, entries 1 and 11) took place faster with higher yields than the others. a,b-Unsaturated carbonyl compounds and nitriles having substituents at either the a-(Table 1, ...
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