Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism

The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, indicating that collybolide has been mischaracterized as a KOR agonist and leaving open the basis for antipruritic effects in mice.

Metabolic Pathways and Pathological Outcomes of Aflatoxins: A Review

Aflatoxin is a secondary fungal metabolite that contaminates foods, mostly staple diets like maize, peanuts, chillies, and even rice. These foods are also a major constituent of weaning food for infants in Asia and Sub-Saharan Africa. The fungal metabolite contaminates food during production, harvest, storage, and processing. The contamination is largely promoted by genotypes of crops, soil conditions, temperate regions, and insect activity. Once ingested into the body, aflatoxins get metabolized into different hydroxylated derivatives such as AFb1, AfM1, AFP1, aflatoxicol, and Aflatoxin B1. AFB1 is the most carcinogenic and potent of the known metabolites and they have been categorized as Group I carcinogenic agents by the International Agency for Research on Cancer. The toxic metabolites of aflatoxins have been found in blood samples, breast milk and also have been shown to traverse the placental route. Through various metabolic pathways aflatoxins are responsible for different types of pathological outcomes like gut enteropathy, anemia, stunting, and other immunological disorders. Moreover, socioeconomic determinants have indirectly shown to be strong predictors of aflatoxins exposure and thus its related pathological outcomes. Since we have a very limited number of researches about aflatoxins, this review altogether puts forward what is known about the toxin and its harmful metabolites. Keywords: Aflatoxins; aflatoxinB1; carcinogens; fungal toxins.

Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism

The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, raising the specter of a yet-unidentified contaminant responsible for the reported activity.

Regioselective Enzymatic Synthesis of Kojic Acid Monoesters

Kojic acid is a fungal metabolite and one of the strongest tyrosinase inhibitors. Its esters are used as lipid-compatible skin whitening components in cosmetic formulations. In this study, lipase PS, lipase AK, Lipolyve AN and pig pancreatic lipase catalyzed the acetylation of kojic acid under selective formation of the same product, kojic 7-acetate. However, the enzymes differed in their regioselectivity when catalyzing the alcoholysis of kojic acid diacetate. While lipase PS and lipase AK produced mixtures of both monoacetate regioisomers (7-acetate and 5-acetate of kojic acid), the pancreatic lipase almost exclusively produced 5-acetate. The enzyme displayed the same regioselectivity in the palmitoylation of kojic acid and in the alcoholysis of kojic acid dipalmitate. Simple reaction engineering with PPL as a catalyst thus provides the complementary monoesters of kojic acid. Kojic 7-acetate, 5-acetate, 7-palmitate and 5-palmitate were prepared with yields after purification of 57.3%, 38.2%, 31.7% and 31.4%, respectively.

Toward the Synthesis of the Fungal Metabolite (-)-TAN-2483B

<p>In the search of chemical species with potential therapeutic biological activity, synthetic chemists have looked to nature for inspiration. Molecules built by biological machinery often have structures predisposed for biological interaction. (-)-TAN-2483B and the related compounds (-)-TAN-2483A, and waol A are fungal metabolites that display biological activity in kinase inhibition and parathyroid-induced bone resorption. Though total syntheses of (-)-TAN-2483A and waol A have been achieved, the established methodology does not afford access to (-)-TAN-2483B owing to the unique relative configuration about the ring system. Derivatives of D-galactal have been synthesised, and functionalised at the C-1 and C-2 positions, laying the groundwork for a route to (-)-TAN-2483B and analogues. Using D-galactal derivatives is advantageous as it circumvents some difficult transformations in the existing method for analogue synthesis. The functionalities installed were halide and formyl groups at the C-2 position, and acetylenes at the C-1 position. The synthesis of 2-haloglycals from tri-O-acetyl-D-galactal using N-halosuccinimides was achieved in 32% and <37% for the bromo- and iodo- variants respectively. Vilsmeier-Haack formylation was explored using per-benzylated and per-acetylated galactals as substrates. Formylation of the per-benzylated species was achieved in 78% yield in accordance with literature values. Vilsmeier-Haack formylation on the per-acetylated galactal has not been reported and the glycal was found to be a poor substrate for the formylation. Theories regarding the incompatibility of the per-acetylated species with Vilsmeier-Haack conditions were developed. Ferrier-type alkynylation of the 2-halo/formylglycals was explored, with yields up to 17% and 13% for the bromo- and iodo- species (unoptimised), and 7% for 2-formylglycal (after optimisation studies). The resulting 1-ethynyl-2-formyl/halo-2,3-unsaturated pyrans could be potential intermediates en route to the furanone ring of the target compound.</p>

