Synthesis and structures of regioisomeric hydnocarpin-type flavonolignans.
TL;DR: This work reports syntheses of both regioisomers of the flavonolignan hydnocarpin and one isomer of a plant isolate previously known as 5'-methoxyhydnOCarpin, which was recently shown to be a potent inhibitor of a Staphylococcus aureus multidrug resistant efflux pump.
Abstract: Flavonolignans represent natural compounds whose biosynthesis presumes a radical coupling of a ring B catecholic flavonoid with a molecule of coniferyl alcohol or an analogue. Many natural flavonolignans can exist as regioisomers, depending on how the coupled coniferyl alcohol moiety orients to the flavonoid. These regioisomers are often difficult to separate and have virtually identical NMR spectra. Structural assignments for some have changed with time or have been given without proof. We here report syntheses of both regioisomers of the flavonolignan hydnocarpin and one isomer of a plant isolate previously known as 5'-methoxyhydnocarpin. This isomer, here renamed 5'-methoxyhydnocarpin-D, was recently shown to be a potent inhibitor of a Staphylococcus aureus multidrug resistant efflux pump.
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TL;DR: The activities described here show that there are many potential new classes of anti-staphylococcal agents which should undergo further cytotoxicity, microbial specificity and preclinical in vivo studies to assess their potential.
495 citations
TL;DR: The activities of plant-derived antibacterials show that there are many potential new classes of antibacterial agents which should undergo further cytotoxicity, microbial specificity and preclinical studies.
Abstract: The spread of multidrug-resistant (MDR) strains of bacteria necessitates the discovery of new classes of antibacterials and compounds that inhibit these resistance mechanisms. At present, there are no single chemical entity plant-derived antibacterials used clinically, and this chemically diverse group deserves consideration as a source for two major reasons. First, plants have exceptional ability to produce cytotoxic agents and second there is an ecological rationale that antimicrobial natural products should be present or synthesised de novo in plants following microbial attack to protect the producer from pathogenic microbes in its environment. We have been characterising plant-derived products that are either antibacterial in their own right, or modulators of resistance in bacterial strains possessing multidrug efflux mechanisms. These efflux transporters are responsible for resistance to certain antibiotics and antiseptics and occur in strains of methicillin-resistant Staphylococcus aureus (MRSA), a major clinical problem at present. We are also investigating plant sources for compounds with activity against mycobacteria with a view to discovering drug leads with potential activity toward tuberculosis (TB) producing species. This paper will briefly review the literature on plant derived bacterial resistance modifying agents and antibacterials. Examples in this area from our own work will be given. The activities of plant-derived antibacterials show that there are many potential new classes of antibacterial agents which should undergo further cytotoxicity, microbial specificity and preclinical studies.
232 citations
Cites background from "Synthesis and structures of regiois..."
...These researchers studied the synergistic interaction between berberine (5), a plant antibacterial alkaloid from Berberis fremontii and another natural product, 5¢-methoxyhydnocarpin (6) also present in this species (Stermitz et al., 2000; Guz and Stermitz, 2000 )....
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...These researchers studied the synergistic interaction between berberine (5), a plant antibacterial alkaloid from Berberis fremontii and another natural product, 5¢-methoxyhydnocarpin (6) also present in this species (Stermitz et al., 2000; Guz and Stermitz, 2000)....
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Journal Article•
TL;DR: It is suggested that the further evolution of MDR pumps was determined largely by the barrier function of the membrane they reside in, and transenvelope MDRs of the RND and EmrAB-type extrude their substrates across this barrier.
Abstract: The function of microbial MDRs remains a hotly debated subject. Given the very broad substrate specificities of some MDRs, like the RND pumps that can extrude all classes of amphipathic compounds (cationic, neutral, and anionic), it seems difficult to develop a rationale for pinpointing possible natural substrates of these translocases. At the same time, several clues can be used to guide our search for natural MDR substrates. One is the fact that amphipathic cations appear to be the preferred substrates of MDRs. These substances are extruded by MDRs of all 5 known families and are the almost exclusive substrates of SMR and MF family MDRs. The universal nature of amphipathic cations as MDR substrates suggests that these were the substances that fueled the evolution of MDR pumps. Two factors apparently favored this particular class of molecules for the role of original MDR substrates--need and opportunity. Unlike other substances, amphipathic cations accumulate in the cell driven by the membrane potential, which makes cations potentially the most dangerous toxins. At the same time, amphipathic cations are highly hydrated and do not permeate the membrane as readily as neutral compounds, making it feasible to design a defense based on an efflux pump. The paucity of known cationic (non-basic) antimicrobials might be a result of using MDR-expressing microbial cells for antibiotic discovery. Plant amphipathic cations, the berberine alkaloids, are good MDR substrates. The Berberis plants produce 5'-methoxyhydnocarpin-D, an MDR inhibitor that potentiates the action of berberine. It is suggested that the further evolution of MDR pumps was determined largely by the barrier function of the membrane they reside in. Thus Gram negative bacteria have an outer membrane barrier that slows the penetration of virtually all amphipathic molecules, and transenvelope MDRs of the RND and EmrAB-type extrude their substrates across this barrier. A low permeability of the cytoplasmic membrane of yeast similarly allows for the operation of broad-specificity ABC and MF MDRs. The presence of MDR sensors that regulate the expression of some MDR pumps strongly suggests that defense against external toxins is the function of these MDRs. The BmrR transcriptional activator of the MerR family induces expression of the Bmr pump in B. subtilis and is a sensor specifically designed to recognize amphipathic cations. Similarly, the OacR repressor binds chemically unrelated cations, which leads to the expression of the QacA pump in S. aureus. In E. coli, the EmrR sensor of the MarR repressor family binds unrelated neutral molecules, allowing for expression of the transenvelope EmrAB pump.
