03 Fakultät Chemie

Permanent URI for this collectionhttps://elib.uni-stuttgart.de/handle/11682/4

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Institute: search.filters.UBSInstitut.Fakultätsübergreifend / Sonstige EinrichtungAuthor: search.filters.author.Richert, Clemens

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    Prolinyl phosphoramidates of nucleotides with increased reactivity
    (2024) Humboldt, Adrian; Rami, Fabian; Topp, Franka M.; Arnold, Dejana; Göhringer, Daniela; Pallan, Pradeep S.; Egli, Martin; Richert, Clemens
    Nucleoside monophosphates (NMPs) are the subunits of RNA. They are incorporated into growing complementary strands when sequences are copied in enzyme‐free reactions using organic leaving groups at the phosphates. Amino acids are rarely considered as leaving groups, but proline can act as a leaving group when N‐linked to NMPs, so that prolinyl NMPs hydrolyze in aqueous buffer at 37 °C, with half‐life times as short as 2.4 h, and they act as monomers in enzyme‐free primer extension. Still, their level of reactivity is insufficient for practical purposes, requiring months for some extensions. Herein we report the synthesis of eight substituted prolinyl AMPs together with seven related compounds and the results of a study of their reactivity. A δ‐carboxy prolinyl NMP was found to be converted with a half‐life time of just 11 min in magnesium‐free buffer, and a δ‐isopropyl prolinyl NMP was shown to react sevenfold faster than its prolinyl counterpart in enzyme‐free genetic copying of RNA. Our results indicate that both anchimeric and steric effects can be employed to increase the reactivity of aminoacidyl nucleotides, i.e. compounds that combine two fundamental classes of biomolecules in one functional entity.
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    Non-porous organic crystals and their interaction with guest molecules from the gas phase
    (2020) Casco, Mirian Elizabeth; Krupp, Felix; Grätz, Sven; Schwenger, Alexander; Damakoudi, Vassiliki; Richert, Clemens; Frey, Wolfgang; Borchardt, Lars
    Some organic molecules encapsulate solvents upon crystallization. One class of compounds that shows a high propensity to form such crystalline solvates are tetraaryladamantanes (TAAs). Recently, tetrakis(dialkoxyphenyl)-adamantanes have been shown to encapsulate a wide range of guest molecules in their crystals, and to stabilize the guest molecules against undesired reactions. The term ‘encapsulating organic crystals’ (EnOCs) has been coined for these species. In this work, we studied the behavior of three TAAs upon exposition to different guest molecules by means of sorption technique. We firstly measured the vapor adsorption/desorption isotherms with water, tetrahydrofuran and toluene, and secondly, we studied the uptake of methane on dry and wet TAAs. Uptake of methane beyond one molar equivalent was detected for wet crystals, even though the materials showed a lack of porosity. Thus far, such behavior, which we ascribe to methane hydrate formation, had been described for porous non-crystalline materials or crystals with detectable porosity, not for non-porous organic crystals. Our results show that TAA crystals have interesting properties beyond the formation of conventional solvates. Gas-containing organic crystals may find application as reservoirs for gases that are difficult to encapsulate or are slow to form crystalline hydrates in the absence of a host compound. Wet tetraaryladamantane crystals take up methane in form of methane hydrate structure I, even though they appear non-porous to argon.
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    Derivatives of 3′‐azidothymidine with 6‐cyanopyridone as base or as phosphoramidate ester and their antiretroviral activity
    (2022) Han, Jianyang; Arnold, Jakob; Pannecouque, Christophe; Andrei, Graciela; Snoeck, Robert; Richert, Clemens
    Strongly pairing ethynylpyridone C‐nucleosides are attractive surrogates for thymidine in oligonucleotides. Exploratory work on the antiviral activity of 3′‐azidothymidine (AZT) derivatives with ethynylpyridone as base had identified strong lipophilicity as a limiting factor. Two strategies are being pursued to overcome this issue. In order to make the base more polar, the ethynyl group has been replaced with a cyano group, leading to a cyanopyridone C‐nucleoside, whose eleven‐step synthesis is reported here, together with the synthesis of a 3′‐azido‐2′,3′‐dideoxynucleoside derivative. The base pairing with adenine in a DNA duplex was studied by UV melting analysis of a self‐complementary hexamer containing the 6‐cyano‐2′‐deoxynucleoside instead of thymidine. A melting point increase of 2 °C compared to the unmodified control was found. The other strategy employs a phosphoramidate prodrug design with less lipophilic amino acid esters. Here, anti‐HIV test of the alaninyl and prolinyl methyl esters of AZT gave promising results in cell culture experiments, increasing the selectivity index up to 5.8‐fold for the IIIB strain and up to 5‐fold for the ROD strain of the virus, as compared to the parent nucleoside. These findings help to design the next generation of pyridone C‐nucleosides with potential applications as antivirals.