Structure–activity studies of oxazolidinone analogs as RNA-binding agents

Means, John A.; Katz, Steven J.; Nayek, Abhijit; Anupam, Rajaneesh; Hines, Jennifer V.; Bergmeier, Stephen C.

doi:10.1016/j.bmcl.2006.03.068

Cited by 47 publications

(42 citation statements)

References 53 publications

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“…This element must be stabilized by interaction with the acceptor end of the tRNA. The structure of this domain [31–32] was therefore used as the basis for design of families of compounds that were predicted to bind to the antiterminator, and the resulting compounds were tested for effects on tRNA binding, tRNA-dependent stabilization of the antiterminator and antitermination [38–43]. Further development of these compounds holds promise for development of useful new antimicrobial compounds that are predicted to be specific for Gram-positive organisms, avoiding more general effects on the commensal flora.…”

Section: Targeting Of the T Box Riboswitch With Novel Antimicrobiamentioning

confidence: 99%

The T box riboswitch: A novel regulatory RNA that utilizes tRNA as its ligand

Henkin

2014

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The T box riboswitch is a cis-acting regulatory RNA that controls expression of amino acid-related genes in response to the aminoacylation state of a specific tRNA. Multiple genes in the same organism can utilize this mechanism, with each gene responding independently to its cognate tRNA. The uncharged tRNA interacts directly with the regulatory RNA element, and this interaction promotes readthrough of an intrinsic transcriptional termination site upstream of the regulated coding sequence. A second class of T box elements uses a similar tRNA-dependent response to regulate translation initiation. This review will describe the current state of our knowledge about this regulatory system.

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Section: Targeting Of the T Box Riboswitch With Novel Antimicrobiamentioning

confidence: 99%

The T box riboswitch: A novel regulatory RNA that utilizes tRNA as its ligand

Henkin

2014

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…23-30 Although significant advances have recently been made towards rationally designing small molecule ligands for RNA, 9,14,31-37 the limited available knowledge of the guiding principles of small molecule:RNA recognition has remained a significant hurdle. At the same time, some of the most successful screens have been conducted on RNA-targeted libraries generated by the diversification of molecular scaffolds known to interact with RNA, such as phenylbenzamidazoles, 38-40 oxazolidinones, 41-44 and diphenylfurans 45-47 though the library sizes and number of scaffolds tested has been fairly limited. 40,48 Based on these results, we see an urgent need for the identification and development of new RNA-targeted scaffolds that can expand scientists' repertoire for probing RNA structure and function, particularly RNA structures critical to infectious agents such as HIV.…”

Section: Introductionmentioning

confidence: 99%

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

et al. 2017

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Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [1H-13C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members. Cheminformatic analysis revealed distinct differences between selective and non-selective ligands. In this study, we evolved dimethylamiloride from a weak TAR ligand to one of the tightest binding selective TAR ligands reported to date through a novel combination of synthetic methods and analytical techniques. We expect these methods to allow for rapid library expansion and tuning of the amiloride scaffold for a range of RNA targets and for SOFAST NMR to allow unprecedented evaluation of small molecule:RNA interactions.

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“…These include the RNA binding agent 131 [109], antithrombotic agent 132 [110], antipsychotic agent panamesine 133 [111], and they are MAO-A inhibitors [112][113][114][115]. Toloxatone 134 and Befloxatone 135 [113][114] are reversible MAO-A inhibitors, and are useful as antidepressant agents.…”

Section: Oxazolidinone Derivatives With Other Biological Activitiesmentioning

confidence: 99%

Synthesis and Antibacterial Properties of Oxazolidinones and Oxazinanones

Wang¹

2008

AIAMC

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Oxazolidinones are important synthetic antibacterial agents useful for the treatment of multi antibiotic resistant Gram-positive bacterial infections. Since the launch of Linezolid, the first member of the oxazolidinone antibacterial family, there have been many studies directed towards structural optimization and the development of second generation oxazolidinones. The N-aryl 5-acetamido methyl oxazolidinone is the core structure for this class of antibacterial agents and the oxazolidinone component is essential for antibacterial activities. The chiral cyclic carbamate 5-hydroxymethyloxazolidin-2-one and 6-hydroxymethyl-[1,3]oxazinan-2-one are also important building blocks for synthesizing other biologically active compounds. Because of the importance of these compounds, many methods have been developed for their facile syntheses. In the first part of this paper, the synthesis of Linezolid and its analogs, as well as the preparation of the oxazolidinone core structures, will be reviewed. Secondly, recent developments in the area of oxazolidinone antibacterial agents including structure-activity relationships will be reviewed.

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Structure–activity studies of oxazolidinone analogs as RNA-binding agents

Cited by 47 publications

References 53 publications

The T box riboswitch: A novel regulatory RNA that utilizes tRNA as its ligand

The T box riboswitch: A novel regulatory RNA that utilizes tRNA as its ligand

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

Synthesis and Antibacterial Properties of Oxazolidinones and Oxazinanones

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