			Home About us Contact

Ring Moieties (ring + moiety)

Distribution by Scientific Domains

Chemistry	100%

Selected Abstracts

Design syntheses and mitochondrial complex I inhibitory activity of novel acetogenin mimics

FEBS JOURNAL, Issue 9 2000
Kaoru Kuwabara
Some natural acetogenins are the most potent inhibitors of mitochondrial complex I. These compounds are characterized by two functional units [i.e. hydroxylated tetrahydrofuran (THF) and ,,,-unsaturated ,-lactone ring moieties] separated by a long alkyl spacer. To elucidate which structural factors of acetogenins, including their active conformation, are crucial for the potent inhibitory activity we synthesized a novel bis-acetogenin and its analogues possessing two ,-lactone rings connected to bis-THF rings by flexible alkyl spacers. The inhibitory potency of the bis-acetogenin with bovine heart mitochondrial complex I was identical to that of bullatacin, one of the most potent natural acetogenins. This result indicated that one molecule of the bis-acetogenin does not work as two reactive inhibitors, suggesting that a ,-lactone and the THF ring moieties act in a cooperative manner on the enzyme. In support of this, either of the two ring moieties synthesized individually showed no or very weak inhibitory effects. Moreover, combined use of the two ring moieties at various molar ratios exhibited no synergistic enhancement of the inhibitory potency. These observations indicate that both functional units work efficiently only when they are directly linked by a flexible alkyl spacer. Therefore, some specific conformation of the spacer must be important for optimal positioning of the two units in the enzyme. Furthermore, the ,,,-unsaturated ,-lactone, the 4-OH group in the spacer region, the long alkyl tail attached to the THF unit and the stereochemistry surrounding the hydroxylated bis-THF rings were not crucial for the activity, although these are the most common structural features of natural acetogenins. The present study provided useful guiding principles not only for simplification of complicated acetogenin structure, but also for further wide structural modifications of these molecules. [source]

Mycobacterium tuberculosis Thymidine Monophosphate Kinase Inhibitors: Biological Evaluation and Conformational Analysis of 2,- and 3,-Modified Thymidine Analogues

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 15 2003
Philippe Van Rompaey
Abstract Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has recently been introduced as a potential target for the structure-based design of anti-tuberculosis drugs. Based on the TMPKmt X-ray structure and previous S.A.R. studies, we synthesised the nucleoside analogues 3a,b, 6a,b, 7a,b, and 8a,b, modified in 2,- and 3,-position of the ribofuranose ring moiety. To our surprise, these analogues showed only moderate binding affinity (i.e. Ki between 118 and 1260 ,M). This prompted us to investigate the conformational features of these nucleosides. We concluded that compounds of this series, especially 8a,b, are strongly biased towards the "Northern" furanose ring conformation, whereas X-ray crystallography reveals a preference of TMPKmt for the opposite "Southern" conformers. This paper covers the synthesis, biological evaluation and conformational features (i.e. preferred ring puckering) of the 2,- and 3,-modified dT analogues. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source]

Evidence for an aryl migration during the electron impact induced fragmentation of substituted aryloxymethylquinoxalines

RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 3 2002
I. Starke
The electron impact (EI) mass spectra of 34 differently substituted 2-phenoxymethyl-, 2-naphthyloxymethyl-, 2-pyridinyloxymethyl- and 2-chinolinyloxymethylquinoxalines were recorded. The fragmentation patterns were examined by metastable ion analysis and exact mass measurements, employing finally also selective deuterium labelling. The inclusion of the substituted aryl ring moiety appears to be important for the fragmentation of the aryloxymethylquinoxalines. A molecular ion rearrangement is proposed for the observed loss of OH· and CHO· radicals. The influence of the different substituents on the aryl ring moiety on the rearrangement in the gas phase and on the resulting fragmentation was investigated. Copyright © 2001 John Wiley & Sons, Ltd. [source]