Solution-Phase Synthesis of Novel Linear Oxyamine Combinatorial Libraries with Antibacterial Activity

Kung, Pei‐Pei; Bharadwaj, Ramesh; Fraser, Allister S.; Cook, D. R.; Kawasaki, Andrew M.; Cook, P. Dan

doi:10.1021/jo971655u

Cited by 16 publications

(28 citation statements)

References 30 publications

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“…Similarly, an energetic analysis of the binding elements comprising 2-(2)-13 was not possible because of the extremely weak inhibition by the 5-formyluracil O-methyl oxime (50) and the dihydroxybenzaldoxime O-methyl ether (47). Nevertheless, the 140-fold greater binding affinity of 3-(3)-27 as compared to the 6-formyluracil O-methyl oxime binding element (51) alone indicates that a large benefit can be derived from tethering 50 .…”

Section: Inhibition By the Untethered Partsmentioning

confidence: 99%

Uracil-Directed Ligand Tethering: An Efficient Strategy for Uracil DNA Glycosylase (UNG) Inhibitor Development

et al. 2005

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Uracil DNA glycosylase (UNG) is an important DNA repair enzyme that recognizes and excises uracil bases in DNA using an extrahelical recognition mechanism. It is emerging as a desirable target for small molecule inhibitors given its key role in a wide range of biological processes including the generation of antibody diversity, DNA replication in a number of viruses, and the formation of DNA strand breaks during anticancer drug therapy. To accelerate the discovery of inhibitors of UNG we have developed a uracil-directed ligand tethering strategy. In this efficient approach, a uracilaldehyde ligand is tethered via alkyloxyamine linker chemistry to a diverse array of aldehyde binding elements. Thus, the mechanism of extrahelical recognition of the uracil ligand is exploited to target the UNG active site, and alkyloxyamine linker tethering is used to randomly explore peripheral binding pockets. Since no compound purification is required, this approach rapidly identified the first small molecule inhibitors of human UNG with micromolar to submicromolar binding affinities. In a surprising result, these uracil-based ligands are found not only to bind to the active site, but also to a second noncompetitive site. The weaker noncompetitive site suggests the existence of a transient binding site for uracil during the multistep extrahelical recognition mechanism. This very general inhibitor design strategy can be easily adapted to target other enzymes that recognize nucleobases, including other DNA repair enzymes that recognize other types of extrahelical DNA bases.

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Section: Inhibition By the Untethered Partsmentioning

confidence: 99%

Uracil-Directed Ligand Tethering: An Efficient Strategy for Uracil DNA Glycosylase (UNG) Inhibitor Development

et al. 2005

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“…[1,4,7] O,N,N-Triorganohydroxylamines are versatile intermediates in organic synthesis and can be used as initiators or regulators in nitroxide-mediated radical polymerizations. Moreover, O,N,N-trisubstituted hydroxylamines display antibacterial, [708] anticonvulsant, [709] renin-inhibiting, [710] MAO-inhibiting, [640] and insecticidal [711,712] activity and represent attractive structural motifs for drugs and agrochemicals. .…”

Section: Onn-trialkylhydroxylaminesmentioning

confidence: 99%

Product Class 5: Hydroxylamines

Enders¹,

Schaumann²

2009

Category 5, Compounds With One Saturated Carbon Heteroatom Bond

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“…After the removal of both phthaloyl groups from these derivatives, the α-aminooxy-ω-aminoalkanes 56 were obtained (Scheme 49). 79 A library of oxapolyamine derivatives 59 was synthesised using the combinatorial chemistry approach 80 as depicted in Scheme 50. Protected diamine alcohol 58 was condensed with PhthN-OH under the Mitsunobu conditions to give the fully protected oxapolyamine.…”

Section: Synthesis Of Primary Aminooxypolyaminesmentioning

confidence: 99%

Synthesis of Polyamines, Their Derivatives, Analogues and Conjugates

2000

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The role of polyamines in biological systems is now well recognised. In this review an introduction to polyamines and their biological significance is first outlined. The main focus of this review is on the chemical strategies used in the synthesis of polyamines, their derivatives, analogues and conjugates. Recent developments in solid phase synthesis of more complex polyamine molecules is also covered.

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Solution-Phase Synthesis of Novel Linear Oxyamine Combinatorial Libraries with Antibacterial Activity

Cited by 16 publications

References 30 publications

Uracil-Directed Ligand Tethering: An Efficient Strategy for Uracil DNA Glycosylase (UNG) Inhibitor Development

Uracil-Directed Ligand Tethering: An Efficient Strategy for Uracil DNA Glycosylase (UNG) Inhibitor Development

Product Class 5: Hydroxylamines

Synthesis of Polyamines, Their Derivatives, Analogues and Conjugates

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