30 research outputs found
Countercurrent Separation of Natural Products: An Update
This work assesses the current instrumentation,
method development,
and applications in countercurrent chromatography (CCC) and centrifugal
partition chromatography (CPC), collectively referred to as countercurrent
separation (CCS). The article provides a critical review of the CCS
literature from 2007 since our last review (<i>J. Nat. Prod.</i> <b>2008</b>, <i>71</i>, 1489ā1508), with
a special emphasis on the applications of CCS in natural products
research. The current state of CCS is reviewed in regard to three
continuing topics (instrumentation, solvent system development, theory)
and three new topics (optimization of parameters, workflow, bioactivity
applications). The goals of this review are to deliver the necessary
background with references for an up-to-date perspective of CCS, to
point out its potential for the natural product scientist, and thereby
to induce new applications in natural product chemistry, metabolome,
and drug discovery research involving organisms from terrestrial and
marine sources
Analysis and Purification of Bioactive Natural Products: The AnaPurNa Study
Based on a meta-analysis of data mined from almost 2000
publications
on bioactive natural products (NPs) from >80ā000 pages of
13
different journals published in 1998ā1999, 2004ā2005,
and 2009ā2010, the aim of this systematic review is to provide
both a survey of the status quo and a perspective for analytical methodology
used for isolation and purity assessment of bioactive NPs. The study
provides numerical measures of the common means of sourcing NPs, the
chromatographic methodology employed for NP purification, and the
role of spectroscopy and purity assessment in NP characterization.
A link is proposed between the observed use of various analytical
methodologies, the challenges posed by the complexity of metabolomes,
and the inescapable residual complexity of purified NPs and their
biological assessment. The data provide inspiration for the development
of innovative methods for NP analysis as a means of advancing the
role of naturally occurring compounds as a viable source of biologically
active agents with relevance for human health and global benefit
Natural Deep Eutectic Solvents: Properties, Applications, and Perspectives
As functional liquid media, <u>n</u>atural <u>d</u>eep <u>e</u>utectic <u>s</u>olvent (NADES) species can dissolve
natural or synthetic chemicals
of low water solubility. Moreover, the special properties of NADES,
such as biodegradability and biocompatibility, suggest that they are
alternative candidates for concepts and applications involving some
organic solvents and ionic liquids. Owing to the growing comprehension
of the eutectic mechanisms and the advancing interest in the natural
eutectic phenomenon, many NADES applications have been developed in
the past several years. However, unlike organic solvents, the basic
structural unit of NADES media primarily depends on the intermolecular
interactions among their components. This makes NADES matrices readily
influenced by various factors, such as water content, temperature,
and component ratio and, thus, extends the metabolomic challenge of
natural products (NPs). To enhance the understanding of the importance
of NADES in biological systems, this review focuses on NADES properties
and applications in NP research. The present thorough chronological
and statistical analysis of existing report adds to the recognition
of the distinctiveness of (NA)ĀDES, involves a discussion of NADES-related
observations in NP research, and reportes applications of these eutectic
mixtures. The work identifies potential areas for future studies of
(NA)ĀDES by evaluating relevant applications, including their use as
extraction and chromatographic media as well as their biomedical relevance.
The chemical diversity of natural metabolites that generate or participate
in NADES formation highlights the growing insight that biosynthetically
primordial metabolites (PRIMs) are as essential to the biological
function and bioactivity of unrefined natural products as the biosynthetically
more highly evolutionary metabolites (HEVOs) that can be isolated
from crude mixtures
Digital NMR Profiles as Building Blocks: Assembling <sup>1</sup>H Fingerprints of Steviol Glycosides
This report describes a fragment-based
approach to the examination
of congeneric organic compounds by NMR spectroscopy. The method combines
the classic interpretation of 1D- and 2D-NMR data sets with contemporary
computer-assisted NMR analysis. Characteristic NMR profiles of key
structural motifs were generated by <sup>1</sup>H iterative full spin
analysis and then joined together as building blocks to recreate the <sup>1</sup>H NMR spectra of increasingly complex molecules. To illustrate
the methodology described, a comprehensive analysis of steviol (<b>1</b>), seven steviol glycosides (<b>2</b>ā<b>8</b>) and two structurally related isosteviol compounds (<b>9</b>, <b>10</b>) was carried out. The study also assessed
the potential impact of this method on relevant aspects of natural
product research including structural verification, chemical dereplication,
and mixture analysis
Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?
