Dear Andrea, I thank you very much for the opportunity to have assisted you in your carbohydrate research projects. In 1975, I was at the end of my diploma stay in the group of Professor Albert Eschenmoser and asked the professor for a doctoral research study in his group. But he answered: ‘I am sorry, I have no free space and no money, but there is a young researcher in the house who is looking for a collaborator. His name is Andrea Vasella. A young supervisor may be an advantage as he can teach you more than me. Will you ask him for a doctoral research study?’ Thus, I went and saw Andrea in his laboratory. First, he asked me about my diploma work. I was astonished that he had specific questions and advice to all steps. Then he asked me about my preferences. I answered that I like to do a synthetic work, but not carbohydrate chemistry, since Professor Oskar Jeger had told in his lecture that carbohydrates are terrible mixtures of hardly crystallizing compounds. Then he replied: ‘I do not carbohydrate chemistry, I do organic chemistry with carbohydrates.’ Later on, I have understood this fine difference as carbohydrates are organic molecules with several hydroxy groups. I left his laboratory with the intention to investigate sugars as I will benefit a lot from the knowledge of this young researcher. Andrea had just started his own research after returning from the postdoctoral stays in the groups of the Professors Jack E. Baldwin and Robert B. Woodward. He had selected Professor Albert Eschenmoser as his mentor and followed regularly the tea breaks of this group in the cafeteria. Andrea analyzed the diastereoselectivity of the cycloaddition of glycosyl nitrones. In 1977, he was elected as an Assistant Professor of the University of Freiburg im Üechtland. The second doctoral student Heinrich Steinlin and me, we transported the equipment of the group laboratory into the new university building in Pérolles. In my thesis, I investigated a new method for opening of glycopyranosides where the C(5)−O bond is broken. A reductive fragmentation of 6-halopyranosides led to hex-5-enoses which in the presence of N-alkylhydroxylamines were transformed into cyclopentisoxazolidines. The first step was adapted by many groups worldwide as e. g. to selectively cleave oligosaccharides and to transform carbohydrate derivatives into carbocyles (e. g. prostaglandin analogs and cyclohexenes) and piperidines. In 1979, I left the group for a postdoctoral stay in the laboratories of Professor Pierre Deslongchamps in Sherbrooke (Québec). Interestingly, I worked with the same compound as Andrea in the postdoctoral stay in the Woodward group, namely with erythromycin A. The knowledge of carbohydrates helped me a lot since this antibiotic is also a polyhydroxylated compound. I tended to an industrial career, but in 1980, the large Swiss chemical companies had personal stops due to internal reorganizations and the few free positions were appointed to applicants with industrial experience. Andrea informed me that he was elected as an Associate Professor of the university of Zürich and offered me the position of the scientific assistant (Oberassistent) which I accepted with pleasure since I like research very much and could stay in Zürich. Hence, the group equipment was moved into the new laboratories of the Irchel campus. At the universities of Freiburg and Zürich, Andrea exploited the chemistry of glycosyl nitrones. Thus, a variety of products were prepared, e. g. 5-oxaprolines, α-aminophosphonates, nojirimycin, glycosylidene oximes, 1-nitrosoglycosyl chlorides which upon a Diels-Alder reaction gave bicyclic oxazines, and 1-nitro-1-deoxyglycoses. These nitro derivatives allowed the synthesis of higher monosaccharides, especially of neuraminic acid, a C9 saccharide, whose chemistry and biological function were at this time a research goal in carbohydrate chemistry. An equally strong inhibitor of neuraminidase as Tamiflu® from F. Hoffmann-La Roche AG was synthesized albeit by a commercially uninteresting route. Protection of the double bond by a triple bond in a Sharpless oxidation led to a short and efficient asymmetric synthesis of d-erythro-sphingosine. At the university of Zürich, the Vasella group implemented computers for making electronic manuscripts. We were pioneers for using ChemDraw, Word, and EndNote on the early cubic Macintoshes SEs. Gone the time for the preparation of drawings with formula stencils, ink, Letraset, and stencil paper. Selective glycosylation is a central topic in carbohydrate chemistry. Andrea found a promoter-free variant, the addition of alcohols to carbenes obtained from glycosylidene diazirines. This method is especially useful for sterically hindered alcohols, phosphines, and di- and triols where the kinetically most acidic OH group is preferentially attacked. This led to an extensive investigation of intramolecular hydrogen bonding in partially protected glycosides and inositols. The inclusion of fluorinated carbohydrates refined the famous statement of Professor Jack Dunitz: ‘Organic fluorine hardly ever accepts hydrogen bonds’ to ‘Organic fluorine accepts hydrogen bonds in the absence of a better hydrogen bond acceptor’. A scalar coupling between F and OH, present only in apolar solvents, proved that there is indeed a hydrogen bond and not only a dipolar interaction. Later on, molecular modeling of other groups corroborated this finding. Addition of glycosylidene carbenes to olefins yielded spirocyclopropanes. At the International Carbohydrate