Rhodotorulic Acid and its Derivatives: Synthesis, Properties, and Applications.

Siderophores are low molecular weight compounds produced by microorganisms to scavenge iron in iron-deficient environments. Rhodotorulic acid, a natural hydroxamate siderophore, plays a vital role in iron acquisition for fungi and bacteria. As the simplest natural hydroxamate siderophore, it exhibits a high affinity for ferric ions, enabling it to form stable complexes that facilitate iron uptake and transport within microorganisms. This article provides a comprehensive analysis of this hydroxamate siderophore, rhodotorulic acid, its synthesis, physicochemical properties, and biological significance. It also explores its applications in antifungal and plant protection strategies. Insights into RA derivatives reveal distinct biological effects and applications with potential in various fields, from antioxidants to antifungals. Rhodotorulic acid and its derivatives show promise for novel therapies, plant protection strategies, and iron supplementation in agriculture. Understanding their properties could advance science and medicine with sustainable practices.

Ginsentide-like Coffeetides Isolated from Coffee Waste Are Cell-Penetrating and Metal-Binding Microproteins.

Coffee processing generates a huge amount of waste that contains many natural products. Here, we report the discovery of a panel of novel cell-penetrating and metal ion-binding microproteins designated coffeetide cC1a-c and cL1-6 from the husk of two popular coffee plants, Coffea canephora and Coffea liberica, respectively. Combining sequence determination and a database search, we show that the prototypic coffeetide cC1a is a 37-residue, eight-cysteine microprotein with a hevein-like cysteine motif, but without a chitin-binding domain. NMR determination of cC1a reveals a compact structure that confers its resistance to heat and proteolytic degradation. Disulfide mapping together with chemical synthesis reveals that cC1a has a ginsentide-like, and not a hevein-like, disulfide connectivity. In addition, transcriptomic analysis showed that the 98-residue micrcoproten-like coffeetide precursor contains a three-domain arrangement, like ginsentide precursors. Molecular modeling, together with experimental validation, revealed a Mg2+ and Fe3+ binding pocket at the N-terminus formed by three glutamic acids. Importantly, cC1a is amphipathic with a continuous stretch of 19 apolar amino acids, which enables its cell penetration to target intracellular proteins, despite being highly negatively charged. Our findings suggest that coffee by-products could provide a source of ginsentide-like bioactive peptides that have the potential to target intracellular proteins.

Functional Characterization of a New Degradation Peptide BmTX4-P1 from Traditional Chinese Scorpion Medicinal Material.

Thermally processed Buthus martensii Karsch scorpion is an important traditional Chinese medical material that has been widely used to treat various diseases in China for over one thousand years. Our recent work showed that thermally processed Buthus martensii Karsch scorpions contain many degraded peptides; however, the pharmacological activities of these peptides remain to be studied. Here, a new degraded peptide, BmTX4-P1, was identified from processed Buthus martensii Karsch scorpions. Compared with the venom-derived wild-type toxin peptide BmTX4, BmTX4-P1 missed some amino acids at the N-terminal and C-terminal regions, while containing six conserved cysteine residues, which could be used to form disulfide bond-stabilized α-helical and ß-sheet motifs. Two methods (chemical synthesis and recombinant expression) were used to obtain the BmTX4-P1 peptide, named sBmTX4-P1 and rBmTX4-P1. Electrophysiological experimental results showed that sBmTX4-P1 and rBmTX4-P1 exhibited similar activities to inhibit the currents of hKv1.2 and hKv1.3 channels. In addition, the experimental electrophysiological results of recombinant mutant peptides of BmTX4-P1 indicated that the two residues of BmTX4-P1 (Lys22 and Tyr31) were the key residues for its potassium channel inhibitory activity. In addition to identifying a new degraded peptide, BmTX4-P1, from traditional Chinese scorpion medicinal material with high inhibitory activities against the hKv1.2 and hKv1.3 channels, this study also provided a useful method to obtain the detailed degraded peptides from processed Buthus martensii Karsch scorpions. Thus, the study laid a solid foundation for further research on the medicinal function of these degraded peptides.

Bioactive Flavonoids: A Comparative Overview of the Biogenetic and Chemical Synthesis Approach.

