Theoretical Insight into Psittacofulvins and Their Derivatives.

Psittacofulvins are polyenal dyes responsible for coloring parrot feathers and protecting them against photo-oxidation, harmful radicals, and bacterial degradation. To explain the unusual properties of these compounds, the thermodynamic and global chemical activity descriptors characterizing four natural and three synthetic psittacofulvins, as well as their hydroxyl, carboxyl and dialdehyde derivatives, were determined. To this aim, the DFT method at the B3LYP/QZVP theory level and the C-PCM solvation model were used. The calculations enabled the selection of the projected compounds for the greatest bioactivity and potential applicability as multifunctional ingredients in medicines, cosmetics, supplements, and food, in which they may play a triple role as preservative, radical scavenger, and coloring agent. The results obtained provide arguments for the identification of a fifth psittacofulvin within the parrot feather pigment, characterized by ten conjugated double bonds (docosadecaenal).

Integrating Regioselective E→Z Isomerization of Trienones with Cascade Sequences under Photosensitizer-Free Direct Irradiation at 390†nm.

The regioselective E→Z isomerization of a target olefin unit embedded in a conjugated polyene is challenging. Examples are limited to retinal and its derivatives only. The problem is further amplified when such an isomerization is integrated into cascade sequences, among which the regioselectivity and subsequent directionality are the major bottlenecks. Indeed, there are no reports till date for such a transformation. Herein, it is reported that such a controlled isomerization and subsequent cyclization cascade can be enabled by photosensitizer-free direct irradiation of linearly conjugated acyclic polyenes in dichloromethane solvent using a 390 nm LED. The directionality results from deconjugation of the extended π-system in the transient Z-isomer due to stabilizing n→π* interactions between 1,4-dicarbonyls (C=O→C=O) or 1,4-carbonyl/-aryl (C=O→aryl) groups. The involvement of such noncovalent interactions has been supported by X-ray crystallography and control experiments. Thus, conjugated trienones can be stereoselectively converted into oxabicyclo[3.2.1]octadienes in an atom- and step-economic manner, including the first example by regioselective isomerization of a tetrasubstituted alkene. The reaction conditions are very general (>46 examples). The reaction can be conducted under open air atmosphere at ambient temperature. Such a cascade cyclization can also be realized in solid state.

Reversing the Bond Length Alternation Order in Conjugated Polyenes by Substituent Effects.

We have synthesised several push-pull substituted conjugated polyenes and determined their accurate C-C bond lengths and charge-density distributions by utilising quantum crystallographic techniques. In a series of alkene, dienes, and triene bearing two (trifluoromethyl)sulfonyl (triflyl) groups on the terminal carbon atom, unique reversal of the bond-length alternation (BLA) order has been observed. This is a pronounced aberration from the molecular structure predicted by the Lewis-structure-based neutral resonance structure. Such reversal of BLA order has not been observed in push-pull compounds bearing conventional electron-withdrawing groups such as carbonyl and cyano groups instead of triflyl groups. Bonding behaviour of both normal and reversed bond length alternating systems has been revealed by complementary bonding analysis using several bond descriptors based on the experimentally fitted wavefunctions.

Three new long-chain polyenes from the mangrove-derived fungus Penicillium herquei JX4.

One new epimer pair of long-chain polyenes penicilqueis E (1) and F (2), and one new long-chain polyene pinophol G (3), along with one known compound (4), were obtained from EtOAc extract of the mangrove-derived fungus Penicillium herquei JX4. Their structures were elucidated by detailed analysis of comprehensive spectroscopic data. The inhibitory activities of all compounds against the nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro were evaluated.

Geometric Isomerisation of Bifunctional Alkenyl Fluoride Linchpins: Stereodivergence in Amide and Polyene Bioisostere Synthesis.