Symposium 1992 in Paris, Andrea was honored with the Roy L. Whistler Award from the International Carbohydrate Organization and could present the first glycosylated fullerenes. He was also elected as the first non-British organizer of the Gregynog symposium. The buta-1,3-diynyl group is isometric to a pyranosyl unit. Thus, alternating carbohydrate moieties were replaced by buta-1,3-diyn-1,4-diyl groups preventing any intramolecular interaction between the carbohydrate moieties and afforded analogues of oligocelluloses (up to a hexadecamer), oligomers of cellobiose, and of cyclodextrins. An ethynylated and a buta-1,3-diynylated cellooctaosyl moiety were attached to anthraquinone to mimic cellulose I. Indeed, CP/MAS 13C-NMR spectroscopy and X-ray powder-diffraction showed that this model mimics cellulose I. The inhibition of glycosidases and related enzymes by carbohydrate-derived hydroximinolactones and -lactams and by imidazo- to tetrazopiperidines were intensely investigated partly in collaboration with other groups worldwide. In 1993, Andrea was appointed as a Full Professor of the ETH Zürich where he could take the office and laboratories of his well-honored mentor, the Emeritus Professor Albert Eschenmoser. We were lucky that we had hired Thomas Mäder as laboratory technician. He kept the equipment of the group in excellent conditions and repaired many items by himself. Advanced programs allowed to do literature research and synthesis planning directly from the working place. The tedious scrolling in volumes of Chemical Abstracts in the library was now a thing of the past. Force-field calculations with the program Macromodel on a unix work station showed that phosphate-free oligonucleotide analogs where C(5) of the ribose unit is linked by an ethynediyl moiety to C(9) of the purine or C(6) of the pyrimidine base of the next unit can pair. Hence, oligomers with an ethynediyl, thiomethylene, or aminomethylene linker were prepared and their base pairing intensely studied (32 publications in this series). The fourth and last movement was in 2003, when the chemistry department of the ETH left the city center for new buildings on the Hönggerberg campus. The school management had abstained from a cooling system for the offices. Unfortunately, the extremely hot summer in 2003 led in the afternoons to high, uncomfortable room temperatures up to 36 °C. I was able to move my working place into the cooled computer room. Powerpoint replaced slide presentations which had required a special photographic procedure and did not allow last-minute changes. A carbohydrate moiety of the aminoglycoside antibiotics kanamycin and paromomycin was selectively modified. Professor Erik C. Böttger from the university of Zürich investigated the interaction of these modifications with ribosomes featuring single point mutations. From beginning, Andrea was consultant of the chemical industry, first of Sandoz AG, both in Basel and Wien (research on carbohydrates), and later on of F. Hoffmann-La Roche AG and Syngenta AG. After 2000, he had strong consulting projects with university and industrial researchers in France and in India, and therefore got the Honorary Degree of the INSERM and was elected as Honorary Member of the Indian Society for Chemical Research. He was always well prepared for these consulting sessions. Whenever strong differences appeared in a board, he was estimated as conciliator in finding a convenient solution for all. Thus, he helped a lot Helvetica Chimica Acta to get out of a crisis. Andrea has inspired and supervised PhD students and postdoctoral coworkers from all over the world, mostly from European and Asian countries. His laboratories were a place of intense scientific and cultural exchange. I remember with pleasure the group Christmas events when the coworkers prepared specialties from their home countries. At the farewell parties, Andrea always foregrounded the merits of the leaving coworker and handed over the gifts of the group, and the leaving person had to guess the content from the properties of the parcels. A special highlight were the seminaries of the group at the beginning on Thursday evening and afterward late on Friday afternoon. Here, Andrea presented synthetic and mechanistic problems from the actual literature, but always outside carbohydrate chemistry. Together, we should find the best solution. I remember the many sessions in his office where we searched a rationalization for different experimental and spectroscopic data and he formulated the conclusion in a short and concise sentence. In 2008, Andrea was emeritus (Figure 1), and I joined the group of Professor François Diederich who kindly allowed me to help Andrea in the preparation of the last publications in the oligonucleotide series and to continue investigations of intramolecular hydrogen bonding of organofluorine compounds in collaboration with Professor Véronique Gouverneur at the university of Oxford. Pictures taken from the emeritus party 2008 where I have handed over the book ‘The Vasella Group from 1975 to 2008’ to Andrea. Andrea introduced functional groups well known in organic chemistry (many more than mentioned in this article) into carbohydrates ascertaining his statement at my thesis application: ‘I do organic chemistry with carbohydrates’. Thus, he had a huge impact on the renaissance of the carbohydrate chemistry. I thank the destiny which had directed me twice into the Vasella group and I am extremely proud to have spent thirty-three years in this group.

