Steviol glycosides were subjected to bacteria present in a soil sample collected from a Stevia plantation in Paraguay. During the incubation experiments, next to the aglycon steviol, steviol ...degradation products were also formed. X-ray analysis and NMR methods in combination with chemical synthesis and GIAO NMR calculations were used to fully characterize the structure of these compounds as a tricyclic ketone and the corresponding reduced form. They were nicknamed monicanone and monicanol. The latter has the (S)-configuration at the alcohol site.
This study presents a synthesis of 4H‐1,2,3triazolo1,5‐aindol‐4‐ones. The key step in the synthesis of this new heterocyclic scaffold is an intramolecular cyclization via an unprecedented ...carbonylative C–H functionalization of 1‐(2‐bromoaryl)‐1,2,3‐triazoles. Isotopic labelling of the carbonyl carbon atom is possible using near stoichiometric amounts of 13CO. Additionally, an alternative pathway via carbonylative Sonogashira coupling followed by a two‐step, one‐pot azidation/cycloaddition is also investigated, giving rise to the same scaffold.
PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this ...study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin's antiseizure action.
The supramolecular gelation of small molecules is typically preceded by an external stimulus to trigger the self-assembly. The need for this trigger stems from the metastable nature of most ...supramolecular gels and can limit their applicability. Herein, we present a small urea-based molecule that spontaneously forms a stable hydrogel by simple mixing without the addition of an external trigger. Single particle tracking experiments and observations made from scanning electron microscopy indicated that triggerless gelation occurred in a similar fashion as the archetypical heat-triggered gelation. These results could stimulate the search for other supramolecular hydrogels that can be obtained by simple mixing. Furthermore, the mechanism of the heat-triggered supramolecular gelation was elucidated by a combination of molecular dynamics simulations and quantitative NMR experiments. Surprisingly, hydrogelation seemingly occurs via a stepwise self-assembly in which spherical nanoparticles mature into an entangled fibrillary network.
A carbonylative route towards the synthesis of benzimidazo2,1‐bquinazolin‐12‐ones was developed. The key step in this strategy consists of an intramolecular carbonylative lactam formation, starting ...from N‐(2‐bromophenyl)‐1H‐benzimidazol‐2‐amines. These precursor molecules were synthesized by two different methods to introduce a variety of substituents on the aromatic ring systems. Interestingly, only near‐stoichiometric amounts of carbon monoxide were required in the ring‐closing aminocarbonylation reaction, rendering the developed strategy also suitable for late‐stage 13C‐isotopic labelling.
A new synthetic route towards benzimidazo2,1‐bquinazolin‐12‐ones has been developed, which relies on the Pd‐catalyzed intramolecular aminocarbonylation of N‐(2‐bromophenyl)‐1H‐benzimidazol‐2‐amines. Using near stoichiometric amounts of 13CO, isotopically labelled benzimidazo2,1‐bquinazolin‐12‐ones were synthesized.
A carbonylative route towards the synthesis of benzimidazo2,1‐bquinazolin‐12‐ones was developed. The key step in this strategy consists of an intramolecular carbonylative lactam formation, starting ...from N‐(2‐bromophenyl)‐1H‐benzimidazol‐2‐amines. These precursor molecules were synthesized by two different methods to introduce a variety of substituents on the aromatic ring systems. Interestingly, only near‐stoichiometric amounts of carbon monoxide were required in the ring‐closing aminocarbonylation reaction, rendering the developed strategy also suitable for late‐stage 13C‐isotopic labelling.
Bacterial trans‐acyltransferase polyketide synthases (trans‐AT PKSs) are modular megaenzymes that employ unusual catalytic domains to assemble diverse bioactive natural products. One such PKS is ...responsible for the biosynthesis of the oximidine anticancer agents, oxime‐substituted benzolactone enamides that inhibit vacuolar H+‐ATPases. Here, we describe the identification of the oximidine gene cluster in Pseudomonas baetica and the characterization of four novel oximidine variants, including a structurally simpler intermediate that retains potent anticancer activity. Using a combination of in vivo, in vitro and computational approaches, we experimentally elucidate the oximidine biosynthetic pathway and reveal an unprecedented mechanism for O‐methyloxime formation. We show that this process involves a specialized monooxygenase and methyltransferase domain and provide insight into their activity, mechanism and specificity. Our findings expand the catalytic capabilities of trans‐AT PKSs and identify potential strategies for the production of novel oximidine analogues.
The anticancer agent oximidine I and three novel variants were discovered as products of a cryptic trans‐AT PKS/NRPS in Pseudomonas baetica. By manipulating the biosynthetic pathway, a key intermediate was identified that retains potent anticancer properties. A combination of bioinformatics analysis and genetic and biochemical experiments illuminated the oximidine biosynthetic pathway, including a novel mechanism for O‐methyloxime formation.
