@article{FudickarBauchIhmelsetal.2021, author = {Fudickar, Werner and Bauch, Marcel and Ihmels, Heiko and Linker, Torsten}, title = {DNA-triggered enhancement of singlet oxygen production by pyridinium alkynylanthracenes}, series = {Chemistry - a European journal}, volume = {27}, journal = {Chemistry - a European journal}, number = {54}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1521-3765}, doi = {10.1002/chem.202101918}, pages = {13591 -- 13604}, year = {2021}, abstract = {There is an ongoing interest in O-1(2) sensitizers, whose activity is selectively controlled by their interaction with DNA. To this end, we synthesized three isomeric pyridinium alkynylanthracenes 2 o-p and a water-soluble trapping reagent for O-1(2). In water and in the absence of DNA, these dyes show a poor efficiency to sensitize the photooxygenation of the trapping reagent as they decompose due to electron transfer processes. In contrast, in the presence of DNA O-1(2) is generated from the excited DNA-bound ligand. The interactions of 2 o-p with DNA were investigated by thermal DNA melting studies, UV/vis and fluorescence spectroscopy, and linear and circular dichroism spectroscopy. Our studies revealed an intercalative binding with an orientation of the long pyridyl-alkynyl axis parallel to the main axis of the DNA base pairs. In the presence of poly(dA : dT), all three isomers show an enhanced formation of singlet oxygen, as indicated by the reaction of the latter with the trapping reagent. With green light irradiation of isomer 2 o in poly(dA : dT), the conversion rate of the trapping reagent is enhanced by a factor >10. The formation of O-1(2) was confirmed by control experiments under anaerobic conditions, in deuterated solvents, or by addition of O-1(2) quenchers. When bound to poly(dG : dC), the opposite effect was observed only for isomers 2 o and 2 m, namely the trapping reagent reacted significantly slower. Overall, we showed that pyridinium alkynylanthracenes are very useful intercalators, that exhibit an enhanced photochemical O-1(2) generation in the DNA-bound state.}, language = {en} } @article{KruegerLinker2021, author = {Kr{\"u}ger, Tobias and Linker, Torsten}, title = {Synthesis of gamma-spirolactams by Birch reduction of arenes}, series = {European journal of organic chemistry}, volume = {2021}, journal = {European journal of organic chemistry}, number = {10}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1099-0690}, doi = {10.1002/ejoc.202100056}, pages = {1585 -- 1591}, year = {2021}, abstract = {A convenient method for the synthesis of gamma-spirolactams in only three steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of chloroacetonitrile affords nitriles in moderate to good yields. Suitable precursors are methyl-substituted benzoic acids, naphthoic, and anthroic acid. Subsequent catalytic hydrogenation proceeds smoothly with PtO2 or Raney Ni as catalysts and lactams are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation at different pressures, affording products with 0, 1, or 2 double bonds. Overall, more than 15 new gamma-spirolactams have been synthesized in analytically pure form.}, language = {en} } @article{FudickarLinker2020, author = {Fudickar, Werner and Linker, Torsten}, title = {Structural motives controlling the binding affinity of 9,10-bis(methylpyridinium)anthracenes towards DNA}, series = {Bioorganic \& medicinal chemistry : a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on biomolecular chemistry, medicinal chemistry and related disciplines}, volume = {28}, journal = {Bioorganic \& medicinal chemistry : a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on biomolecular chemistry, medicinal chemistry and related disciplines}, number = {8}, publisher = {Elsevier}, address = {Oxford}, issn = {0968-0896}, doi = {10.1016/j.bmc.2020.115432}, pages = {7}, year = {2020}, abstract = {In the search of new DNA groove binding agents a series of substituted 9,10-methylpyridiniumanthracenes have been synthesized and their interactions with DNA have been studied by UV/vis absorption, CD and fluorescence spectroscopy. A minor groove binding mode is confirmed by DNA melting studies, strong CD effects, the dependence of the binding affinity on ionic strength, and the differentiation between AT and GC base pairs. No binding occurs to GC sequences. Binding constants to calf thymus DNA (ct-DNA) and poly(dA:dT) in the range between 1 x 10(4) and 3 x 10(5) M-1 have been determined. The binding strength decreases with the size of substituents attached at the anthracene site. Variation of the substitution pattern of the charged groups shows that methyl groups in meta position cause slightly stronger binding than methyl groups in para position. In contrast, with these groups in ortho position, no binding interaction has been observed. The strongest binding is achieved with an expansion of the peripheral heterocycle from pyridine to quinoline. Molecular modeling reveals the pivotal role of the substitution pattern: Anthracenes with para and meta pyridines align along the minor grooves. On the other hand, the ortho derivative adopts no groove-alignment.