Amide groups are pervasive across the chemical space continuum, where their structural and pharmacological importance, juxtaposed with the hydrolytic vulnerabilities, continues to fuel bioisostere development. Alkenyl fluorides have a venerable history as effective mimics (Ψ[CF=CH]) owing to the planarity of the motif and intrinsic polarity of the C(sp2 )-F bond. However, emulating the s-cis to the s-trans isomerisation of a peptide bond with fluoro-alkene surrogates remains challenging, and current synthetic solutions only enable access to a single configuration. Through the design of an ambiphilic linchpin based on a fluorinated ß-borylacrylate, it has been possible to leverage energy transfer catalysis to affect this unprecedented isomerisation process: this provides geometrically-programmable building blocks that can be functionalised at either terminus. Irradiation at λmax =402 nm with inexpensive thioxanthone as a photocatalyst enables rapid, effective isomerisation of tri- and tetra-substituted species (up to E/Z 98 : 2 in 1 h), providing a stereodivergent platform for small molecule amide and polyene isostere discovery. Application of the methodology in target synthesis and initial laser spectroscopic studies are disclosed together with crystallographic analyses of representative products.

Cytochrome†P450 Catalyzes Benzene Ring Formation in the Biosynthesis of Trialkyl-Substituted Aromatic Polyketides.

Lorneic acid and related natural products are characterized by a trialkyl-substituted benzene ring. The formation of the aromatic core in the middle of the polyketide chain is unusual. We characterized a cytochrome P450 enzyme that can catalyze the hallmark benzene ring formation from an acyclic polyene substrate through genetic and biochemical analysis. Using this P450 as a beacon for genome mining, we obtained 12 homologous type I polyketide synthase (PKS) gene clusters, among which two gene clusters are activated and able to produce trialkyl-substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the plausible mechanism for P450-catalyzed benzene ring formation. Our work expands our knowledge of the catalytic diversity of cytochrome P450.

The Diversity of Linear Conjugated Polyenes and Colours in Nature: Raman Spectroscopy as a Diagnostic Tool.

This review is centered on the linear conjugated polyenes, which encompasses chromatic biomolecules, such as carotenoids, polyunsaturated aldehydes and polyolefinic fatty acids. The linear extension of the conjugated double bonds in these molecules is the main feature that determines the spectroscopic properties as light-absorbing. These classes of compounds are responsible for the yellow, orange, red and purple colors which are observed in their parent flora and fauna in nature. Raman spectroscopy has been used as analytical tool for the characterization of these molecules, mainly due to the strong light scattering produced by the delocalized pi electrons in the carbon chain. In addition, conjugated polyenes are one of the main target molecular species for astrobiology, and we also present a brief discussion of the use of Raman spectroscopy as one of the main analytical tools for the detection of polyenes extra-terrestrially.

Escherichia coli Nissle 1917 secondary metabolism: aryl polyene biosynthesis and phosphopantetheinyl transferase crosstalk.

Escherichia coli Nissle 1917 (EcN) is a Gram-negative bacterium that is used to treat inflammatory bowel diseases. The probiotic character of EcN is not well-understood, but its ability to produce secondary metabolites plays an important role in its activity. The EcN genome encodes for an aryl polyene (APE) biosynthetic gene cluster (BGC), and APE products have a role in biofilm formation. We show here that this unusual polyketide assembly line synthase produces four APE molecules which are likely cis/trans isomers. Within the APE BGC, two acyl carrier proteins are involved in biosynthesis. Acyl carrier proteins require activation by post-translational modification with a phosphopantetheinyl transferase (PPTase). Through analysis of single, double, and triple mutants of three PPTases, the PPTase-BGC crosstalk relationship in EcN was characterized. Understanding PPTase-BGC crosstalk is important for the engineering of secondary metabolite production hosts and for targeting of PPTases with new antibiotics. KEY POINTS: • Escherichia coli Nissle 1917 biosynthesizes four aryl polyene isoforms. • Phosphopantetheinyl transferase crosstalk is important for biosynthesis.

Cumulene Wires Display Increasing Conductance with Increasing Length.

One-dimensional sp-hybridized carbon wires, including cumulenes and polyynes, can be regarded as finite versions of carbynes. They are likely to be good candidates for molecular-scale conducting wires as they are predicted to have a high-conductance. In this study, we first characterize the single-molecule conductance of a series of cumulenes and polyynes with a backbone ranging in length from 4 to 8 carbon atoms, including [7]cumulene, the longest cumulenic carbon wire studied to date for molecular electronics. We observe different length dependence of conductance when comparing these two forms of carbon wires. Polyynes exhibit conductance decays with increasing molecular length, while cumulenes show a conductance increase with increasing molecular length. Their distinct conducting behaviors are attributed to their different bond length alternation, which is supported by theoretical calculations. This study confirms the long-standing theoretical predictions on sp-hybridized carbon wires and demonstrates that cumulenes can form highly conducting molecular wires.

