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Synthesis and Nucleic-Acid-Binding Properties of Sulfamide and 3'-N-Sulfamate-Modified

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Synthesis and Nucleic-Acid-Binding Properties of Sulfamide and 3'-N-Sulfamate-Modified View Article Online / Journal Homepage / Table of Contents for this issue PERKIN Synthesis and nucleic-acid-binding properties of sulfamide- and 3Ј-N-sulfamate-modified DNA† Kevin J. Fettes,a,b Nigel Howard,b David T. Hickman,a,b Steven Adah,c Mark R. Player,c Paul F. Torrence d and Jason Micklefield*a a Department of Chemistry, University of Manchester Institute of Science and Technology, 1 Faraday Building, PO Box 88, Manchester, UK M60 1QD b Department of Chemistry, Birkbeck College, University of London, 29 Gordon Square, London, UK WC1H 0PP c Laboratory of Medicinal Chemistry, NIDDK, NIH Bethesda, MD, 20892-0805, USA d Department of Chemistry, Northern Arizona University, Flagstaff, AZ, 86011-5698, USA Received (in Cambridge, UK) 19th November 2001, Accepted 13th December 2001 First published as an Advance Article on the web 29th January 2002 A novel synthetic route for the preparation of sulfamide- and 3Ј-N-sulfamate-modified dinucleosides has been developed. The synthesis utilises 4-nitrophenyl chlorosulfate to prepare 4-nitrophenyl 3Ј- or 5Ј-sulfamates (e.g., 18 and 27), which couple smoothly with the alcohol or amine functionalities of other nucleosides. The conformational properties of the sulfamide- and 3Ј-N-sulfamate-modified dinucleosides d(TnsnT) and d(TnsoT) were compared with the native dinucleotide d(TpT) using NMR and CD spectroscopy. Whilst both modifications result in a shift in the conformational equilibrium of the 5Ј-terminal ribose rings from C2Ј-endo to a preferred C3Ј-endo conformation, only the 3Ј-N-sulfamate-modified dimer exhibits an increased propensity to adopt a base-stacked helical conformation. Incorporation of the sulfamide- and 3Ј-N-sulfamate modifications into the DNA sequence d(GCGT10GCG) allowed the duplex melting temperature to be determined using UV thermal denaturation experiments. This reveals that the sulfamide modification significantly destabilises duplexes with both complementary DNA and RNA. However, the 3Ј-N-sulfamate modification has little effect on duplex stability and even stabilises DNA duplexes at low salt concentration. These results indicate that the 3Ј-N-sulfamate group is one of the most promising neutral replacements of the phosphodiester group in nucleic acids, that have been developed to date, for therapeutic and other important applications. Introduction stable to nuclease digestion and increase the lipophilicity of 1–3 fi backbone, possibly aiding cellular uptake. In addition it was Nucleic acids have been extensively modi ed by replacing anticipated that introducing neutral linkages would improve the nucleobase, sugar, phosphodiester linkage or the whole affinity for complementary DNA and RNA, by reducing 1–5 ff backbone with alternative structures. Evaluating the e ects electrostatic repulsion between stands. One of the earliest Published on 29 January 2002. Downloaded by NORTHERN ARIZONA UNIVERSITY 09/03/2016 00:51:22. fi of the various structural modi cations on the conformation examples of this class are the methylphosphonate-modified and recognition properties of nucleic acids can provide an oligonucleotides 1 (Scheme 1).14,15 Replacement of one of alternative perspective from which the structure and function of native DNA and RNA can be better understood. More- over, if the modifications investigated could potentially have arisen under prebiotic conditions then it is possible to speculate about the origins of the genetic material.6,7 Modified oligonucleotides have also been developed as antisense or antigene therapeutic agents.1–3 Similarly, modification strategies can be used to stabilise aptamers 8,9 or ribozymes 10,11 for use in vivo via exogenous delivery. Furthermore, modified nucleic acids also have significant potential as diagnostic agents or bio-analytical tools which depend upon hybridis- ation.12 For example, novel microarrays have been developed which utilise peptide nucleic acid probes.13 Here improved stability, affinity and sequence specificity can also be advantageous. Scheme 1 In antisense and antigene research there has been consider- able interest in the replacement of the phosphodiester group the non-bridging oxygen atoms with a methyl group in 1 results of oligonucleotides with alternative neutral linkages that are in a chiral phosphorus atom. Although the R-configured methylphosphonates form duplexes which are as stable as iso- sequential native duplexes, oligonucleotides consisting of a † Electronic supplementary information (ESI) available: typical melting ffi curves obtained from thermal denaturation of modified oligonucleo- mixture of diastereoisomers have relatively poor a nity for 14 ffi tides with complementary DNA and RNA. See http://www.rsc.org/ complementary nucleic acids. Despite this, e cient synthetic suppdata/p1/b1/b110603c/ methodology for the enantioselective synthesis of mixed- DOI: 10.1039/b110603c J. Chem. Soc., Perkin Trans. 