}, language = {en} } @article{FudickarMetzMaiLindeetal.2021, author = {Fudickar, Werner and Metz, Melanie and Mai-Linde, Yasemin and Kr{\"u}ger, Tobias and Kelling, Alexandra and Sperlich, Eric and Linker, Torsten}, title = {Influence of functional groups on the ene reaction of singlet oxygen with 1,4-cyclohexadienes}, series = {Photochemistry and photobiology : the official journal of the American Society for Photobiology}, volume = {97}, journal = {Photochemistry and photobiology : the official journal of the American Society for Photobiology}, number = {6}, publisher = {Wiley}, address = {Malden, Mass.}, issn = {0031-8655}, doi = {10.1111/php.13422}, pages = {1289 -- 1297}, year = {2021}, abstract = {The photooxygenation of 1,4-cyclohexadienes has been studied with a special focus on regio- and stereoselectivities. In all examples, only the methyl-substituted double bond undergoes an ene reaction with singlet oxygen, to afford hydroperoxides in moderate to good yields. We explain the high regioselectivities by a "large-group effect" of the adjacent quaternary stereocenter. Nitriles decrease the reactivity of singlet oxygen, presumably by quenching, but can stabilize proposed per-epoxide intermediates by polar interactions resulting in different stereoselectivities. Spiro lactams and lactones show an interesting effect on regio- and stereoselectivities of the ene reactions. Thus, singlet oxygen attacks the double bond preferentially anti to the carbonyl group, affording only one regioisomeric hydroperoxide. If the reaction occurs from the opposite face, the other regioisomer is exclusively formed by severe electrostatic repulsion in a perepoxide intermediate. We explain this unusual behavior by the fixed geometry of spiro compounds and call it a "spiro effect" in singlet oxygen ene reactions.}, language = {en} } @article{HaubitzFudickarLinkeretal.2020, author = {Haubitz, Toni and Fudickar, Werner and Linker, Torsten and Kumke, Michael Uwe}, title = {pH-sensitive fluorescence switching of pyridylanthracenes}, series = {The journal of physical chemistry : A, Molecules, spectroscopy, kinetics, environment \& general theory}, volume = {124}, journal = {The journal of physical chemistry : A, Molecules, spectroscopy, kinetics, environment \& general theory}, number = {52}, publisher = {American Chemical Society}, address = {Washington}, issn = {1089-5639}, doi = {10.1021/acs.jpca.0c09911}, pages = {11017 -- 11024}, year = {2020}, abstract = {9,10-substituted anthracenes are known for their useful optical properties like fluorescence, which makes them frequently used probes in sensing applications. In this article, we investigate the fundamental photophysical properties of three pyridyl-substituted variants. The nitrogen atoms in the pyridinium six-membered rings are located in the ortho-, meta-, and para-positions in relation to the anthracene core. Absorption, fluorescence, and transient absorption measurements were carried out and were complemented by theoretical calculations. We monitored the photophysics of the anthracene derivatives in chloroform and water investigating the protonated as well as their nonprotonated forms. We found that the optical properties of the nonprotonated forms are strongly determined by the anthracene chromophore, with only small differences to other 9,10-substituted anthracenes, for example diphenyl anthracene. In contrast, protonation leads to a strong decrease in fluorescence intensity and lifetime. Transient absorption measurements and theoretical calculations revealed the formation of a charge-transfer state in the protonated chromophores, where electron density is shifted from the anthracene moiety toward the protonated pyridyl substituents. While the para- and ortho-derivatives' charge transfer is still moderately fluorescent, the meta-derivative is affected much stronger and shows nearly no fluorescence. This nitrogen-atom-position-dependent sensitivity to hydronium activity makes a combination of these fluorophores very attractive for pH-sensing applications covering a broadened pH range.}, language = {en} } @article{MaiLindeLinker2020, author = {Mai-Linde, Yasemin and Linker, Torsten}, title = {Radical clock probes to determine carbohydrate radical stabilities}, series = {Organic letters}, volume = {22}, journal = {Organic letters}, number = {4}, publisher = {American Chemical Society}, address = {Washington}, issn = {1523-7060}, doi = {10.1021/acs.orglett.0c00111}, pages = {1525 -- 1529}, year = {2020}, abstract = {Carbohydrate radical stabilities in the 1- and 2-position have been determined by a radical clock approach, starting from cyclopropanated sugars with xanthates as precursors. Various hexoses and pentoses afforded 1-deoxy sugars as main products, indicating that anomeric radicals are more stable than radicals in the 2-position. An additional influence of the configurations on radical stabilities has been observed. Our results should be interesting for the understanding of 1,2-radical rearrangements in carbohydrate chemistry and offer an easy access to deoxy-vinyl sugars.