New Polyenes from the Marine-Derived Fungus Talaromyces cyanescens with Anti-Neuroinflammatory and Cytotoxic Activities.

Three new polyene compounds, talacyanols A-C (1-3), along with two known compounds, ramulosin (4) and eurothiocin A (5), were isolated from the marine fungus Talaromyces cyanescens derived from a seaweed Caulerpa sp. Structures of 1-5 were established by one-dimensional and two-dimensional (1D/2D) NMR, HR-ESIMS, and the modified Mosher's methods, as well as comparison with previously reported literature data. All the compounds (1-5) were tested for their in vitro cytotoxic and anti-neuroinflammatory activities. Among them, 1 showed moderate cytotoxic activity against a panel of cancer cell lines (HCT-15, NUGC-3, NCI-H23, ACHN, PC-3, and MDA-MB-231) with GI50 values ranging from 44.4 to 91.6 µM, whereas compounds 2 and 5 exhibited anti-neuroinflammatory effect without cytotoxicity against all the tested cell lines.

Synthesis of Symmetrical and Nonsymmetrical Polyenes by Iterative and Bidirectional Palladium-Catalyzed Cross-Coupling Reactions.

Bifunctional unsaturated reagents designed to undergo palladium-catalyzed cross-coupling reactions with complementary polyenyl connective fragments are highly useful for the undoubtedly challenging synthesis of polyenes. The current toolkit of building blocks for the bidirectional formation of Csp2 -Csp2 single bonds of polyenes includes homo-bisfunctionalized reagents with equal or unequal reactivity (due to steric and/or electronic factors), and hetero-bisfunctionalized counterparts containing either two different nucleophiles, two electrophiles or one of these functionalities and a latent nucleophile that can be unmasked when desired. The combination of these bifunctional linchpin reagents using tactics that modulate the reactivity of each terminus in order to achieve the required connection have streamlined the synthesis of polyenes of great complexity using (iterative) cross-coupling methods for Csp2 -Csp2 bond formation. Reaction conditions for the Pd-catalyzed cross-coupling reactions are mild and functional-group-tolerant, and therefore these protocols allow to construct the polyene structures using shorter unsaturated reactants with the desired geometries, since in general the products preserve the stereochemical information of the connected cross-coupling partners.

Impairment of mixed melanin-based pigmentation in parrots.

Parrots and allies (Order Psittaciformes) have evolved an exclusive capacity to synthesize polyene pigments called psittacofulvins at feather follicles, which allows them to produce a striking diversity of pigmentation phenotypes. Melanins are polymers constituting the most abundant pigments in animals, and the sulphurated form (pheomelanin) produces colors that are similar to those produced by psittacofulvins. However, the differential contribution of these pigments to psittaciform phenotypic diversity has not been investigated. Given the color redundancy, and physiological limitations associated to pheomelanin synthesis, we hypothesized that the latter would be avoided by psittaciform birds. Here we test this by using Raman spectroscopy to identify pigments in feathers exhibiting colors suspicious of being produced by pheomelanin (i.e., dull red, yellow and grey- and green-brownish) in 26 species from the three main lineages of Psittaciformes. We detected the non-sulphurated melanin form (eumelanin) in black, grey and brown plumage patches, and psittacofulvins in red, yellow and green patches, but no evidence of pheomelanin. As natural melanins are assumed to be composed of eumelanin and pheomelanin in varying ratios, our results represent the first report of impairment of mixed melanin-based pigmentation in animals. Given that psittaciforms also avoid the uptake of circulating carotenoid pigments, these birds seem to have evolved a capacity to avoid functional redundancy between pigments, likely by regulating follicular gene expression. Ours study provides the first vibrational characterization of different psittacofulvin-based colors and thus helps to determine the relative polyene chain length in these pigments, which is related to their antireductant protection activity.

Impairment of mixed melanin-based pigmentation in parrots.

