Disciformycins A and B: 12‐Membered Macrolide Glycoside Antibiotics from the Myxobacterium Pyxidicoccus fallax Active against Multiresistant Staphylococci

Two macrolide glycosides with a unique scaffold were isolated from cultures of the myxobacterium Pyxidicoccus fallax. Their structures, including absolute configurations, were elucidated by a combination of NMR, MS, degradation, and molecular modeling techniques. Analysis of the proposed biosynthetic gene cluster led to insights into the biosynthesis of the polyketide and confirmed the structure assignment. The more active compound, disciformycin B, potently inhibits methicillin‐ and vancomycin‐resistant Staphylococcus aureus.     

Discovery of New Natural Products by Intact‐Cell Mass Spectrometry and LC‐SPE‐NMR: Malbranpyrroles,Novel Polyketides from Thermophilic Fungus Malbranchea sulfurea

Six photosensitive polyketides, malbranpyrroles A–F, were discovered from the thermophilic fungus Malbranchea sulfurea by using intact‐cell desorption/ionization on silicon mass (ICD‐MS) and LC‐SPE‐NMR. These two strategies facilitate the searching and structural determination of unstable natural products. The ICD‐MS indicated that only brown hyphae of M. sulfurea can produce malbranpyrroles. The biosynthetic pathway of malbranpyrroles was evidenced by ¹³C isotope precursors and amino acid feeding experiments. The cytotoxicity data revealed that the conformation of the conjugated system in malbranpyrroles does not affect cytotoxic potency against cancer cell lines. In addition, the chlorine atom was shown to be the pharmacophore for cytotoxicity.     

Kibdelones: novel anticancer polyketides from a rare Australian actinomycete

The kibdelones are a novel family of bioactive heterocyclic polyketides produced by a rare soil actinomycete, Kibdelosporangium sp. (MST-108465). Complete relative stereostructures were assigned to kibdelones A-C (1-3), kibdelone B rhamnoside (5), 13-oxokibdelone A (7), and 25-methoxy-24-oxokibdelone C (8) on the basis of detailed spectroscopic analysis and chemical interconversion, as well as mechanistic and biosynthetic considerations. Under mild conditions, kibdelones B (2) and C (3) undergo a facile equilibration to kibdelones A-C (1-3), while kibdelone B rhamnoside (5) equilibrates to a mixture of kibdelone A-C rhamnosides (4-6). A plausible mechanism for this equilibration is proposed and involves air oxidation, quinone/hydroquinone redox transformations, and a choreographed sequence of keto/enol tautomerizations that aromatize ring C via a quinone methide intermediate. Kibdelones exhibit potent and selective cytotoxicity against a panel of human tumor cell lines and display significant antibacterial and nematocidal activity.     

Structure and Biosynthetic Assembly of Gulmirecins,Macrolide Antibiotics from the Predatory Bacterium Pyxidicoccus fallax

The gulmirecins constitute a new class of glycosylated macrolides that were isolated from the predatory bacterium Pyxidicoccus fallax HKI 727. Their structures were solved by a combination of NMR spectroscopic experiments and chemical derivatization. Analysis of the annotated gulmirecin gene cluster complemented the configurational assignment and provided insights into the stereochemical course of the biosynthetic assembly. The gulmirecins exhibit strong activity against staphylococci, including methicillin‐resistant Staphylococcus aureus, but no cytotoxic effects on human cells.     

Total Synthesis of (−)‐Spirangien A,an Antimitotic Polyketide Isolated from the Myxobacterium Sorangium Cellulosum

A stereocontrolled total synthesis of the cytotoxic spiroacetal‐containing polyketide (?)‐spirangien A is described. This utilizes an aldol‐based strategy to construct a common stereotetrad intermediate that was elaborated into the spiroacetal core, followed by the introduction of the unstable pentaene‐containing side chain, performed with exclusion of light, using sequential Stille cross‐coupling reactions.

     

Forazoline A: Marine‐Derived Polyketide with Antifungal In Vivo Efficacy

Forazoline A, a novel antifungal polyketide with in vivo efficacy against Candida albicans, was discovered using LCMS‐based metabolomics to investigate marine‐invertebrate‐associated bacteria. Forazoline A had a highly unusual and unprecedented skeleton. Acquisition of ¹³C–¹³C gCOSY and ¹³C–¹⁵N HMQC NMR data provided the direct carbon–carbon and carbon–nitrogen connectivity, respectively. This approach represents the first example of determining direct ¹³C–¹⁵N connectivity for a natural product. Using yeast chemical genomics, we propose that forazoline A operated through a new mechanism of action with a phenotypic outcome of disrupting membrane integrity.     