Vasella! Our PhD supervisor (Figure 1) was born in 1943 in Fribourg, Switzerland, where he first attended the St. Michael college and then studied Botany, Zoology and Chemistry at the local University. Following his graduation in 1966, he moved to the ETH in Zürich to earn his doctorate1 in 1971 under the supervision of Duilio Arigoni. After two post-doctorate fellowships in the research groups of Jack E. Baldwin (Kings College, London und M.I.T.) and Robert Burns Woodward (Harvard), he returned to the ETH Zürich in 1974. In 1977, he became Assistant Professor at the University of Fribourg, subsequently Associate Professor at the University of Zürich (1981–1988) and held full Professor positions at the University of Zürich (1988–1993) and at the Laboratorium für Organische Chemie at the ETH Zürich (1993–2008). Andrea Vasella, 2023 (Photo: R. Häfliger). You are cordially invited to read this special issue of Helvetica Chimica Acta, which is dedicated to the 80th birthday of Andrea Vasella. Andrea loved to quote aphorisms by Gracián,2 Schopenhauer3 as well as Goethe4 such as parts of the ‘Makarien's archive in Wilhelm Meister's Wanderjahre’: ‘Es ist nicht genug zu wissen, man muss auch anwenden; es ist nicht genug zu wollen, man muss auch tun.’ In other words: to be successful, one has to translate knowledge and desire into action. In this spirit, the six of us became Guest Editors of this special issue and decided in February of 2023 to make it happen. Andrea's educational style was well known as intellectually challenging, tough and probing, but equally inspiring, rewarding and encouraging as he infected many of us with great enthusiasm for Science. Words like these can be found in the acknowledgments of our dissertations.5-10 As a mentor and supervisor, Andrea had a clear strategy; his evaluations, perceptions and directions were transparent, and every group member knew the boundaries of what is tolerable and expected. With the support of Bruno Bernet, Thomas Mäder and Nina-May Haydon, Andrea provided a group atmosphere, which required an adequate level of necessary discipline as well as scientific rigour. Optimal laboratory practices, aimed at the highest standards of health and safety, as well as a careful usage of equipment were always top priority. In the same vein, spectroscopic data had to be fully understood and reported correctly. Equally important was the attendance and active participation in our weekly group seminars; these sessions, often far outside of regular working hours, almost felt like a ‘sport’, whereby Andrea challenged the group with a scientific puzzle followed by a clever and deep analysis. Overall, the amalgamate of intellectual challenges, high expectations and enthusiasm for Science has created a lovely and lasting connectivity amongst group members (Figures 23–4). Farewell party of Monica Palme, ETH 1995. 28 years later: Monica Palme and Andrea Vasella in a lively discussion (Photos: A.E., R. Häfliger). Almens, Graubünden, June 2023. Members of the Vasella Group at a reunion (Photo: R. Häfliger). AV Group Christmas Party, Zürich 1995 (Photo: A.E.). Andrea‘s relationship with his group members has always been characterised by an enormous mutual respect – the basis of this appreciation were encouragement and inspiration combined with an appreciation of everyone‘s achievements. Andrea's sharp wit and humour as well as his iron-clad argumentation style are rare qualities and taught us students ever so important lessons for life. One of the most unique aspects of Andrea's approach was the individualised education and personal development of every single group member. He had the capability and energy to dedicate his time to each individual co-worker, aiming to help them identify a weakness and turn it into a strength. For instance, he often spent late evenings on weekends with a Ph.D. student to mill over the latest draft of a thesis or a manuscript. At the time we were young scientists, hardly realising that not only were we sitting opposite of a brilliant teacher, but also a family father, who dedicated his full attention and time to us. Thank you. We would like to express our thanks to Professors Antonio Togni (ETH Zürich) and Peter Wipf (University of Pittsburgh) for taking on the role as Editors of this issue. We are also grateful to Richard Smith (Executive Editor at Wiley-VHCA AG), representing Helvetica Chimica Acta, who supported this project from the outset with great enthusiasm and dedication. Thank you. Finally, Andrea: We wish you the very best, continuous good health and look forward to a next group reunion. We hope that you will enjoy reading the essays in this special issue. Thank you. A.E. wrote the manuscript in German including inputs from R.B. and all other authors. R.B. translated the manuscript into British English.