Parrots and allies (Order Psittaciformes) have evolved an exclusive capacity to synthesize polyene pigments called psittacofulvins at feather follicles, which allows them to produce a striking diversity of pigmentation phenotypes. Melanins are polymers constituting the most abundant pigments in animals, and the sulphurated form (pheomelanin) produces colors that are similar to those produced by psittacofulvins. However, the differential contribution of these pigments to psittaciform phenotypic diversity has not been investigated. Given the color redundancy, and physiological limitations associated with pheomelanin synthesis, we hypothesized that the latter would be avoided by psittaciform birds. Here, we tested this using Raman spectroscopy to identify pigments in feathers exhibiting colors suspected of being produced by pheomelanin (i.e. dull red, yellow, greyish-brown and greenish-brown) in 26 species from the three main lineages of Psittaciformes. We detected the non-sulphurated melanin form (eumelanin) in black, grey and brown plumage patches, and psittacofulvins in red, yellow and green patches, but there was no evidence of pheomelanin. As natural melanins are assumed to be composed of eumelanin and pheomelanin in varying ratios, our results represent the first report of impairment of mixed melanin-based pigmentation in animals. Given that psittaciforms also avoid the uptake of circulating carotenoid pigments, these birds seem to have evolved a capacity to avoid functional redundancy between pigments, likely by regulating follicular gene expression. Our study provides the first vibrational characterization of different psittacofulvin-based colors and thus helps to determine the relative polyene chain length in these pigments, which is related to their antireductant protection activity.

Risk factors for mortality in patients with pulmonary mucormycosis.

BACKGROUND: Pulmonary mucormycosis (PM) represents a serious burden in terms of morbidity and mortality in immunocompromised patients. Studies of prognostic factors in patients with PM are limited and have involved small numbers of patients. METHODS: Adult patients diagnosed with proven and probable PM according to the modified definitions of the EORTC/MSG 2008 in a tertiary hospital in Seoul, South Korea, between 2008 and 2019 were retrospectively enrolled. RESULTS: A total of 49 patients including 31 (63%) with proven PM and 18 (37%) with probable PM were enrolled. The 90-day mortality rate was 49% (24/49). Neutropenia, thrombocytopenia, use of voriconazole at clinical suspicion, positivity of non-sterile culture, use of steroid and treatment without surgery were more common in fatal cases than non-fatal cases. Voriconazole use at clinical suspicion for invasive mould pneumonia (OR 6.91, P = .01) and prolonged neutropenia (OR 4.86, P = .03) were independent risk factors for mortality. Voriconazole use at clinical suspicion was associated with positive galactomannan (GM) assay (OR 5.93, P = .02) and history of invasive pulmonary aspergillosis (OR, 6.88, P = .05). CONCLUSION: About half of the patients with PM died within 90 days of diagnosis, and fatal outcomes were common in patients with prolonged neutropenia and empirical voriconazole use. Caution is needed in using voriconazole even in patients with positive GM results and prior histories of invasive pulmonary aspergillosis in whom PM cannot be ruled out by differential diagnosis.

Epipyrone A, a Broad-Spectrum Antifungal Compound Produced by Epicoccum nigrum ICMP 19927.

We have isolated a filamentous fungus that actively secretes a pigmented exudate when growing on agar plates. The fungus was identified as being a strain of Epicoccum nigrum. The fungal exudate presented strong antifungal activity against both yeasts and filamentous fungi, and inhibited the germination of fungal spores. The chemical characterization of the exudate showed that the pigmented molecule presenting antifungal activity is the disalt of epipyrone A-a water-soluble polyene metabolite with a molecular mass of 612.29 and maximal UV-Vis absorbance at 428 nm. This antifungal compound showed excellent stability to different temperatures and neutral to alkaline pH.

Discovery and Elucidation of the Biosynthesis of Aspernidgulenes: Novel Polyenes from Aspergillus Nidulans by Using Serial Promoter Replacement.

Through serial promoter exchanges, we isolated several novel polyenes, the aspernidgulenes, from Aspergillus nidulans and uncovered their succinct biosynthetic pathway involving only four enzymes. An enoyl reductase (ER)-less highly reducing polyketide synthase (HR-PKS) putatively produces a 5,6-dihydro-α-pyrone polyene, which undergoes bisepoxidation, epoxide ring opening, cyclization, and hydrolytic cleavage by three tailoring enzymes to generate aspernidgulene A1 and A2. Our findings demonstrate the prowess of fungal-tailoring enzymes to transform a polyketide scaffold concisely and efficiently into complex structures. Moreover, comparison with citreoviridin and aurovertin biosynthesis suggests that methylation of the α-pyrone hydroxy group by methyltransferase (CtvB or AurB) is the branching point at which the biosynthesis of these two classes of compounds diverge. Therefore, scanning for the presence or absence of the gatekeeping α-pyrone methyltransferase gene in homologous clusters might be a potential way to classify the product bioinformatically as belonging to methylated α-pyrone polyenes or polyenes containing rings derived from the cyclization of the unmethylated 5,6-dihydro-α-pyrone, such as 2,3-dimethyl-γ-lactone and oxabicyclo[2.2.1]heptane.