High-throughput biology has contributed
a wealth of data on chemicals,
including natural products (NPs). Recently, attention was drawn to
certain, predominantly synthetic, compounds that are responsible for
disproportionate percentages of hits but are false actives. Spurious
bioassay interference led to their designation as <u>p</u>an-<u>a</u>ssay <u>in</u>terference
compound<u>s</u> (PAINS). NPs lack comparable scrutiny,
which this study aims to rectify. Systematic mining of 80+ years of
the phytochemistry and biology literature, using the NAPRALERT database,
revealed that only 39 compounds represent the NPs most reported by
occurrence, activity, and distinct activity. Over 50% are not explained
by phenomena known for synthetic libraries, and all had manifold ascribed
bioactivities, designating them as <u>i</u>nvalid <u>m</u>etabolic <u>p</u>anaceas (IMPs). Cumulative
distributions of ā¼200,000 NPs uncovered that NP research follows
power-law characteristics typical for behavioral phenomena. Projection
into occurrenceābioactivityāeffort space produces the
hyperbolic black hole of NPs, where IMPs populate the high-effort
base
Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?
High-throughput biology has contributed
a wealth of data on chemicals,
including natural products (NPs). Recently, attention was drawn to
certain, predominantly synthetic, compounds that are responsible for
disproportionate percentages of hits but are false actives. Spurious
bioassay interference led to their designation as <u>p</u>an-<u>a</u>ssay <u>in</u>terference
compound<u>s</u> (PAINS). NPs lack comparable scrutiny,
which this study aims to rectify. Systematic mining of 80+ years of
the phytochemistry and biology literature, using the NAPRALERT database,
revealed that only 39 compounds represent the NPs most reported by
occurrence, activity, and distinct activity. Over 50% are not explained
by phenomena known for synthetic libraries, and all had manifold ascribed
bioactivities, designating them as <u>i</u>nvalid <u>m</u>etabolic <u>p</u>anaceas (IMPs). Cumulative
distributions of ā¼200,000 NPs uncovered that NP research follows
power-law characteristics typical for behavioral phenomena. Projection
into occurrenceābioactivityāeffort space produces the
hyperbolic black hole of NPs, where IMPs populate the high-effort
base
Digital NMR Profiles as Building Blocks: Assembling <sup>1</sup>H Fingerprints of Steviol Glycosides
This report describes a fragment-based
approach to the examination
of congeneric organic compounds by NMR spectroscopy. The method combines
the classic interpretation of 1D- and 2D-NMR data sets with contemporary
computer-assisted NMR analysis. Characteristic NMR profiles of key
structural motifs were generated by <sup>1</sup>H iterative full spin
analysis and then joined together as building blocks to recreate the <sup>1</sup>H NMR spectra of increasingly complex molecules. To illustrate
the methodology described, a comprehensive analysis of steviol (<b>1</b>), seven steviol glycosides (<b>2</b>ā<b>8</b>) and two structurally related isosteviol compounds (<b>9</b>, <b>10</b>) was carried out. The study also assessed
the potential impact of this method on relevant aspects of natural
product research including structural verification, chemical dereplication,
and mixture analysis
2D NMR Barcoding and Differential Analysis of Complex Mixtures for Chemical Identification: The <i>Actaea</i> Triterpenes
The interpretation of NMR spectroscopic
information for structure
elucidation involves decoding of complex resonance patterns that contain
valuable molecular information (Ī“ and <i>J</i>), which
is not readily accessible otherwise. We introduce a new concept of
2D-NMR barcoding that uses clusters of fingerprint signals and their
spatial relationships in the Ī“āĪ“ coordinate space
to facilitate the chemical identification of complex mixtures. Similar
to widely used general barcoding technology, the structural information
of individual compounds is encoded as a specifics pattern of their
C,H correlation signals. Software-based recognition of these patterns
enables the structural identification of the compounds and their discrimination
in mixtures. Using the triterpenes from various <i>Actaea</i> (syn. <i>Cimicifuga</i>) species as a test case, heteronuclear
multiple-bond correlation (HMBC) barcodes were generated on the basis
of their structural subtypes from a statistical investigation of their
Ī“<sub>H</sub> and Ī“<sub>C</sub> data in the literature.