Flavonoids are natural polyphenolic compounds and constitute a major class of plant secondary metabolites. To date, structures of more than 10,000 different flavonoids have been elucidated, and most of them are present in cells and tissues of plant parts. Flavonoids have been reported to exert multiple physiological activities and are also consumed as dietary supplements. Flavonoids have been extensively explored as anticancer, anti-inflammatory, antidiabetic, antirheumatic, antioxidant, antimalarial, neuroprotective, cardioprotective, anti-angiogenic, and antiproliferative agents. Most of the flavonoids are biosynthesized in plants via the phenylpropanoid pathway. However, they are associated with some limitations. Chemical synthesis is an alternative strategy to improve the yield and obtain purified products but is hampered by drawbacks, such as intolerance to stressful lab conditions. Pharmacokinetics is the rate-limiting step defining the bioavailability and metabolism of flavonoids, though greatly influenced by their chemical structure. However, nanoformulation is an emerging technique to improve biopharmaceutical fate and achieve target drug delivery. Thus, much attention should be given to identifying other possible chemical approaches for synthesizing flavonoids and improving their pharmacokinetic profiling, hence potentiating their efficacy in clinic.

Cucurbitacins as potential anticancer agents: new insights on molecular mechanisms.

Since ancient times, plants have been an extensive reservoir of bioactive compounds with therapeutic interest for new drug development and clinical application. Cucurbitacins are a compelling example of these drug leads, primarily present in the plant kingdom, especially in the Cucurbitaceae family. However, these natural compounds are also known in several genera within other plant families. Beyond the Cucurbitaceae family, they are also present in other plant families, as well as in some fungi and one shell-less marine mollusc. Despite the natural abundance of cucurbitacins in different natural species, their obtaining and isolation is limited, as a result, an increase in their chemical synthesis has been developed by researchers. Data on cucurbitacins and their anticancer activities were collected from databases such as PubMed/MedLine, TRIP database, Web of Science, Google Scholar, and ScienceDirect and the information was arranged sequentially for a better understanding of the antitumor potential. The results of the studies showed that cucurbitacins have significant biological activities, such as anti-inflammatory, antioxidant, antimalarial, antimicrobial, hepatoprotective and antitumor potential. In conclusion, there are several studies, both in vitro and in vivo reporting this important anticancer/chemopreventive potential; hence a comprehensive review on this topic is recommended for future clinical research.

Safety of ß-hydroxybutyrate salts as a novel food pursuant to Regulation (EU) 2015/2283.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on ß-hydroxybutyrate (BHB) salts as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The NF consists of sodium, magnesium and calcium BHB salts, and is proposed to be used by adults as a food ingredient in a number of food categories and as food supplement. The data provided by the applicant about the identity, the production process and the compositional data of the NF over the course of the risk assessment period were overall considered unsatisfactory. The Panel noted inconsistencies in the reporting of the test item used in the subchronic toxicity study and human studies provided by the applicant. Owing to these deficiencies, the Panel cannot establish a safe intake level of the NF. The Panel concludes that the safety of the NF has not been established.

Silver and copper-oxide nanoparticles prepared with GA3 induced defense in rice plants and caused mortalities to the brown planthopper, Nilaparvata lugens (Stål).

BACKGROUND: Nanoparticles have been employed as nanopesticides for pest control in agriculture. However, the harmful effects of their chemical synthesis on human and environmental health have resulted in increased use of green synthetic approaches, including the use of plant extracts. The brown planthopper, Nilaparvata lugens (Stål) (BPH), is a severe pest of rice plants (Oryza sativa L.), especially in Asia. It is usually controlled chemically but has developed resistance against many insecticides. RESULTS: In this study, we synthesized metallic silver (Ag-NPs) and copper-oxide (CuO-NPs) nanoparticles using the exogenous phytohormone, gibberellic acid (GA3), as a reducing agent. We then sprayed them separately on rice plants and BPH together and evaluated their effects on the plants and insects. SEM and TEM images showed that the synthesis was successful, indicated by the sizes (25-60 nm), uniform shape and spherical and cubical structures of Ag-NPs, as well as by the rugby sheet-like of CuO-NPs with lateral sizes of 150-340 nm and thickness of 30-70 nm. Independent applications of the nanoparticles and GA3 on rice plants induced different volatile profiles, of which the highest number emitted was under Ag-NPs, including the highest emission of linalool. Transcriptome analysis showed that Ag-NPs-treated rice plants showed different transcriptome profiles compared to the control, 24 h after treatment, including the upregulation of the linalool synthase gene, genes of plants transcription factors such as WRKY, bHLH and NAC and other genes involved in plant defense responses. In all treatments, the mortality rate of BPH increased with an increase in NPs concentrations over time but was prominent under Ag-NPs treatment. The LC50 values for Ag-NPs and CuO-NPs decreased with an increase in time. Also, the nanoparticles increased the activities of protective enzymes (POD, SOD and CAT), inhibited that of detoxification enzymes (A-CHE, ACP and AKP), and reduced total protein concentrations in the BPH. CONCLUSIONS: These results show that synthesizing nanoparticles using phytohormones may be a safer and environmentally friendly option, which also holds promise for controlling the BPH in rice production.