A Broad-Spectrum Synthesis of Tetravinylethylenes.

The first general synthesis of compounds of the tetravinylethylene (TVE) family is reported. Ramirez-type dibromo-olefination of readily accessible penta-1,4-dien-3-ones generates 3,3-dibromo[3]dendralenes, which undergo twofold Negishi, Suzuki-Miyaura or Mizoroki-Heck reactions with a wide variety of olefinic coupling partners. This route delivers a broad range of unsymmetrically substituted tetravinylethylenes with up to three different alkenyl substituents attached to the central C=C bond. The extensive scope of the approach is demonstrated by the preparation of the first higher order oligo-alkenic through-conjugated/cross-conjugated hybrid compounds. An unsymmetrically substituted TVE is shown to undergo a domino electrocyclization-cycloaddition with high site-selectivity and diastereoselectivity, thereby demonstrating the substantial synthetic potential of substituted TVEs for controlled, rapid structural complexity generation.

Highly Stereoselective and Catalytic Desulfitative C-O and C-I Dienylation with Sulfolenes: the Importance of Basic Additives.

Conjugated dienes and polyenes are central structural motifs of natural products, and key synthetic intermediates in organic synthesis and materials science. We describe herein a palladium-catalyzed dienylation of aryl, heteroaryl, and vinyl triflates, nonaflates and iodides that were previously identified as recalcitrant substrates for the sulfolene-mediated catalytic dienylation. The method has now been successfully expanded to C-O and C-I dienylation, demonstrating broad scope with respect to sulfonates, iodides and sulfolenes. The reactions proceed with high regio- and stereoselectivity, and efficiency that are strongly influenced by basic additives, whose influence on the reaction performance was systematically studied.

Tetravinylallene.

The first chemical synthesis of tetravinylallene (3,5-divinylhepta-1,3,4,6-tetraene) is reported. The final, key step of the synthesis involves a palladium-catalyzed, Negishi-type cross-coupling involving 1,5-transposition of a penta-2-en-4-yn-1-ol methanesulfonate. The unprecedented fundamental hydrocarbon is sufficiently stable to be purified by flash chromatography. A similar synthetic pathway grants access to the first substituted tetravinylallenes, which provide insights into the influence of substitution upon stability and reactivity. Tetravinylallenes are shown to break new ground in swift structural complexity creation, with three novel sequences reported.

Progress in Definition, Prevention and Treatment of Fungal Infections in Cystic Fibrosis.

Cystic fibrosis (CF) is a chronic lethal multi-system condition; however, most of the morbidity and mortality is dependent on the status of the respiratory system. Progressive respiratory decline is mediated by chronic infection and inflammation, punctuated by important acute events known as pulmonary exacerbations which can lead to accelerated decline. The main bacterial species causing infections include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Achromobacter xylosoxidans. In addition to bacteria, fungi are detected in a significant number of patients. The impact of fungal colonization of the airways is still not completely elucidated, but an increasing body of evidence suggests an important role for moulds and yeasts. Although fungal infections are rare, fungi can cause severe pneumonia requiring appropriate targeted treatment. The most common fungi in respiratory samples of patients with CF are Aspergillus fumigatus, Aspergillus terreus and Scedosporium species for filamentous fungi, and yeasts such as Candida albicans and Candida glabrata. Therapeutic strategies depend on the detected fungus and the underlying clinical status of the patient. The antifungal therapy can range from a simple monotherapy up to a combination of three different drugs. Treatment course may be indicated in some patients for two weeks and in others for up to six months, and in rare cases even longer. New antifungal drugs have been developed and are being tested in clinical studies offering the hope of therapeutic alternatives to existing drugs. Identifying relevant risk factors and diagnostic criteria for fungal colonization and infection is crucial to enabling an adequate prevention, diagnosis and treatment.