AbstracttRNA‐Guanin‐Transglycosylase, ein Target zur Therapie der Shigellen‐Ruhr, erkennt tRNA nur als Homodimer und führt einen kompletten Nucleobasen‐Austausch an dessen Wobble‐Position durch. Inhibitoren des aktiven Zentrums blockieren die Enzymfunktion durch kompetitive Verdrängung der tRNA. In Lösung dissoziiert der homodimere Wildtyp nur geringfügig, während mutierte Varianten eine erhebliche Monomerisierung in Lösung aufzeigen. Ein Inhibitor transformiert das Protein in einen verdrehten Zustand, wobei eine Monomereinheit um etwa 130° rotiert. In dieser veränderten Geometrie ist das Enzym nicht länger in der Lage, die tRNA zu binden und zu prozessieren. Drei Zucker‐basierte Inhibitoren wurden entworfen und synthetisiert, die das Protein sowohl im funktionell kompetenten als auch im verdrehten inaktiven Zustand binden. Beide Zustände kristallisieren unter identischen Bedingungen nebeneinander im selben Kristallisationsgefäß. Möglicherweise entspricht die verdrehte inaktive Form mit einem Ruhezustand des Enzyms, der wichtig für dessen funktionelle Regulation sein könnte.

The enzyme tRNA-guanine transglycosylase, a target to fight Shigellosis, recognizes tRNA only as a homodimer and performs full nucleobase exchange at the wobble position. Active-site inhibitors block the enzyme function by competitively replacing tRNA. In solution, the wild-type homodimer dissociates only marginally, whereas mutated variants show substantial monomerization in solution. Surprisingly, one inhibitor transforms the protein into a twisted state, whereby one monomer unit rotates by approximately 130°. In this altered geometry, the enzyme is no longer capable of binding and processing tRNA. Three sugar-type inhibitors have been designed and synthesized, which bind to the protein in either the functionally competent or twisted inactive state. They crystallize with the enzyme side-by-side under identical conditions from the same crystallization well. Possibly, the twisted inactive form corresponds to a resting state of the enzyme, important for its functional regulation.