Review of Shikonin and Derivatives: Isolation, Chemistry, Biosynthesis, Pharmacology and Toxicology.

Shikonin and its derivatives, isolated from traditional medicinal plant species of the genus Lithospermum, Alkanna, Arnebia, Anchusa, Onosma, and Echium belonging to the Boraginaceae family, have numerous applications in foods, cosmetics, and textiles. Shikonin, a potent bioactive red pigment, has been used in traditional medicinal systems to cure various ailments and is well known for its diverse pharmacological potential such as anticancer, antithrombotic, neuroprotective, antidiabetic, antiviral, anti-inflammatory, anti-gonadotropic, antioxidants, antimicrobial and insecticidal. Herein, updated research on the natural sources, pharmacology, toxicity studies, and various patents filed worldwide related to shikonin and approaches to shikonin's biogenic and chemical synthesis are reviewed. Furthermore, recent studies to establish reliable production systems to meet market demand, functional identification, and future clinical development of shikonin and its derivatives against various diseases are presented.

Chicoric Acid: Natural Occurrence, Chemical Synthesis, Biosynthesis, and Their Bioactive Effects.

Chicoric acid has been widely used in food, medicine, animal husbandry, and other commercial products because of its significant pharmacological activities. However, the shortage of chicoric acid limits its further development and utilization. Currently, Echinacea purpurea (L.) Moench serves as the primary natural resource of chicoric acid, while other sources of it are poorly known. Extracting chicoric acid from plants is the most common approach. Meanwhile, chicoric acid levels vary in different plants as well as in the same plant from different areas and different medicinal parts, and different extraction methods. We comprehensively reviewed the information regarding the sources of chicoric acid from plant extracts, its chemical synthesis, biosynthesis, and bioactive effects.

Chemical approaches towards installation of rare functional groups in bacterial surface glycans.

Bacterial surface glycans perform a diverse and important set of biological roles, and have been widely used in the treatment of bacterial infectious diseases. The majority of bacterial surface glycans are decorated with diverse rare functional groups, including amido, acetamidino, carboxamido and pyruvate groups. These functional groups are thought to be important constituents for the biological activities of glycans. Chemical synthesis of glycans bearing these functional groups or their variants is essential for the investigation of structure-activity relationships by a medicinal chemistry approach. To date, a broad choice of synthetic methods is available for targeting the different rare functional groups in bacterial surface glycans. This article reviews the structures of naturally occurring rare functional groups in bacterial surface glycans, and the chemical methods used for installation of these groups.

Chemical synthesis of a synthetically useful L-galactosaminuronic acid building block.

Most bacterial cell surface glycans are structurally unique, and have been considered as ideal target molecules for the developments of detection and diagnosis techniques, as well as vaccines. Chemical synthesis has been a promising approach to prepare well-defined oligosaccharides, facilitating the structure-activity relationship exploration and biomedical applications of bacterial glycans. L-Galactosaminuronic acid is a rare sugar that has been only found in cell surface glycans of gram-negative bacteria. Here, an orthogonally protected L-galactosaminuronic acid building block was designed and chemically synthesized. A synthetic strategy based on glycal addition and TEMPO/BAIB-mediated C6 oxidation served well for the transformation of commercial L-galactose to the corresponding L-galactosaminuronic acid. Notably, the C6 oxidation of the allyl glycoside was more efficient than that of the selenoglycoside. In addition, a balance between the formation of allyl glycoside and the recovery of selenoglycoside was essential to improve efficiency of the NIS/TfOH-catalyzed allylation. This synthetically useful L-galactosaminuronic acid building block will provide a basis for the syntheses of complex bacterial glycans.

Chemical synthesis of saponins: An update.

Saponins, as secondary metabolites in terrestrial plants and marine invertebrate, constitute one of the largest families of natural products. The long history of folk medicinal applications of saponins makes them attractive candidates for innovative drug design and development. Chemical synthesis has become a practical alternative to the availability of the natural saponins and their modified analogs, so as to facilitate SAR studies and the discovery of optimal structures for clinical applications. The recent achievements in the synthesis of these complex saponins reflect the advancements of both steroid/triterpene chemistry and carbohydrate chemistry. This chapter provides an updated review on the chemical synthesis of natural saponins, covering the literature from 2014 to 2020.

Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy.

Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay. We adopted activity-directed combinatorial chemical synthesis strategy to optimize this hit compound. Compound b36 was found to be the noncompetitive and the most promising one with IC50 values of 5.96 ± 0.61 µM against PHGDH. Compound b36 inhibited the proliferation of human breast cancer and ovarian cancer cells, reduced intracellular serine synthesis, damaged DNA synthesis, and induced cell cycle arrest. Collectively, our results suggest that b36 is a novel PHGDH inhibitor, which could be a promising modulator to reprogram the serine synthesis pathway and might be a potential anticancer lead worth further exploration.

Silver nanoparticles synthesized using leaf extract of Azadirachta indica exhibit enhanced antimicrobial efficacy than the chemically synthesized nanoparticles: A comparative study.

A wide variety of methods have synthesized silver nanoparticles (Ag-NPs) in the recent past; however, biological methods have attracted much attention over the traditional chemical synthesis method due to being non-hazardous and eco-friendly. Here, a detailed and systemic study was performed to compare two different synthesis routes for Ag-NPs, that is, the chemical and the biological; their possible outcomes have also been described. Ag-NPs were synthesized chemically (cAg-NPs) using a chemical reductant and biologically (bAg-NPs) by using aqueous leaf extract of Azadirachta indica (neem). The synthesized nanoparticles were characterized using UV-visible spectrophotometry, FT-IR, EDX, and TEM. The average particle sizes (APS) of cAg-NPs were found to be 8 and 13 nm and of bAg-NPs to be 19 and 43 nm under different AgNO3 concentrations. The antimicrobial tests of differently sized NPs were performed against Escherichia coli (Gram -ve) and Staphylococcus aureus (Gram +ve). The results revealed that bAg-NPs of APS 43 nm were highly antimicrobial against both the tested bacterial stains followed by cAg-NPs of 8 nm. We found the effect of cAg-NPs to be size-dependent, whereas bAg-NPs showed a more significant antimicrobial effect than cAg-NPs.

Study on the impacts of chemical and green synthesized (Leucas aspera and oxy-cyclodextrin complex) dietary zinc oxide nanoparticles in Nile tilapia (Oreochromis niloticus).

The present study was designed to evaluate the health effects of dietary nanozinc prepared by two methods: conventional chemical method and green method. The parameters evaluated were the extent of bioaccumulation, antioxidant status, histological, immunological changes and DNA damage in Nile tilapia fed nanozinc feed. Zinc oxide nanoparticles were first prepared by green and chemical methods. Before feed preparation, the in vitro antioxidant activity and antibacterial activity of both types of nanoparticle solutions were tested and the results revealed enhanced activities in green synthesized ZnO NP solution. After the acclimatization period, 420 Nile tilapias were distributed randomly into 21 glass tanks with 20 fish per tank in triplicates. Fish were fed control diet without any ZnO NP and (i) GT1-green synthesized ZnO NP diet at 100 mg/kg, (ii) CT1-chemically synthesized ZnO NP diet at 100 mg/kg, (iii) GT2-green synthesized ZnO NP diet at 200 mg/kg, (iv) CT2-chemically synthesized ZnO NP diet at 200 mg/kg, (v) GT3-green synthesized ZnO NP diet at 400 mg/kg and (vi) CT3-chemically synthesized ZnO NP diet at 400 mg/kg for 60 days. After 60 days, gill and liver samples were collected for analysing oxidative stress, histopathological alterations and bioaccumulation of zinc, whereas serum samples were collected for evaluating immune response. The results revealed that the GT3 diet significantly (P < 0.05) enhanced the level of antioxidant enzymes (CAT, SOD, GPx, GR and GSH) than dietary nanozinc prepared by the chemical method. Similarly, the innate immunological parameters were significantly (P < 0.05) augmented in fish fed GT3 diet. Comparative histological study of liver and gill tissues revealed normal architecture in the tissues of fish fed green synthesized NP-enriched feed, whereas the tissues of fish fed chemically synthesized NP feed exhibited histological alterations. Bioaccumulation of zinc was more in the liver followed by the muscle and least in the gills and DNA damage was more evident in fish fed chemically synthesized ZnO NP-enriched feed. In conclusion, the results suggest that the inclusion of 400 mg/kg GT3 diet in fish diet enhanced the level of antioxidant enzymes, boosted immune response and did not cause histological damage to organs, and therefore, GT3 nanofeed can be recommended for fish health improvement.

Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8-O-(12-Aminododecanoyl)-8-O-Debutanoylthapsigargin.