Steviol glycosides are fully deglycosylated to steviol in the presence of bacterial populations that were isolated from different soil samples. Heating (20 min at 80 °C) or boiling (10 min at 100 °C) ...of soils had little effect on the steviol formation. It is suggested that bacteria that survived with highly resistant spores are responsible for the deglycosylation of steviol glycosides. A bio-organic preparation method for steviol was developed which had a total yield of 90%. Beside deglycosylation, other reactions also occur. The steviol formed can be degraded. Under anaerobic conditions, rebaudioside A was not hydrolyzed while stevioside was degraded to steviol via rubusoside. Moreover, after an extended incubation (4 weeks) and repetitive sub-cultivation, a bacterial community was selected that converted steviol glycosides to a new and unknown ketone, given the nickname Monicanone. It appeared to be the steviol nucleus without the A-ring that underwent a Walden inversion at its original C-10. A second and related unknown compound could be isolated from an impure preparation of Monicanone by chromatographic separation and purification; this compound was a reduced form of Monicanone and named Monicanol. Steviol glycosides that were incubated with a UASB effluent of an industrial wastewater treatment system – supplemented or not – with sludge of a lab scale nitrification or denitrification unit – were completely degraded via steviol and Monicanone.
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•Steviol glycosides (SG) were initially hydrolyzed to steviol by soil samples.•Steviol was fully degraded by extension of the incubation period.•In anaerobic conditions, the deglycosylation pathway was different.•SG were converted to Monicanone by a specific bacterial consortium.•SG were fully degraded via steviol and Monicanone by a sample of an UASB effluent.
Epilepsy is a neurological disease that affects more than 70 million people worldwide and is characterized by the presence of spontaneous unprovoked recurrent seizures. Existing anti-seizure drugs ...(ASDs) have side effects and fail to control seizures in 30% of patients due to drug resistance. Hence, safer and more efficacious drugs are sorely needed. Flavonoids are polyphenolic structures naturally present in most plants and consumed daily with no adverse effects reported. These structures have shown activity in several seizure and epilepsy animal models through allosteric modulation of GABAA receptors, but also via potent anti-inflammatory action in the brain. As such, dietary flavonoids offer an interesting source for ASD and anti-epileptogenic drug (AED) discovery, but their pharmaceutical potential is often hampered by metabolic instability and low oral bioavailability. It has been argued that their drug-likeness can be improved via methylation of the free hydroxyl groups, thereby dramatically enhancing metabolic stability and membrane transport, facilitating absorption and highly increasing bioavailability. Since no scientific data is available regarding the use of methylated flavonoids in the fight against epilepsy, we studied naringenin (NRG), kaempferol (KFL), and three methylated derivatives, i.e., naringenin 7-O-methyl ether (NRG-M), naringenin 4′,7-dimethyl ether (NRG-DM), and kaempferide (4′-O-methyl kaempferol) (KFD) in the zebrafish pentylenetetrazole (PTZ) seizure model. We demonstrate that the methylated flavanones NRG-DM and NRG-M are highly effective against PTZ-induced seizures in larval zebrafish, whereas NRG and the flavonols KFL and KFD possess only a limited activity. Moreover, we show that NRG-DM is active in two standard acute mouse seizure models, i.e., the timed i.v. PTZ seizure model and the 6-Hz psychomotor seizure model. Based on these results, NRG-DM is proposed as a lead compound that is worth further investigation for the treatment of generalized seizures and drug-resistant focal seizures. Our data therefore highlights the potential of methylated flavonoids in the search for new and improved ASDs.
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•Methylated flavonoids are proposed as a source for anti-seizure drug discovery.•Methylated flavanones are highly active against seizures in zebrafish larvae.•Naringenin 4′,7-dimethyl ether is highly active against seizures in zebrafish larvae.•Naringenin 4′,7-dimethyl ether is active against drug-resistant seizures in mice.•Naringenin 4′,7-dimethyl ether is proposed as a lead anti-seizure compound.
Bacterial trans‐acyltransferase polyketide synthases (trans‐AT PKSs) are modular megaenzymes that employ unusual catalytic domains to assemble diverse bioactive natural products. One such PKS is ...responsible for the biosynthesis of the oximidine anticancer agents, oxime‐substituted benzolactone enamides that inhibit vacuolar H+‐ATPases. Here, we describe the identification of the oximidine gene cluster in Pseudomonas baetica and the characterization of four novel oximidine variants, including a structurally simpler intermediate that retains potent anticancer activity. Using a combination of in vivo, in vitro and computational approaches, we experimentally elucidate the oximidine biosynthetic pathway and reveal an unprecedented mechanism for O‐methyloxime formation. We show that this process involves a specialized monooxygenase and methyltransferase domain and provide insight into their activity, mechanism and specificity. Our findings expand the catalytic capabilities of trans‐AT PKSs and identify potential strategies for the production of novel oximidine analogues.
The anticancer agent oximidine I and three novel variants were discovered as products of a cryptic trans‐AT PKS/NRPS in Pseudomonas baetica. By manipulating the biosynthetic pathway, a key intermediate was identified that retains potent anticancer properties. A combination of bioinformatics analysis and genetic and biochemical experiments illuminated the oximidine biosynthetic pathway, including a novel mechanism for O‐methyloxime formation.
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