The design and synthesis of Aviram-Ratner-type molecular rectifiers, featuring an anilino-substituted extended tetracyanoquinodimethane (exTCNQ) acceptor, covalently linked by the σ-spacer bicyclo[2.2.2]octane (BCO) to a tetrathiafulvalene (TTF) donor moiety, are described. The rigid BCO spacer keeps the TTF donor and exTCNQ acceptor moieties apart, as demonstrated by X-ray analysis. The photophysical properties of the TTF-BCO-exTCNQ dyads were investigated by UV/Vis and EPR spectroscopy, electrochemical studies, and theoretical calculations. Langmuir-Blodgett films were prepared and used in the fabrication and electrical studies of junction devices. One dyad showed the asymmetric current-voltage (I-V) curve characteristic for rectification, unlike control compounds containing the TTF unit but not the exTCNQ moiety or comprising the exTCNQ acceptor moiety but lacking the donor TTF part, which both gave symmetric I-V curves. The direction of the observed rectification indicated that the preferred electron current flows from the exTCNQ acceptor to the TTF donor.

The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are attractive targets for drugs against various diseases, including malaria. We describe herein the structure-based design, synthesis, conformational analysis, and biological evaluation of several 8-brominated or 8-aminated adenosine derivatives with different substituents at C(5′), targeting the ATP-adenine binding site of the IspE protein from the non-mevalonate pathway. An exhaustive conformational analysis of the adenosine derivatives both in solution and in the solid state confirmed the desired syn orientation of the adenine moiety. Despite this favorable pre-organization for binding to the cofactor pocket, biological evaluation of the inhibitors showed only a very modest inhibitory activity.

Chemistry for the efficient modification of the kanamycin class of 4,6-aminoglycosides at the 4'-position is presented. In all kanamycins but kanamycin B, 4'-O-alkylation is strongly detrimental to antiribosomal and antibacterial activity. Ethylation of kanamycin B at the 4″-position entails little loss of antiribosomal and antibacterial activity, but no increase of ribosomal selectivity. These results are contrasted with those for the 4,5-aminoglycosides, where 4'-O-alkylation of paromomycin causes only a minimal loss of activity but results in a significant increase in selectivity with a concomitant loss of ototoxicity.

The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The G[s]G dinucleoside 6 and the G[s]G* dinucleoside 8 were prepared by alkylation of the guanosine thiols derived from 2 and 5, respectively, by the C(8)-chloromethylated guanosine 4 that was obtained from alcohol 3. Dinucleosides 6 and 8 were deacylated to 7 and 9, and fully deprotected to 10 and 11, respectively. The G[N]G dinucleoside 16 was obtained by reductive amination of aldehyde 13 with an iminophosphorane derived from azide 14 and deprotection of the resulting dimer 15. In the solid state of 6, and in a solution of 6 and 8 in CDCl3, H-N(1/I) and H-N(1/II) are engaged in intramolecular H-bonds to the C=O of the isobutyryl protecting groups, and HN of the isobutyryl group of unit I forms an interresidue, intramolecular H-bond to N(7/II), leading to a syn orientation of the nucleobase at unit I, to a tg orientation of the sulfanyl moiety, and to an orthogonal orientation of the nucleobases, preventing any base pairing. The silylated and isopropylidenated dinucleosides 7 and 9 are present in DMSO solution as solvated monoplexes. Broad H-1-NMR signals of the nucleosides 7 and 16 in CHCl3 solution evidence equilibrating G-quadruplexes. The quadruplex formation of 7 and 16 was established by H-1-NMR spectroscopy (only of 16), vapour pressure osmometry, mass spectrometry, and CD spectroscopy. The C(6(I))-hydroxymethylated analogue 9 in CDCl3 and the fully deprotected dinucleosides 10 and 11 in H2O form only weakly pi-pi stacked associates, but no G-quadruplexes, as evidenced by CD spectroscopy.

AbstractThe self‐complementary guanosine‐ and cytidine‐derived aminomethylene‐linked C*[n]G dinucleoside 9 was synthesized by reductive amination of aldehyde 3 with an iminophosphorane derived from azide 7. Deacylation of 9 gave the isopropylidene‐protected dinucleoside 10. The sequence‐isomeric G*[n]C dinucleoside 11 was similarly prepared from aldehyde 8 and azide 5, and deacylated to 12. The association of 10 and 12 in CHCl3 or in CHCl3/DMSO mixtures, and the structure of the associates were studied by 1H‐NMR, ESI‐MS, CD, and vapor pressure osmometry (VPO). Broad 1H‐NMR signals of dinucleosides 10 and 12 evidence an equilibrium between duplexes and quadruplexes (Hoogsteen base pairing between the WatsonCrick base‐paired duplexes). The quadruplex dominates for the G*[n]C dinucleoside 12 between −50° and room temperature. The sequence‐isomeric C*[n]G 10 forms mostly only a cyclic duplex in CDCl3 and in CDCl3/(D6)DMSO 9 : 1.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

ABSTRACT The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity. IMPORTANCE The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms.