Suffrutines A and B: A Pair of Z/E Isomeric Indolizidine Alkaloids from the Roots of Flueggea suffruticosa

Suffrutines A ( 1 ) and B ( 2 ), a pair of novel photochemical Z/E isomeric indolizidine alkaloids, with a unique and highly conjugated C₂₀ skeleton, were isolated from the roots of Flueggea suffruticosa. The structures were elucidated by extensive analysis of NMR spectra and single‐crystal X‐ray diffraction. The light‐induced isomerization and hypothetical biogenetic pathway to 1 and 2 , as well as their activity for regulating the morphology of Neuro‐2a cells are also discussed.     

Assignment of Relative Configuration of Desoxypropionates by 1H NMR Spectroscopy: Method Development,Proof of Principle by Asymmetric Total Synthesis of Xylarinic Acid A and Applications

The determination of the relative configuration of 1,3‐dimethyl‐substituted alkyl chains is possible by interpretation of ¹H NMR shift differences. Additionally, assignments are feasible in a variety of deuterated solvents, because the corresponding shift differences are not significantly influenced by the solvent. The trends for Δδ values depending on functional groups adjacent to the stereogenic centers are shown. Based on a thorough comparison with literature data, the relative configuration of natural products can be predicted. For this purpose, we derived an empirical rule for the ranges in which Δδ values usually occur. Furthermore, we were able to proof the validity of our method by the successful prediction of the relative configuration for the polyketide natural product xylarinic acid A, which was confirmed by the asymmetric total synthesis of its enantiomer. Based on the proposed simple analysis of published ¹H NMR data and the determination of the relevant chemical‐shift differences, we predicted the relative configurations of several previously unassigned natural products.     

Molecular Recognition of Rosmarinic Acid from Salvia sclareoides Extracts by Acetylcholinesterase: A New Binding Site Detected by NMR Spectroscopy

Acetylcholinesterase (AChE) inhibition is one of the most currently available therapies for the management of Alzheimer’s disease (AD) symptoms. In this context, NMR spectroscopy binding studies were accomplished to explain the inhibition of AChE activity by Salvia sclareoides extracts. HPLC‐MS analyses of the acetone, butanol and water extracts eluted with methanol and acidified water showed that rosmarinic acid is present in all the studied samples and is a major constituent of butanol and water extracts. Moreover, luteolin 4′‐O‐glucoside, luteolin 3′,7‐di‐O‐glucoside and luteolin 7‐O‐(6′′‐O‐acetylglucoside) were identified by MS² and MS³ data acquired during the LC‐MSⁿ runs. Quantification of rosmarinic acid by HPLC with diode‐array detection (DAD) showed that the butanol extract is the richest one in this component (134 μg mg^?1 extract). Saturation transfer difference (STD) NMR spectroscopy binding experiments of S. sclareoides crude extracts in the presence of AChE in buffer solution determined rosmarinic acid as the only explicit binder for AChE. Furthermore, the binding epitope and the AChE‐bound conformation of rosmarinic acid were further elucidated by STD and transferred NOE effect (trNOESY) experiments. As a control, NMR spectroscopy binding experiments were also carried out with pure rosmarinic acid, thus confirming the specific interaction and inhibition of this compound against AChE. The binding site of AChE for rosmarinic acid was also investigated by STD‐based competition binding experiments using Donepezil, a drug currently used to treat AD, as a reference. These competition experiments demonstrated that rosmarinic acid does not compete with Donepezil for the same binding site. A 3D model of the molecular complex has been proposed. Therefore, the combination of the NMR spectroscopy based data with molecular modelling has permitted us to detect a new binding site in AChE, which could be used for future drug development.     

Total Syntheses of Periconiasins A–E

The first and collective total syntheses of periconiasins A–E, a group of naturally occurring cytochalasans, were achieved by a series of rationally designed or bioinspired transformations. Salient features of the syntheses include a tandem aldol condensation/Grob fragmentation to assemble the linear polyketide–amino acid hybrid precursor, a Diels–Alder macrocylization to construct the 9/6/5 tricyclic core of periconiasins A–C, and a transannular carbonyl–ene reaction to forge the polycyclic framework of periconiasins D and E.     

One‐Pot Enzymatic Synthesis of Merochlorin A and B

The polycycles merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities and are produced by the marine bacterium Streptomyces sp. strain CNH‐189. Heterologously produced enzymes and chemical synthesis are employed herein to fully reconstitute the merochlorin biosynthesis in vitro. The interplay of a dedicated type III polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide‐terpene hybrid intermediate which features an unprecedented branched sesquiterpene moiety from isosesquilavandulyl diphosphate. As supported by in vivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorin A and isomeric merochlorin B by a single vanadium‐dependent haloperoxidase, thus completing the remarkably efficient pathway.