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Investigations into the biosynthetic pathways of three families of actin-targeting macrolides lead to insights into their convergent or combinatorial evolution, along with the identification of the first free-living bacterial source of macroalga-derived luminaolides. Actin-targeting macrolides comprise a large, structurally diverse group of cytotoxins isolated from remarkably dissimilar micro- and macroorganisms. In spite of their disparate origins and structures, many of these compounds bind actin at the same site and exhibit structural relationships reminiscent of modular, combinatorial drug libraries. Here we investigate biosynthesis and evolution of three compound groups: misakinolides, scytophycin-type compounds and luminaolides. For misakinolides from the sponge Theonella swinhoei WA, our data suggest production by an uncultivated 'Entotheonella' symbiont, further supporting the relevance of these bacteria as sources of bioactive polyketides and peptides in sponges. Insights into misakinolide biosynthesis permitted targeted genome mining for other members, providing a cyanobacterial luminaolide producer as the first cultivated source for this dimeric compound family. The data indicate that this polyketide family is bacteria-derived and that the unusual macrolide diversity is the result of combinatorial pathway modularity for some compounds and of convergent evolution for others.

Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo , by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells. Cancer stem cells are typically refractory to conventional treatments. Now, an unprecedented mechanism has been discovered by which salinomycin and derivatives can sequester iron in lysosomes leading to cytoplasmic iron depletion and the subsequent production of reactive oxygen species that are lethal to the cell. This discovery of the importance of iron in cancer stem cell maintenance provides an opportunity for developing new therapeutics.

Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function ofCFTR. Here, we report two cryo–electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)–approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.

A straightforward approach for the construction of the new class of conjugated pyrans based on enamination of 2-methyl-4-pyrones with DMF-DMA was developed. 2-(2-(Dimethylamino)vinyl)-4-pyrones are highly reactive substrates that undergo 1,6-conjugate addition/elimination or 1,3-dipolar cycloaddition/elimination followed by substitution of the dimethylamino group without ring opening. This strategy includes selective transformations leading to conjugated and isoxazolyl-substituted 4-pyrone structures. The photophysical properties of the prepared 4-pyrones were determined in view of further design of novel merocyanine fluorophores. A solvatochromism was found for enamino-substituted 4-pyrones accompanied by a strong increase in fluorescence intensity in alcohols. The prepared conjugated structures demonstrated valuable photophysical properties, such as a large Stokes shift (up to 204 nm) and a good quantum yield (up to 28%).

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammatory, and anti-proliferative properties and, therefore, exhibit anti-cancer activity. This review summarizes the most recent findings regarding the pharmacological properties, molecular targets, and action mechanisms of secoiridoids, focusing attention on their preventive and anti-cancer activities. It provides a critical analysis of preclinical, in vitro and in vivo, studies of these natural bioactive compounds used as agents against various human cancers. The prospects for their possible use in human cancer prevention and treatment is also discussed.

A mild, efficient, and environmentally benign protocol for the synthesis of tetrahydrobenzo[b]pyran derivatives in the presence of readily accessible, biodegradable, and choline hydroxide based ionic liquid as catalyst has been established. The key features of the reported methodology include good to excellent yields of desired products, simple work-up procedure and good recyclability of catalysts, which may be a practical alternative to the existing conventional processes for the preparation of 4-H pyrans to cater to the requirements of academia as well as industry.

The enzyme LepI is found to be capable of catalysing several natural-product pericyclic transformations, including a hetero-Diels–Alder reaction and a retro-Claisen rearrangement. A (cyclo)addition to nature's toolbox Although common in synthesis, naturally occurring pericyclic reactions, in which two fragments combine to form a cyclic molecule, are rare. Several examples of cyclohexene-forming enzymes called Diels–Alderases have been discovered. However, biosynthetic inverse electron demand Diels–Alder reactions are still unknown. These reactions often involve heteroatoms (non-carbon atoms) in the cycloaddition step, so are important in the synthesis of both heterocyclic and natural products. Here, the authors report the versatile S -adenosyl-L-methionine (SAM)-dependent enzyme, LepI, which is capable of catalysing several pericyclic transformations, including a hetero-Diels–Alder reaction. The biosynthesis of the cytotoxic leporin B proceeds via a bifurcated reaction pathway regulated by LepI, a direct hetero-Diels–Alder reaction and an indirect Diels–Alder/retro-Claisen rearrangement sequence, converging to give the heterocyclic pyran product. Pericyclic reactions—which proceed in a concerted fashion through a cyclic transition state—are among the most powerful synthetic transformations used to make multiple regioselective and stereoselective carbon–carbon bonds 1 . They have been widely applied to the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centres 2 , 3 , 4 , 5 , 6 . Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples (the intramolecular Diels–Alder reaction 7 , and the Cope 8 and the Claisen rearrangements 9 ) have been characterized. Here we report a versatile S -adenosyl- l -methionine (SAM)-dependent enzyme, LepI, that can catalyse stereoselective dehydration followed by three pericyclic transformations: intramolecular Diels–Alder and hetero-Diels–Alder reactions via a single ambimodal transition state, and a retro-Claisen rearrangement. Together, these transformations lead to the formation of the dihydropyran core of the fungal natural product, leporin 10 . Combined in vitro enzymatic characterization and computational studies provide insight into how LepI regulates these bifurcating biosynthetic reaction pathways by using SAM as the cofactor. These pathways converge to the desired biosynthetic end product via the (SAM-dependent) retro-Claisen rearrangement catalysed by LepI. We expect that more pericyclic biosynthetic enzymatic transformations remain to be discovered in naturally occurring enzyme ‘toolboxes’ 11 . The new role of the versatile cofactor SAM is likely to be found in other examples of enzyme catalysis.