Toward the Synthesis of the Fungal Metabolite (-)-TAN-2483B

<p>In the search of chemical species with potential therapeutic biological activity, synthetic chemists have looked to nature for inspiration. Molecules built by biological machinery often have structures predisposed for biological interaction. (-)-TAN-2483B and the related compounds (-)-TAN-2483A, and waol A are fungal metabolites that display biological activity in kinase inhibition and parathyroid-induced bone resorption. Though total syntheses of (-)-TAN-2483A and waol A have been achieved, the established methodology does not afford access to (-)-TAN-2483B owing to the unique relative configuration about the ring system. Derivatives of D-galactal have been synthesised, and functionalised at the C-1 and C-2 positions, laying the groundwork for a route to (-)-TAN-2483B and analogues. Using D-galactal derivatives is advantageous as it circumvents some difficult transformations in the existing method for analogue synthesis. The functionalities installed were halide and formyl groups at the C-2 position, and acetylenes at the C-1 position. The synthesis of 2-haloglycals from tri-O-acetyl-D-galactal using N-halosuccinimides was achieved in 32% and <37% for the bromo- and iodo- variants respectively. Vilsmeier-Haack formylation was explored using per-benzylated and per-acetylated galactals as substrates. Formylation of the per-benzylated species was achieved in 78% yield in accordance with literature values. Vilsmeier-Haack formylation on the per-acetylated galactal has not been reported and the glycal was found to be a poor substrate for the formylation. Theories regarding the incompatibility of the per-acetylated species with Vilsmeier-Haack conditions were developed. Ferrier-type alkynylation of the 2-halo/formylglycals was explored, with yields up to 17% and 13% for the bromo- and iodo- species (unoptimised), and 7% for 2-formylglycal (after optimisation studies). The resulting 1-ethynyl-2-formyl/halo-2,3-unsaturated pyrans could be potential intermediates en route to the furanone ring of the target compound.</p>

Comprehensive Account on the Synthesis of (-)-Balanol and its Analogues

Background: A variety of diseases have been associated with hyperactivation of protein kinase C (PKC) enzymes such as cancer, diabetes, asthma, cardiovascular and central nervous system disorders. There is a dire need to selectively inhibit these enzymes by synthesizing new potent inhibitors. Balanol, a fungal metabolite belonging to the PKC inhibitor family, is especially included in this aspect. Tremendous effort has been put towards the synthesis of balanol by different research groups. Objective: The aim of this review is to provide a detailed description of synthetic approaches adopted for the synthesis of key fragments of balanol (azepane and benzophenone). All the factors that resulted in excellent yield and high enantioselectivity have also been mentioned. Conclusion: It has been shown throughout this review that the synthesis of hexahydroazepine and benzophenone cores of balanol was achieved by employing a variety of important key steps with commercially available starting precursors, which make this total synthesis more valuable. Moreover, this article provides ideas to the synthetic as well as pharmaceutical chemists for the synthesis of (-)-balanol and its analogues.

Asymmetric cross-strain protection for amphibians exposed to a fungal-metabolite prophylactic treatment

Chytridiomycosis, an infectious disease of amphibians caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), poses an imminent conservation threat. The global spread of Bd has led to mass mortality events in many amphibian species, resulting in at least 90 species' extinctions to date. Exposure to Bd metabolites (i.e. non-infectious antigenic chemicals released by Bd) partially protects frogs during subsequent challenges with live Bd, suggesting its use as a prophylactic treatment and potential vaccine. However, we do not know whether Bd metabolite exposure protects against strains beyond the one used for treatment. To address this knowledge gap, we conducted a 3 × 2 experiment where we exposed adult Cuban treefrogs, Osteopilus septentrionalis , to one of three treatments (Bd metabolites from California-isolated strain JEL-270, Panamá-isolated strain JEL-419, or an artificial spring water control) and then challenged individuals with live Bd from either strain. We found that exposure to Bd metabolites from the California-isolated strain significantly reduced Bd loads of frogs challenged with the live Panamá-isolated strain, but no other treatments were found to confer protective effects. These findings demonstrate asymmetric cross-protection of a Bd metabolite prophylaxis and suggest that work investigating multiple, diverse strains is urgently needed.

Marine Fungal Metabolite Butyrolactone I Prevents Cognitive Deficits and Inflammation Evoked by AlCl3 in zebrafish

BackgroundMounting evidences indicate that oxidative stress and neuroinflammation are related to neurodegenerative disorders (NDs). Butyrolactone I (BTL-I), a marine fungal metabolite, was previously reported as an in-vitro neuroprotectant and inflammation inhibitor. However, little is known about its in-vivo effects. Zebrafish (Danio rerio) could be used as a convenient model in evaluation of toxicology and central nervous system (CNS) diseases. MethodsHere, we employ the in-vivo and in-silico methods to investigate the anti-NDs potential of BTL-I. Specifically, we established cognitive deficits model in zebrafish by intraperitoneal (i.p.) injection of AlCl3 (21 μg), and assessed their behaviors in the T-maze test. Proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well as acetylcholinesterase (AChE) activity, glutathione (GSH) levels were assayed 24 h after the AlCl3 injection. The intestinal flora of the zebrafish were investigated by 16 S rDNA high-throughput analysis. A marine fungal metabolite, butyrolactone I (BTL-I) was used to modulate zebrafish cognitive deficits evoked by AlCl3. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of BTL-I were studied by in-silico tool of ADMETlab.ResultsBTL-I dose-dependently ameliorated AlCl3-induced cognitive deficits in zebrafish. While, AlCl3 treatment elevated the levels of central and peripheral proinflammatory cytokines, increased AChE activity, and lowered GSH in the brain of zebrafish, these effects except GSH reducing were reversed by 25–100 mg/kg BTL-I administration. 16S rDNA high-throughput sequencing of intestinal flora of zebrafish showed that AlCl3 decreased Gram-positive bacteria and increased proinflammatory Gram-negative bacterial while BTL-I contributed to maintain the predominance of beneficial Gram-positive bacteria. The in-silico analysis indicated that BTL-I exhibits acceptable drug-likeness and ADMET profiles.ConclusionsThe present findings suggest BTL-I as a potential therapeutic agent for preventing CNS deficits caused by inflammation, neurotoxicity, and gut flora imbalance.