}, language = {en} } @article{FudickarRoderListeketal.2021, author = {Fudickar, Werner and Roder, Phillip and Listek, Martin and Hanack, Katja and Linker, Torsten}, title = {Pyridinium alkynylanthracenes as sensitizers for photodynamic therapy}, series = {Photochemistry and photobiology}, volume = {98}, journal = {Photochemistry and photobiology}, number = {1}, publisher = {Wiley}, address = {Hoboken}, issn = {0031-8655}, doi = {10.1111/php.13554}, pages = {193 -- 201}, year = {2021}, abstract = {Photodynamic therapy (PDT) is a mild but effective method to treat certain types of cancer upon irradiation with visible light. Here, three isomeric methylpyridinium alkynylanthracenes 1op were evaluated as sensitizers for PDT. Upon irradiation with blue or green light, all three compounds show the ability to initiate strand breaks of plasmid DNA. The mayor species responsible for cleavage is singlet oxygen (O-1(2)) as confirmed by scavenging reagents. Only isomers 1m and 1p can be incorporated into HeLa cells, whereas isomer 1o cannot permeate through the membrane. While isomer 1m targets the cell nucleus, isomer 1p assembles in the cellular cytoplasm and impacts the cellular integrity. This is in accordance with a moderate toxicity of 1p in the dark, whereas 1m exhibits no dark toxicity. Both isomers are suitable as PDT reagents, with a CC50 of 3 mu m and 75 nm, for 1p and 1m, respectively. Thus, derivative 1m, which can be easily synthesized, becomes an interesting candidate for cancer therapy.}, language = {en} } @article{FudickarLinker2021, author = {Fudickar, Werner and Linker, Torsten}, title = {Photooxygenation of naphthalene}, series = {ChemPhotoChem}, volume = {5}, journal = {ChemPhotoChem}, number = {11}, publisher = {Wiley-VCH}, address = {Weinheim}, doi = {10.1002/cptc.202100097}, pages = {1004 -- 1008}, year = {2021}, abstract = {The photooxygenation of naphthalene to the corresponding endoperoxide (EPO) under various conditions is described. Substantial conversion is only observed at -10 degrees C and after more than two days, indicating that the [4+2] cycloaddition of singlet oxygen to this acene proceeds much more slowly than corresponding reactions of substituted naphthalenes, a rate constant of k = 5.4 +/- 0.3 M(-1)s(-1) was determined by competition kinetics. Another problem is the thermal lability and photochemical cleavage of the naphthalene EPO. We investigated the mechanism of this radical process depending on the light source and sensitizer in comparison to known cyclohexadiene EPO. Thus, bisepoxides and keto epoxides are formed after homolysis of the O-O bond by irradiation with sodium lamps or blue LEDs and subsequent cyclization. This process is accelerated by the sensitizers methylene blue and 9,10-dicyanoanthracene, indicating an electron transfer mechanism. Finally, the cleavage of the peroxidic bond is inhibited with red LEDs, and photooxygenation under such conditions affords 20 \% EPO. Thus, we could demonstrate that contrary to literature statements singlet oxygen does indeed react with naphthalene.}, language = {en} } @article{KruegerBramborgKellingetal.2021, author = {Kr{\"u}ger, Tobias and Bramborg, Andrea and Kelling, Alexandra and Sperlich, Eric and Linker, Torsten}, title = {Birch Reduction of Arenes as an Easy Entry to γ-Spirolactones}, series = {European journal of organic chemistry}, volume = {2021}, journal = {European journal of organic chemistry}, number = {46}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1434-193X}, doi = {10.1002/ejoc.202101018}, pages = {6383 -- 6391}, year = {2021}, abstract = {A convenient method for the synthesis of γ-spirolactones in only 2-3 steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of ethylene oxide affords hydroxy acids, which undergo direct lactonization during work-up. Suitable precursors are methyl-substituted benzoic acids, naphthoic, and dicarboxylic acids. Subsequent hydrogenation proceeds smoothly with Pd/C as catalyst and saturated γ-spirolactones are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation with Raney nickel or Wilkinson's catalyst to obtain products with 1 double bond. Overall, more than 30 new γ-spirolactones have been synthesized in analytically pure form.}, language = {en} } @article{KruegerKellingSchildeetal.2016, author = {Kr{\"u}ger, Tobias and Kelling, Alexandra and Schilde, Uwe and Linker, Torsten}, title = {Simple Synthesis of gamma-Spirolactams by Birch Reduction of Benzoic Acids}, series = {European journal of organic chemistry}, journal = {European journal of organic chemistry}, number = {6}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1434-193X}, doi = {10.1002/ejoc.201601650}, pages = {1074 -- 1077}, year = {2016}, abstract = {A convenient synthesis of gamma-spirolactams in only two steps was developed. Birch reduction of benzoic acids and immediate alkylation with chloroacetonitrile afforded cyclohexadienes in high yields. The products could be isolated by crystallization on a large scale in analytically pure form. Subsequent hydrogenation with platinum(IV) oxide as the catalyst reduced the nitrile functionality and the double bonds in the same step with excellent stereoselectivity. The relative configurations were determined unequivocally by X-ray analyses. Direct cyclization of the intermediary formed amino acids afforded the desired gamma-spirolactams in excellent overall yields. The procedure is characterized by few steps, cheap reagents, and can be performed on a large scale, interesting for industrial processes.}, language = {en} }