These reference barcodes allowed in silico identification of known
triterpenes in enriched fractions obtained from an extract of <i>A. racemosa</i> (black cohosh). After dereplication, a differential
analysis of heteronuclear single-quantum correlation (HSQC) spectra
even allowed for the discovery of a new triterpene. The 2D barcoding
concept has potential application in a natural product discovery project,
allowing for the rapid dereplication of known compounds and as a tool
in the search for structural novelty within compound classes with
established barcodes
Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism
Many
women consider botanical dietary supplements (BDSs) as safe
alternatives to hormone therapy for menopausal symptoms. However,
the effect of BDSs on breast cancer risk is largely unknown. In the
estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens
to 4-hydroxylated catechols, which are oxidized to genotoxic quinones
that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed
2-hydroxylation represents a detoxification pathway. The current study
evaluated the effects of red clover, a popular BDS used for womenās
health, and its isoflavones, biochanin A (BA), formononetin (FN),
genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy
estrogen metabolites (2-MeOE<sub>1</sub>, 4-MeOE<sub>1</sub>) were
measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed
by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A)
and ER-positive breast cancer cells (MCF-7) were derived from normal
breast epithelial tissue and ER+ breast cancer tissue. Red clover
extract (RCE, 10 Ī¼g/mL) and isoflavones had no effect on estrogen
metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments
downregulated CYP1A1 expression and enhanced genotoxic metabolism
(4-MeOE<sub>1</sub>/CYP1B1 > 2-MeOE<sub>1</sub>/CYP1A1). Experiments
with the isoflavones showed that the AhR agonists (BA, FN) preferentially
induced CYP1B1 expression as well as 4-MeOE<sub>1</sub>. In contrast,
the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through
an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated
isoflavone-induced XRE-luciferase reporter activity and reversed GN
and DZ induced downregulation of CYP1A1 expression. Overall, these
studies show that red clover and its isoflavones have differential
effects on estrogen metabolism in ānormalā vs breast
cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic
metabolism, and the ER agonists downregulate the detoxification pathway.
These data may suggest that especially breast cancer patients should
avoid red clover and isoflavone based BDSs when making choices for
menopausal symptom relief
2D NMR Barcoding and Differential Analysis of Complex Mixtures for Chemical Identification: The <i>Actaea</i> Triterpenes
The interpretation of NMR spectroscopic
information for structure
elucidation involves decoding of complex resonance patterns that contain
valuable molecular information (Ī“ and <i>J</i>), which
is not readily accessible otherwise. We introduce a new concept of
2D-NMR barcoding that uses clusters of fingerprint signals and their
spatial relationships in the Ī“āĪ“ coordinate space
to facilitate the chemical identification of complex mixtures. Similar
to widely used general barcoding technology, the structural information
of individual compounds is encoded as a specifics pattern of their
C,H correlation signals. Software-based recognition of these patterns
enables the structural identification of the compounds and their discrimination
in mixtures. Using the triterpenes from various <i>Actaea</i> (syn. <i>Cimicifuga</i>) species as a test case, heteronuclear
multiple-bond correlation (HMBC) barcodes were generated on the basis
of their structural subtypes from a statistical investigation of their
Ī“<sub>H</sub> and Ī“<sub>C</sub> data in the literature.
These reference barcodes allowed in silico identification of known
triterpenes in enriched fractions obtained from an extract of <i>A. racemosa</i> (black cohosh). After dereplication, a differential
analysis of heteronuclear single-quantum correlation (HSQC) spectra
even allowed for the discovery of a new triterpene. The 2D barcoding
concept has potential application in a natural product discovery project,
allowing for the rapid dereplication of known compounds and as a tool
in the search for structural novelty within compound classes with
established barcodes