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1.
Org Biomol Chem ; 5(7): 1081-6, 2007 Apr 07.
Article in English | MEDLINE | ID: mdl-17377661

ABSTRACT

A library of stereo- and regiochemically diverse aminoglycoside derivatives was screened at 1 microM using surface plasmon resonance (SPR) against RNA hairpin models of the bacterial A-site, and the HIV viral TAR and RRE sequences. In order to double the stereochemical diversity of the library, the compounds were screened against both enantiomers of each of these sequences. Remarkably, this initial screen suggested that the same four aminoglycoside derivatives bound most tightly to all three of the RNAs, suggesting that these compounds were good RNA binders which, nonetheless, discriminated poorly between the RNA sequences. The interactions between selected isomeric aminoglycoside derivatives and the RNA hairpins were then studied in more detail using an SPR assay. Three isomeric tight-binding aminoglycoside derivatives, which had been identified from the initial screen, were found to bind more tightly to the RNA hairpins (with K(D) values in the range 0.23 to 4.7 microM) than a fourth isomeric derivative (which had K(D) values in the range 6.0 to 30 microM). The magnitude of the tightest RNA-aminoglycoside interactions stemmed, in large part, from remarkably slow dissociation of the aminoglycosides from the RNA targets. The three tight-binding aminoglycoside derivatives were found, however, to discriminate rather poorly between alternative RNA sequences with, at best, around a twenty-fold difference in affinity for alternative RNA hairpin sequences. Within the aminoglycoside derivative library studied, high affinity for an RNA target was not accompanied by good discrimination between alternative RNA sequences.


Subject(s)
Aminoglycosides/chemistry , RNA, Bacterial/chemistry , RNA, Viral/chemistry , Base Sequence , Combinatorial Chemistry Techniques , HIV Long Terminal Repeat , Ligands , Molecular Conformation , Nucleic Acid Conformation , Stereoisomerism , Surface Plasmon Resonance
2.
Org Biomol Chem ; 3(15): 2776-85, 2005 Aug 07.
Article in English | MEDLINE | ID: mdl-16032356

ABSTRACT

A library of forty modified aminoglycosides was prepared in which the configuration and regiochemistry of two or three rings was widely varied. The library was based around three core ring systems: the 2-deoxystreptamine ring system found in the natural products, and both enantiomers of (1R*,2R*,4R*,5R*)-2,5-diamino-cyclohexane-1,4-diol and (1R*,3R*,4R*,6R*)-4,6-diaminocyclohexane-1,3-diol. In each case, the core was modified by glycosylation with one or two sugar rings. The absolute configuration of the sugar substituents (d or l), the configuration of the anomeric centres (alpha or beta), and the regiochemical arrangement of the amine(s) were varied.


Subject(s)
Aminoglycosides/chemical synthesis , Aminoglycosides/chemistry , Glycosylation , Stereoisomerism
3.
Chem Commun (Camb) ; (2): 272-3, 2003 Jan 21.
Article in English | MEDLINE | ID: mdl-12585426

ABSTRACT

The isolation of a stable beta-hydrogen-containing R-PdLn-X complex (R = alkyl; X = halide) issued from a Heck reaction is reported together with some aspects of its reactivity.

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