Integrated Omics Approach to Unveil Antifungal Bacterial Polyynes as acetyl-CoA Acetyltransferase Inhibitors

Bacterial polyynes are highly active natural products with a broad spectrum of antimicrobial activities. However, their detailed mechanism of action remains unclear. By integrating comparative genomics, transcriptomics, functional genetics, and metabolomics analysis, we identified a unique polyyne resistance gene, masL (encoding acetyl-CoA acetyltransferase), in the biosynthesis gene cluster of antifungal polyynes (massilin A 1, massilin B 2, collimonin C 3, and collimonin D 4) of Massilia sp. YMA4. Crystallographic analysis indicated that bacterial polyynes serve as covalent inhibitors of acetyl-CoA acetyltransferase. Moreover, we confirmed that the bacterial polyynes disrupted cell membrane integrity and inhibited cell viability of Candida albicans by targeting ERG10, the homolog of MasL. Thus, this study demonstrated that acetyl-CoA acetyltransferase is a potential target for the development of antifungal agents.

A comprehensive review on pyranoindole-containing agents

: A huge number of nitrogen-containing heterocyclic compounds are ubiquitous in natural products, pharmaceuticals, and bioactive molecules. Among these, the pyranoindole represents an important structural motif, as it constitutes the central subunit in both the biologically active natural products and therapeutic agents. Talathermophilins, notoamides, norgeamides, carneamides, and versicamides are examples of naturally occurring pyranoindoles, while the well-known etodolac and pemedolac are a tetrahydropyrano[3,4-b]indole deriving from synthetic procedures. Besides the well-known antiinflammatory and fibrinolytic activity, molecules comprising the pyranoindole framework have been demonstrated to exhibit various biological activities, such as antiulcer, antidepressant, analgesic, and antiproliferative. Herein, we report the most common natural and synthetic products bearing a pyranoindole nucleus, their syntheses, and biological activities.

Sesquiterpenoids Specially Produced by Fungi: Structures, Biological Activities, Chemical and Biosynthesis (2015–2020)

Fungi are widely distributed in the terrestrial environment, freshwater, and marine habitat. Only approximately 100,000 of these have been classified although there are about 5.1 million characteristic fungi all over the world. These eukaryotic microbes produce specialized metabolites and participate in a variety of ecological functions, such as quorum detection, chemical defense, allelopathy, and maintenance of symbiosis. Fungi therefore remain an important resource for the screening and discovery of biologically active natural products. Sesquiterpenoids are arguably the richest natural products from plants and micro-organisms. The rearrangement of the 15 high-ductility carbons gave rise to a large number of different skeletons. At the same time, abundant structural variations lead to a diversification of biological activity. This review examines the isolation, structural determination, bioactivities, and synthesis of sesquiterpenoids that were specially produced by fungi over the past five years (2015‒2020).

Asymmetric construction of acyclic quaternary stereocenters via direct enantioselective additions of α-alkynyl ketones to allenamides

Acyclic quaternary stereocenters are widely present in a series of biologically active natural products and pharmaceuticals. However, development of highly efficient asymmetric catalytic methods for the construction of these privileged motifs represents a longstanding challenge in organic synthesis. Herein, an efficient chiral phosphoric acid catalyzed direct asymmetric addition of α-alkynyl acyclic ketones with allenamides has been developed, furnishing the acyclic all-carbon quaternary stereocenters with excellent regioselectivities and high enantioselectivities. Extensive and detailed experimental mechanistic studies were performed to investigate the mechanism of this reaction. Despite a novel covalent allyl phosphate intermediate was found in these reactions, further studies indicated that a SN2-type mechanism with the ketone nucleophiles is not very possible. Instead, a more plausible mechanism involving the elimination of the allyl phosphate to give the α,β-unsaturated iminium intermediate, which underwent the asymmetric conjugate addition with the enol form of ketone nucleophiles under chiral anion catalysis, was proposed. In virtue of the fruitful functional groups bearing in the chiral products, the diverse derivatizations of the chiral products provided access to a wide array of chiral scaffolds with quaternary stereocenters.

Herbal Infusions as a Valuable Functional Food

Herbal infusions are an underestimated and easy to intake a source of biologically active natural compounds (polyphenols), which, in the dissolved form, are more easily absorbed. Therefore, this study aimed to assess the potential of herbal infusions as a functional food to reduce postprandial hyperglycemia (inhibition of α-amylase and α-glucosidase) and to reduce the effects of increased blood glucose level (antioxidant effect-DPPH, CUPRAC, and Fe2+ chelating assays, as well as anti-inflammatory activity-inhibition of collagenase). We showed that polyphenols are present in the examined aqueous herbal infusions (including chlorogenic and gallic acids). Subsequently, our research has shown that herbal infusions containing cinnamon bark, mulberry leaves, and blackberry fruits most strongly inhibit glucose release from complex carbohydrates, and that all herbal infusions can, to different degrees, reduce the effects of elevated blood sugar. In conclusion, infusions prepared from herbal blends could be recommended to prevent type II diabetes.

Caffeic acid, a dietary polyphenol, as a promising candidate for combination therapy

Increased effectiveness and decreasing toxicity are prime objectives in drug research. Overwhelming evidence suggests the use of appropriate combination therapy for the better efficacy of drugs owing to their synergistic profile. Dietary active constituents play a major role in health outcomes. Therefore, it is possible to increase the effectiveness of the drug by combining contemporary medication with active natural/semi-synthetic constituents. One such dietary constituent, caffeic acid (CA), is a by-product of the shikimate pathway in plants and is a polyphenol of hydroxycinnamic acid class. Extensive research on CA has proposed its efficacy against inflammatory, neurodegenerative, oncologic, and metabolic disorders. The synergistic/additive effects of CA in combination with drugs like caffeine, metformin, pioglitazone, and quercetin have been reported in several experimental models and thus the present review is an attempt to consolidate outcomes of this research. Multi-target-based mechanistic studies will facilitate the development of effective combination regimens of CA.

Highly Diastereoselective Synthesis of Tetrahydroquinoline Derivatives via [4 + 2] Annulation of Ortho-Tosylaminophenyl-Substituted Para-Quinone Methides and Cyanoalkenes

As a privileged structural motif, tetrahydroquinoline skeletons widely exist in biologically active natural products and pharmaceuticals. In this protocol, a highly diastereoselective [4 + 2] annulation of ortho-tosylaminophenyl-substituted p-QMs and cyanoalkenes to construct tetrahydroquinoline derivatives has been successfully achieved. This strategy proceeds efficiently under mild condition, offering straightforward route to a variety of 4-aryl-substituted tetrahydroquinolines with high yields, excellent diastereoselectivities, broad functional group tolerance as well as gram-scale capacity. Moreover, a one-pot reaction sequence utilizing in situ generated p-QMs under the similar condition to build tetrahydroquinoline framework is smoothly conducted with good reaction performance as well as step and atom economy.