We are interested in developing strategies to bridge (“staple”) enantiomerically pure acyclic alleno-acetylenic oligomers to enhance their conformational preferences for helical secondary structures, which are postulated to be at the origin of their exceptional chiroptical properties. We found that ring-closing metathesis (RCM), which has been used for the stapling of peptide helices, failed with an acyclic alleno-acetylene dimer decorated with lateral olefinic side chains. Instead, enyne RCM to an enantiomerically pure dienyne occurred. We switched to the introduction of diacetylene-containing bridges and report here the 15-step synthesis of a moderately strained, enantiomerically pure cyclohexa-1,3,9,11-tetrayne with an oxidative acetylenic coupling in the key step. The chiroptical properties of the new compounds are discussed.

The self-complementary guanosine-and cytidine-derived aminomethylene-linked C*[n] G dinucleoside 9 was synthesized by reductive amination of aldehyde 3 with an iminophosphorane derived from azide 7. Deacylation of 9 gave the isopropylidene-protected dinucleoside 10. The sequence-isomeric G*[n]C dinucleoside 11 was similarly prepared from aldehyde 8 and azide 5, and deacylated to 12. The association of 10 and 12 in CHCl3 or in CHCl3/DMSO mixtures, and the structure of the associates were studied by H-1-NMR, ESI-MS, CD, and vapor pressure osmometry (VPO). Broad 1H-NMR signals of dinucleosides 10 and 12 evidence an equilibrium between duplexes and quadruplexes (Hoogsteen base pairing between the Watson-Crick base-paired duplexes). The quadruplex dominates for the G*[n]C dinucleoside 12 between -50 degrees and room temperature. The sequence-isomeric C*[n] G 10 forms mostly only a cyclic duplex in CDCl3 and in CDCl3/(D-6)DMSO 9 :1.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The protected G*[s]C*[s]U*[s]A*[s]U*[s]A*[s]G*[s]C* octanucleoside 24 was prepared by S-alkylation of the thiolate derived from tetranucleoside 23 with the methanesulfonate 22, and transformed to the silylated and isopropylidenated 25, and further into the fully deprotected octanucleoside 26. Compound 22 was derived from the methoxytrityl-protected tetranucleoside 21, and 21 was obtained by S-alkylation of the thiolate derived from the dinucleoside 19 with methanesulfonate 17 derived from 16 by detritylation and mesylation. Similarly, tetranucleoside 23 resulted from S-alkylation of the thiolate derived from 18 with the methanesulfonate 20 derived from 19. Dinucleosides 16 and 18 resulted from S-alkylation of the thiolate derived from the known cytidine-derived thioacetate 15 with the C(8)-substituted guanosine-derived methanesulfonates 12 and 14, respectively, that were synthesized from the protected precursors 4 and 7 by formylation, reduction, protection, and mesylation. The structures of the duplexes of 25 and 26 were calculated using AMBER* modelling and based on the known structure of the core tetranucleoside U*[s]A*[s]U*[s]A*. The former shows a helix with a bent helix axis and strong buckle and propeller twists, whereas the latter is a regular, right-handed, and apparently strain-free helix. In agreement with modelling, the silylated and isopropylidenated octanucleoside 25 in (CDCl2)(2) solution led to a mixture of associated species possessing at most four WatsonCrick base pairs, while the fully deprotected octanucleoside 26 in aqueous medium forms a duplex, as evidenced by a decreasing CD absorption upon increasing the temperature and by a UV-melting curve with a melting temperature of ca. 10 degrees below the one of the corresponding RNA octamer, indicating cooperativity between base pairing and base-pair stacking.