The process of creating a series of 3-amino-1-aryl-8-methoxy-1 H -benzo[ f ]chromene-2-carbonitriles ( 4a-q ) involved reacting 6-methoxynaphthalen-2-ol ( 1 ), the appropriate aromatic aldehydes ( 2a-q ), and malononitrile ( 3 ) in an absolute ethanol/piperidine solution under Ultrasonic irradiation. However, the attempt to create 3-amino-1-aryl-1 H -benzo[ f ]chromene-2,8-dicarbonitrile ( 6a, d, e ) was unsuccessful when 6-cyanonaphthalen-2-ol ( 5 ) was stirred at room temperature, reflux, Microwave irradiation, or Ultrasonic irradiation. In addition, the target molecules were screened against Staphylococcus aureus (MRSA) , Staphylococcus aureus , Bacillus subtilis, Bacillus cereus, Escherichia coli and Klebsiella pneumonia, as well as a panel of three human cancer cells lines such as MCF-7, HCT-116, HepG-2 and two normal cell lines HFL-1 and WI-38. The obtained results confirmed that the pyran derivatives ( 4 m, i, k ) which have a double chlorine at 3,4/2,3/2,5-positions, a single halogen atom 3-Cl/4-Br ( 4c, e ) and a double bromine at 3,5-positions with a single methoxy group at 2-position ( 4n ), of phenyl ring, and, to a lesser extent, other pyran derivatives with monoihalogenated ( 4a, b, d, f ), dihalogenated ( 4 g, h, j, l ) or trisubstituent phenyl ring ( 4o, p, q ). Furthermore, compounds 4b-e, g, i, j, m, and n showed negligible activity against the two normal cell lines, HFL-1 and WI-38. Moreover, compound 4 g exhibited the strongest antimicrobial activity among the other pyran derivatives ( 4a-f, g-q ) when compared to Ciprofloxacin. The MIC was assessed and screened for compound 4 g , revealing bactericidal effects. Lastly, SAR and molecular docking were studied.

The role of plant-derived smoke, which is changed in mineral-nutrient status, in enhancing germination and post-germination was effectively established. The majority of plant species positively respond to plant-derived smoke in the enhancement of seed germination and plant growth. The stimulatory effect of plant-derived smoke on normally growing and stressed plants may help to reduce economic and human resources, which validates its candidature as a biostimulant. Plant-derived smoke potentially facilitates the early harvest and increases crop productivity. Karrikins and cyanohydrin are the active compound in plant-derived smoke. In this review, data from the latest research explaining the effect of plant-derived smoke on morphological, physiological, biochemical, and molecular responses of plants are presented. The pathway for reception and interaction of compounds of plant-derived smoke at the cellular and molecular level of plant is described and discussed.

Efficient catalytic reactions that can generate C–C bonds enantioselectively, and ones that can produce trisubstituted alkenes diastereoselectively, are central to research in organic chemistry. Transformations that accomplish these two tasks simultaneously are in high demand, particularly if the catalysts, substrates and reagents are inexpensive and if the reaction conditions are mild. Here we report a facile multicomponent catalytic process that begins with a chemoselective, site-selective and diastereoselective copper–boron addition to a monosubstituted allene; the resulting boron-substituted organocopper intermediates then participate in a similarly selective allylic substitution. The products, which contain a stereogenic carbon centre, a monosubstituted alkene and an easily functionalizable Z -trisubstituted alkenylboron group, are obtained in up to 89 per cent yield, with more than 98 per cent branch-selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly purification procedures. The utility of the approach is demonstrated through enantioselective synthesis of gram quantities of two natural products, namely rottnestol and herboxidiene (also known as GEX1A). A catalytic process is reported that begins with a highly selective copper–boron addition to a monosubstituted allene, and in which the resulting boron-substituted organocopper intermediate then participates in a chemoselective, site-selective and enantioselective allylic substitution; this approach is used in the enantioselective synthesis of gram quantities of two natural products. A new route to organoboron compounds This paper reports a catalytic process that combines two simple unsaturated organic molecules — a highly selective copper–diboron reagent and a monosubstituted allene — to produce a boron-substituted organocopper intermediate that then participates in a chemoselective, site-selective and enantioselective allylic substitution. The authors use this approach in the enantioselective synthesis of gram quantities of two natural products: the anti-tumour agent herboxidiene and stereoisomerically pure rottnestol, a hemiketal originally isolated from a marine sponge. Further development of this procedure should lead to economical protocols for the synthesis of other difficult-to-access alkenylboron-containing organocopper compounds.