1, 2002, 485–495 485 This journal is © The Royal Society of Chemistry 2002 View Article Online sequence oligomers with all R stereocentres has yet to be Results and discussion developed.15 Several neutral achiral phosphodiester replace- Ј fi ments have also been investigated, including methylene- Synthesis of sulfamide- and 3 -N-sulfamate-modi ed (methylimino) (MMI) 2,16 amide 3,2 and 3Ј-thioformacetal 4,17 dinucleosides ffi which exhibit good a nity for nucleic acid targets and hold Previously we have shown that the 2-hydroxyphenyl sulfamate 9 more promise for the development of improved antisense (Scheme 2), derived from catechol sulfate, can be coupled with fi or antigene agents. Other neutral backbone modi cations 5Ј-amino nucleosides to give sulfamide-linked dinucleosides.22 have also been used in the development of oligonucleotides However, these coupling reactions are slow, requiring heating ff with potentially di erent modes of therapeutic action. For under reflux in 1,4-dioxane for extended periods and give only example, dsDNA possessing an Eco RV restriction site was moderate yields of sulfamide products. Moreover, treatment fi modi ed with a single neutral dimethylenesulfone linkage of the 2-hydroxyphenyl sulfamate 9 with nucleoside 5Ј-alcohols 18 6. The resulting duplex adopts a bent conformation and in the presence of base fails to give any sulfamate products. functions as a transition-state analogue inhibiting cleavage Aryl sulfamates 10 are thought to undergo elimination in the of the native dsDNA substrate. Extension of this strategy presence of base to form N-sulfonylamines 12 via the anion 11 fi could lead to modi ed oligonucleotide inhibitors of other by an E1cB mechanism or directly through an E2-type pro- enzymes that process native DNA substrates. Furthermore cess.24 The highly electrophilic N-sulfonylamine 12 is then a thrombin binding DNA aptamer, generated by in vitro trapped by nucleophiles, for example amines or alcohols, fi 9 selection, was modi ed with formacetal linkages 5. The resulting in sulfamides 13 or sulfamates 14, respectively. Given fi modi ed chimeric oligonucleotide aptamer, which adopts a that catechol is a relatively poor leaving group (pK ≈ 9.1) 25 it ffi a1 chair-like structure, retains high a nity for the protein target seems likely that, in the case of the 2-hydroxyphenyl sulfamate but has considerably improved stability and anticoagulant 9, the equilibrium between the sulfamate 10 or the conjugate fi activity in vivo. Finally, methylphosphonate modi cations 1 base 11 and N-sulfonylamine 12 lies on the side of the starting have also been used to probe protein–nucleic acid inter- material. As a consequence of this only more nucleophilic actions using a template-directed interference footprinting amines can compete with catecholate, in the reverse reaction, 19 approach. and trap the low concentration of N-sulfonylamine to give Recently we have been involved in the synthesis and evalu- sulfamide products 13. With this in mind we reasoned that fi 20–22 ation of backbone-modi ed nucleic acids. In particular we more reactive aryl sulfamates 10, sulfamoyl chlorides (RNH- fi have sought to develop modi ed oligonucleotides with neutral SO Cl) or sulfamoyl azides (RNHSO N ), would be required as Ј 2 2 3 sulfamide 7 and 3 -N-sulfamate 8 groups replacing the substrates for coupling with alcohols to give sulfamates 14. 21,22 negatively charged phosphodiester linkage (Scheme 2). In Nucleosides with 5Ј-sulfamoyl azide groups have been employed previously in the synthesis of 5Ј-N-sulfamate dinucleosides.26 Nevertheless we chose to avoid this chemistry given that it necessitates the use the explosive reagent sulfuryl chloride azide and yields were low. Also, earlier attempts to synthesise the sulfamoyl chloride 17 (Scheme 3) from 3Ј-amino Published on 29 January 2002. Downloaded by NORTHERN ARIZONA UNIVERSITY 09/03/2016 00:51:22. Scheme 2 addition to possessing many of the advantageous properties Scheme 3 common to other neutral modifications 1–6, these linkages should be easier to prepare and more closely resemble the nucleoside 15 using sulfuryl dichloride had failed. We therefore phosphodiester group both sterically and conformationally. In chose to investigate the reaction of the 3Ј-amine 15 with 4- the case of native nucleic acids anomeric or gauche effects are, nitrophenyl chlorosulfate 16, anticipating the production of at least in part, responsible for the conformational preferences either the sulfamoyl chloride 17 or the 4-nitrophenyl sulfamate 23 of the phosphodiester P–Oester bonds. Similar stereoelectronic 18. Accordingly, 4-nitrophenyl chlorosulfate 16 was prepared effects are likely to control
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