Replacement of the phosphodiester linkage in DNA with sulfamide and 3′-N-sulfamate groups

Fettes, Kevin J.; Howard, Nigel; Hickman, David T.; Adah, Steven A.; Player, Mark R.; Torrence, Paul F.; Micklefield, Jason

doi:10.1039/b001586p

Cited by 16 publications

(24 citation statements)

References 12 publications

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“…Sulfamoylation of 25 with 4-nitrophenyl chlorosulfate afforded 26 , which was coupled to nucleoside 27 33 followed by global deprotection of the acetonide and benzylidene acetal with 80% aqueous TFA to furnish 5 . 34 …”

Section: Resultsmentioning

confidence: 99%

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Wei

Martinelli

et al. 2014

Bioorganic & Medicinal Chemistry

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The biosynthesis of pantothenate, the core of coenzyme A (CoA), has been considered an attractive target for the development of antimicrobial agents since this pathway is essential in prokaryotes, but absent in mammals. Pantothenate synthetase, encoded by the gene panC, catalyzes the final condensation of pantoic acid with β–alanine to afford pantothenate via an intermediate pantoyl adenylate. We describe the synthesis and biochemical characterization of five PanC inhibitors that mimic the intermediate pantoyl adenylate. These inhibitors are competitive inhibitors with respect to pantoic acid and possess submicromolar to micromolar inhibition constants. The observed SAR is rationalized through molecular docking studies based on the reported co-crystal structure of 1a with PanC. Finally, whole cell activity is assessed against wild-type Mtb as well as a PanC knockdown strain where PanC is depleted to less than 5% of wild-type levels.

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Section: Resultsmentioning

confidence: 99%

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Wei

Martinelli

et al. 2014

Bioorganic & Medicinal Chemistry

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“…This revealed that the sulfamides result in lower affinity for complementary DNA and RNA (ca. -3 ˚C ∆T m /mod), whilst the 3´-Nsulfamates have approximately the same affinity as native DNA [131]. The 3´-N-sulfamates are similar to the N3´→P5´ phosphoramidate in that the 3´-amino group which is less electronegative than the native 3´-oxygen results in a bias of the sugar pucker towards the C3´-endo conformation [132].…”

Section: Formacetal and Thioformacetal Linkagesmentioning

confidence: 97%

“…However, one altogether different therapeutic application of formacetal modified oligos was recently reported [19]. This arose from the earlier discovery of a DNA aptamer, generated by in vitro selection, isomeric 3´-N-sulfamates 54 and related sulfamides 55 [131,132]. Accordingly dimers were synthesised and between one and five modifications were incorporated into a standard sequence of DNA [55].…”

Section: Formacetal and Thioformacetal Linkagesmentioning

confidence: 99%

Backbone Modification of Nucleic Acids: Synthesis, Structure and Therapeutic Applications

Micklefield

2001

CMC

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180

118

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Nucleic acids have been extensively modified by replacing the phosphodiester group or the whole sugar phosphodiester with alternative anionic, neutral and cationic structures. Several of these modified oligonucleotides exhibit improved properties including enhanced recognition and binding to RNA, duplex DNA and proteins. This has resulted in the development of new and more potent antisense and antigene agents, as well as aptamers. Furthermore, backbone modified oligonucleotides have also been used in the development of several alternative strategies, which rely on altogether different mechanisms of action and show significant promise for therapeutic intervention. In this review the latest advances in the synthesis and evaluation of the most promising backbone modified oligos will be discussed, with a view to their future as novel pharmaceuticals.

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“…19,20,21 Moreover, we believed that the resulting sulfamate ester obtained from the C–H amination might provide an opportunity for rapid synthesis of the desired mixed sulfamides by removing the need to prepare the more sensitive sulfamoyl chlorides 22 used in our previous report. 5e Indeed, as a separate part of our studies directed at efficient synthesis of diazenes, 2-hydroxyphenyl 23 and 4-nitrophenyl 24 sulfamate esters had proven effective coupling partners for entry to various sulfamide derivatives. 25 In order to test these hypotheses cyclotryptamine (−)- 14 was synthesized from the cyclotryptophan derivative (+)- 13 in 86% yield via hydrolysis of the ester, Barton ester formation, and subsequent photodecarboxylation (Scheme 2a).…”

Section: Synthesis Of C3a-aminocyclotryptamines Via Catalytic Intermomentioning

confidence: 99%

Application of diazene-directed fragment assembly to the total synthesis and stereochemical assignment of (+)-desmethyl-meso-chimonanthine and related heterodimeric alkaloids

Lathrop

Movassaghi

2014

Chem. Sci.

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We describe the first application of our methodology for heterodimerization via diazene fragmentation towards the total synthesis of (−)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-chimonanthine. Our syntheses of these alkaloids feature an improved route to C3a-aminocyclotryptamines, an enhanced method for sulfamide synthesis and oxidation, in addition to a late-stage diversification leading to the first enantioselective total synthesis of (+)-desmethyl-meso-chimonanthine and its unambiguous stereochemical assignment. This versatile strategy for directed assembly of heterodimeric cyclotryptamine alkaloids has broad implications for the controlled synthesis of higher order derivatives with related substructures.

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Replacement of the phosphodiester linkage in DNA with sulfamide and 3′-N-sulfamate groups

Cited by 16 publications

References 12 publications

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Backbone Modification of Nucleic Acids: Synthesis, Structure and Therapeutic Applications

Application of diazene-directed fragment assembly to the total synthesis and stereochemical assignment of (+)-desmethyl-meso-chimonanthine and related heterodimeric alkaloids

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