In spite of the impressing cytotoxicity of thapsigargin (Tg), this compound cannot be used as a chemotherapeutic drug because of general toxicity, causing unacceptable side effects. Instead, a prodrug targeted towards tumors, mipsagargin, was brought into clinical trials. What substantially reduces the clinical potential is the limited access to Tg and its derivatives and cost-inefficient syntheses with unacceptably low yields. Laser trilobum, which contains a structurally related sesquiterpene lactone, trilobolide (Tb), is successfully cultivated. Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin.

Antibacterial Mode of Action of the Daucus carota Essential Oil Active Compounds against Campylobacter jejuni and Efflux-Mediated Drug Resistance in Gram-Negative Bacteria.

Today, an alarming rise of bacterial gastroenteritis in humans resulting from consuming Campylobacter-tainted foods is being observed. One of the solutions for mitigating this issue may be the antibacterial activity of essential oils. In the present research, we propose to study the antibacterial activity against Campylobacter and other Gram-negative bacteria of Daucus carota essential oil and its active molecules. In addition, a few chemically synthesized molecules such as (E)-methylisoeugenol, Elemicin, and eugenol were also studied. The results showed that the essential oil itself and its most active component, (E)-methylisoeugenol, exhibited bactericidal effects. Similar effects were detected using purified and chemically synthesized molecules. Also, it was observed that the Daucus carota essential oil and its active molecules affected intracellular potassium and intracellular ATP contents in Campylobacter cells. Inhibition of the membrane bound FOF1-ATPase was also observed. Eventually, for the first time, the efflux mechanism of active molecules of Daucus carota essential oil was also identified in gamma proteobacteria and its specific antibacterial activity against Campylobacter jejuni was associated with the lack of this efflux mechanism in this species.

Recent Advances in Iridoid Chemistry: Biosynthesis and Chemical Synthesis.

Iridoids are a large family of monoterpenoids found in traditional medicinal plants and show significant effects for the human species. In addition to their wide range of biological activities, such as neuroprotective and antitumor activities, the cis-fused bicyclic ring systems of iridoids are still attractive as synthetic targets to apply novel synthetic methodologies. Accordingly, recent progress regarding the biosynthesis and chemical synthesis of iridoids is covered in this minireview. Identification of new enzymes for the iridoid biosynthesis in Catharanthus roseus and ingenious synthetic strategies for the construction of the iridoid skeleton are described.

Synthesis and Biological Activity Study of Tanshinone Derivatives: A Literature and Patent Review.

Tanshinones are a class of bioactive compounds present in the Chinese herbal medicine Danshen (Salvia miltiorrhiza Bunge), containing among others, abietane diterpene quinone scaffolds. Chemical synthesis and biological activity studies of natural and unnatural tanshinone derivatives have been reviewed in this article.

Discovery and mechanistic studies of cytotoxic cyclotides from the medicinal herb Hybanthus enneaspermus.

Cyclotides are plant-derived peptides characterized by an ∼30-amino acid-long cyclic backbone and a cystine knot motif. Cyclotides have diverse bioactivities, and their cytotoxicity has attracted significant attention for its potential anticancer applications. Hybanthus enneaspermus (Linn) F. Muell is a medicinal herb widely used in India as a libido enhancer, and a previous study has reported that it may contain cyclotides. In the current study, we isolated 11 novel cyclotides and 1 known cyclotide (cycloviolacin O2) from H. enneaspermus and used tandem MS to determine their amino acid sequences. We found that among these cyclotides, hyen C comprises a unique sequence in loops 1, 2, 3, 4, and 6 compared with known cyclotides. The most abundant cyclotide in this plant, hyen D, had anticancer activity comparable to that of cycloviolacin O2, one of the most cytotoxic known cyclotides. We also provide mechanistic insights into how these novel cyclotides interact with and permeabilize cell membranes. Results from surface plasmon resonance experiments revealed that hyen D, E, L, and M and cycloviolacin O2 preferentially interact with model lipid membranes that contain phospholipids with phosphatidyl-ethanolamine headgroups. The results of a lactate dehydrogenase assay indicated that exposure to these cyclotides compromises cell membrane integrity. Using live-cell imaging, we show that hyen D induces rapid membrane blebbing and cell necrosis. Cyclotide-membrane interactions correlated with the observed cytotoxicity, suggesting that membrane permeabilization and disintegration underpin cyclotide cytotoxicity. These findings broaden our knowledge on the indigenous Indian herb H. enneaspermus and have uncovered cyclotides with potential anticancer activity.