HPLC-Based Activity Profiling for GABA A Receptor Modulators: A New Dihydroisocoumarin from Haloxylon scoparium

Yan

Chemistry Central Journal

et al. 2018

BackgroundRadix Glycyrrhizae is the rhizome of Glycyrrhiza inflata Bat., Glycyrrhiza uralensis Fisch. or Glycyrrhiza glabra L. The present paper describes the isolation and the structural elucidation of three new dihydroisocoumarins obtained from the 70% EtOH extract of Radix Glycyrrhizae. And the cytotoxic activities of these new compounds were also evaluated using four cell lines, subsequently.ResultsA pair of new dihydroisocoumarin epimers ((3R,4S)-4,8-dihydroxy-3-methyl-1-oxoisochroman-5-yl)methyl acetate (1) and ((3R,4R)-4,8-dihydroxy-3-methyl-1-oxoisochroman-5-yl)methyl acetate (2) along with a new dihydroisocoumarin (3R,4R)-4,8-dihydroxy-3,5-dimethylisochroman-1-one (3) were isolated from Radix Glycyrrhizae. Their structures were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR analyses, HR–ESI–MSand ECD calculation comparing with those of experimental CD spectra. Cytotoxic activities of the three compounds were evaluated using the HepG2, A549, LoVo and Hela cell lines, respectively. IC50 values indicated compounds 1–3 exhibited moderate or less cytotoxic activity in vitro.ConclusionsDihydroisocoumarin is not the common components in Radix Glycyrrhizae, a series of dihydroisocoumarin were obtained in this plant could be a supplement to the chemical study of this plant.Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0427-0) contains supplementary material, which is available to authorized users.

Section: Discussionmentioning

confidence: 99%

Dihydroisocoumarins from Radix Glycyrrhizae

Yan

Chemistry Central Journal

et al. 2018

“…Screens were based on various bioassay formats, such as whole organism assays (tropical parasitic diseases), cell-based antiviral (HIV), and functional assays (e.g., GABA A receptor modulation, hERG channel inhibition), and mechanistic screens (e.g., DYRK1A kinase) (l " Table 1). For example, we were able to discover numerous new scaffolds for GABA A receptor modulators, by combining HPLC-profiling with a semiautomated two-microelectrode voltage clamp assay with Xenopus oocytes expressing GABA A channels [10,11,[18][19][20][21][22][23][24][25][26][27][28]. Among these compounds, piperine demonstrated promising ac-tivity in vivo and was used as a starting point for the synthesis of the lead SCT-66 (l " Fig.…”

Section: Selected Applicationsmentioning

confidence: 99%

Combined Use of Extract Libraries and HPLC-Based Activity Profiling for Lead Discovery: Potential, Challenges, and Practical Considerations

Potterat

Hamburger

2014

Planta Med

Self Cite

Introduction !The unique contribution of natural products to drug discovery is undisputed. Approximately 35 % of the new chemical entities approved as drugs over the past 30 years are directly derived from natural products [1]. However, despite this impressive track record, we have witnessed over the past two decades in the pharmaceutical industry a steady decline of interest for natural products. Various factors have contributed to this apparently paradoxical situation. Emerging technologies may have appeared at one time more promising and "easy" than natural products, which are often perceived as "old-fashioned" at the top management level. However, there have also been more objective reasons for this decline. With the advent of high throughput screening (HTS) in the 1990s, natural product research struggled to find its place in the new drug discovery environment. The classical approach relying on several iterative steps of bioactivity-guided fractionation could not keep pace with the fast turnaround and the tight deadline of HTS-based screening programs [2]. At the same time, the technological advances in HTS, in particular with respect to automation and data management, and significant developments in chromatography and spectroscopy have opened entirely new possibilities for the investigation of natural product extracts. In a time where most major pharmaceutical companies have discontinued their natural product screening activities, these new opportunities have been recognized by biotech companies, and by an increasing number of academic research groups. Switching to a database format for extract handling enables efficient library management and smooth data transfer to screening facilities. The use of new strategies combining, in a more or less seamless manner, HPLC microfractionation with spectroscopic and bioactivity data enables prioritization of hits and identification of bioactive constituents at an early stage [2]. In this context, we set up a tailored technology platform for library-based lead discovery. Its core features are an extract library in 96-well format combined with a customized database, automated liquid handling, HPLC-based tracking of bioactivity, on-line (DAD and ESI-and APCI-MS, including HR-MS) and off-line (microprobe NMR) spectroscopy for structure elucidation. We describe here the different components of this platform and discuss the potential of our workflow Abstract ! A 96-well format plant extract library and a tailored technology platform have been set up for the discovery of new natural product lead compounds. The considerable advantages of the library approach are discussed. Key considerations such as sample generation, logistics, and data management are addressed. The potential of a HPLC-based profiling approach combining offline bioassays with in-line and off-line spectroscopy (including HR-ESIMS and microprobe NMR) for tracking bioactivity is demonstrated with a selection of examples encompassing different types of bioassay formats. The information generated by this approac...

“…This approach has been successfully established and used in our labs with various cellbased and biochemical assays [12][13][14]. We recently developed and validated a profiling approach for the discovery of new GABA A receptor ligands [15], which we subsequently employed to identify scaffolds new for the target [16,17]. We here describe HPLC-based activity profiling of the active S. flavescens extract, identification of the active constituents, and preliminary SAR (structure activity relationship) considerations based on a focused compound library generated from the extract.…”

Section: Introductionmentioning

confidence: 99%

HPLC-based activity profiling for GABAA receptor modulators from the traditional Chinese herbal drug Kushen (Sophora flavescens root)

Yang¹,

Baburin²,

Plitzko³

et al. 2011

Mol Divers

Self Cite

An EtOAc extract from the roots of Sophora flavescens (Kushen) potentiated γ -aminobutyric acid (GABA)-induced chloride influx in Xenopus oocytes transiently expressing GABA A receptors with subunit composition, α 1 β 2 γ 2S . HPLC-based activity profiling of the extract led to the identification of 8-lavandulyl flavonoids, kushenol I, sophoraflavanone G, (-)-kurarinone, and kuraridine as GABA A receptor modulators. In addition, a series of inactive structurally related flavonoids were characterized. Among these, kushenol Y (4) was identified as a new natural product. The 8-lavandulyl flavonoids are first representatives of a novel scaffold for the target.