138 citations
Cites background from "Synthesis and structures of regiois..."
...An extract of the plant has at least two different MDR inhibitors that act synergistically with berberine in inhibiting the growth of S. aureus (Stermitz et al., 2000a; Guz and Stermitz, 2000; Stermitz et al., 2000b; Guz et al., 2001)....
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...An extract of the plant has at least two different MDR inhibitors that act synergistically with berberine in inhibiting the growth of S. aureus (Stermitz et al., 2000a; Guz and Stermitz, 2000; Stermitz et al., 2000b; Guz et al., 2001)....
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TL;DR: Six flavonoids including two new flavones and a mixture of two pairs of diastereoisomeric flavonolignans with a 2:1 ratio isolated from the whole plant of Mallotus metcalfianus Croizat have moderate antimicrobial properties and interesting antiradical (DPPH) activity.
87 citations
Cites background from "Synthesis and structures of regiois..."
...In accordance with the literature (Guz and Stermitz, 2000), (1)H NMR doublets for H-12 in the derivative of hydnocarpin and in the derivative of hydnocarpin-D appeared at d 4....
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...In accordance with the literature (Guz and Stermitz, 2000), 1H NMR doublets for H-12 in the derivative of hydnocarpin and in the derivative of hydnocarpin-D appeared at d 4.97 and 5.04, respectively in DMSO-d6....
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...…and confirm the presence of the mixture of the two isomers: for the hydnocarpin derivative, C-12 was at dC 76.4 and C-13 at dC 78.0 while for the hydnocarpin-D derivative, C-12 was at dC 75.9 and C-13 at dC 78.6 in DMSO-d6 (Afifi et al., 1993; Guz and Stermitz, 2000; Stermitz et al., 2000)....
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TL;DR: This study demonstrates how regio- and diastereo-isomers with near-identical NMR spectra can be distinguished and unambiguously assigned using quantum mechanical driven (1)H iterative Full Spin Analysis (HiFSA).
Abstract: This study demonstrates how regio- and diastereo-isomers with near-identical NMR spectra can be distinguished and unambiguously assigned using quantum mechanical driven 1H iterative Full Spin Analysis (HiFSA). The method is illustrated with four natural products, the flavonolignans silybin A, silybin B, isosilybin A, and isosilybin B, which exhibit extremely similar coupling patterns and chemical shift differences well below the commonly reported level of accuracy of 0.01 ppm. The HiFSA approach generated highly reproducible 1H NMR fingerprints that enable distinction of all four isomers at 1H frequencies from 300 to 900 MHz. Furthermore, it is demonstrated that the underlying numeric 1H NMR profiles, combined with iterative computational analysis, allow parallel quantification of all four isomers, even in difficult to characterize reference materials and mixtures. The results shed new light on the historical challenges to the qualitative and quantitative analysis of these therapeutically relevant flavono...
82 citations
References
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TL;DR: The level of accumulation of berberine in the cells was increased strongly in the presence of 5'-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberines antimicrobial.
Abstract: Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5′-methoxyhydnocarpin (5′-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5′-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5′-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5′-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5′-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.
705 citations
TL;DR: The Structure of Silybins: I. Degradative Experiment I. degradative experiments lead to the formulation 1a as the probable structure for silybin, a natural product from the fruits of silybum marianum (Asteraceae).
Abstract: Abbauversuche fuhren zur Aufstellung der Wahrscheinlichen Strukturformel 1a fur Silybin, eine Inhaltsstoff aus den Fruchten von Silybum marianum (Familie Asteraceae). 1a ist (2R, 3R) −3,5,7-Trihydroxy-2-[(2R*, 3R*)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-1,4-benzodioxan-6-yl]-4-chromanon.
The Structure of Silybins: I. Degradative Experiment
Degradative experiments lead to the formulation 1a as the probable structure for silybin, a natural product from the fruits of Silybum marianum (Asteraceae). 1a has the systematic name (2R, 3R)-3,5,7-trihydroxy-2-[(2R*, 3R*)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-1,4-benzodioxan-6yl]-4-chromanone.
61 citations
TL;DR: A one-step biomimetic synthesis in high yield of the natural flavanolignans silybin and isosilybin from 2R,3R-dihydroquercetin and coniferyl alcohol is reported.
Abstract: Oxidative coupling of substituted catechols with isoeugenol or coniferyl alcohol in the presence of silver oxide affords 2,3-trans-1,4-benzodioxans in good yield. The reaction is highly regioselective when the catechol bears an alkyl substituent, much less so in the case of an electrophilic one. A free-radical coupling mechanism is proposed. A one-step biomimetic synthesis in high yield of the natural flavanolignans silybin and isosilybin from 2R,3R-dihydroquercetin and coniferyl alcohol is reported.
53 citations
13 citations