Prenylated Compounds Research Articles

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to β-Amyloid Peptide Monomer.

A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer’s disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aβ42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aβ42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aβ42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aβ42 active site and provide useful information that could benefit the development of new Aβ42 accumulation inhibitors.

Prenylated phenolics as promising candidates for combination antibacterial therapy: Morusin and kuwanon G

Combination of antibiotics with natural products is a promising strategy for potentiating antibiotic activity and overcoming antibiotic resistance. The purpose of the present study was to investigate whether morusin and kuwanon G, prenylated phenolics in Morus species, have the ability to enhance antibiotic activity and reverse antibiotic resistance in Staphylococcus aureus and Staphylococcus epidermidis. Commonly used antibiotics (oxacillin, erythromycin, gentamicin, ciprofloxacin, tetracycline, clindamycin) were selected for the combination studies. Checkerboard and time-kill assays were used to investigate potential bacteriostatic and bactericidal synergistic interactions, respectively between morusin or kuwanon G and antibiotics. According to both fractional inhibitory concentration index and response surface models, twenty combinations (14 morusin-antibiotic combinations, six kuwanon G-antibiotic combinations) displaying bacteriostatic synergy were identified, with 4–512-fold reduction in the minimum inhibitory concentration values of antibiotics in combination. Both morusin and kuwanon G reversed oxacillin resistance of methicillin-resistant Staphylococcus aureus. In addition, morusin reversed tetracycline resistance of Staphylococcus epidermidis. At half of the minimum inhibitory concentrations, combinations of morusin with oxacillin or gentamicin showed bactericidal synergy against methicillin-resistant Staphylococcus aureus. Fluorescence and differential interference contrast microscopy and scanning electron microscopy showed an increase in the membrane permeability and massive leakage of cellular content in methicillin-resistant Staphylococcus aureus exposed to morusin or kuwanon G. Overall, our findings strongly indicate that both prenylated compounds are good candidates for the development of novel antibacterial combination therapies.

Multi-Target Anti-Alzheimer Activities of Four Prenylated Compounds from Psoralea Fructus.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is mediated by multiple signaling pathways. In recent years, the components of Psoralea Fructus (PF) have demonstrated some anti-Alzheimer effects both in vitro and in vivo. To further reveal the active compounds of PF and their mechanisms regulating key targets of AD, in this study, we identified four prenylated compounds from the 70% ethanolic aqueous extract of PF, namely bavachin, bavachinin, bavachalcone, and isobavachalcone. Multi-target bioactivity analysis showed that these compounds could differentially inhibit neuroinflammation, oxidative damage, and key AD-related protein targets, such as amyloid β-peptide 42, β-secretase, glycogen synthase kinase 3β, and acetylcholinesterase. These compounds may generate beneficial effects in AD prevention and treatment.

Rapid membrane permeabilization of Listeria monocytogenes and Escherichia coli induced by antibacterial prenylated phenolic compounds from legumes

Prenylated phenolics from the Fabaceae are promising lead compounds for new antibacterials. Pools enriched in prenylated phenolics were made from lupine, peanut and soybean seedlings. One pool was rich in chain prenylated isoflavones (cIsf), one in chain prenylated stilbenoids (cSti), one in chain prenylated (cPta) and one in ring-closed prenylated pterocarpans (rPta), as characterized by RP-UHPLC-UV-MS. Antibacterial activity of the pools and membrane permeabilization was investigated. Pools showed high antibacterial activity against Listeria monocytogenes: cIsf pool had a minimum inhibitory concentration of 10µg/ml prenylated compounds, followed by cPta pool (25µg/ml) and cSti pool (35µg/ml). Activity against E. coli was found only when the pools were co-administered with an efflux pump inhibitor. The pool enriched in chain prenylated isoflavones permeabilized the bacterial membrane within minutes of exposure, whereas ampicillin did not. Bent conformation and chain prenylation, were molecular features of main prenylated phenolics found in pools with high antibacterial activity.

New anti-trypanosomal active prenylated compounds from African propolis

The secondary metabolite composition of propolis has always been corroborated on the vegetation surrounding the bee hive. The plants chosen by the bees seem to exhibit activity to protect the hive from the surrounding environmental pressures which include protozoal attack. Two new stilbene compounds were isolated from Ghanian propolis which were formed either via geranylation or prenylation. These compounds exhibited moderate activity against Trypanosoma brucei brucei. While a new phlorogucinonone analogue was isolated from a Cameroon propolis that was found to possess high potency comparable to that of suramin.

Negative ion tandem mass spectrometry of prenylated fungal metabolites and their derivatives

Liquid chromatography negative ion electrospray ionisation tandem mass spectrometry has been used for characterisation of naturally occurring prenylated fungal metabolites and synthetic derivatives. The fragmentation studies allow an elucidation of the decomposition pathways for these compounds. It could be shown, that the prenyl side chain is degraded by successive radical losses of C(5) units. Both the benzoquinones and the phenolic derivatives display significant key ions comprising the aromatic ring. In some cases, the formation of significant oxygen-free key ions could be evidenced by high-resolution MS/MS measurements. Furthermore, the different types of basic skeletons, benzoquinones and phenol type as well as cyclic prenylated compounds, can be differentiated by their MS/MS behaviour. Figure Fruiting bodies of Suillus bovinus, the structure of boviquinone-4 and its negative ion MS2 spectrum.

Potential defense-related prenylated isoflavones in lactofen-induced soybean

An integrated LC-MS and NMR metabolomic study was conducted to investigate metabolites whose formation was induced by lactofen ( 1), a soybean ( Glycine max L.) disease resistance-inducing herbicide. First, LC-MS analyses of control and lactofen ( 1)-induced soybean extracts were performed. The LC-MS raw data were then processed by a custom designed bioinformatics program to detect the induced metabolites so formed. Finally, structures of unknown induced metabolites were determined on the basis of their 1D and 2D NMR spectroscopic data. Structure of two previously unreported compounds, 7,8-dihydroxy-4′-methoxy-3′-prenylisoflavone ( 2) and 7-hydroxy-4′,8-dimethoxy-3′-prenylisoflavone ( 3) were elucidated together with four known prenylated compounds, 3′-prenyldaidzein ( 4), 8-prenyldaidzein ( 5), 3′-prenylgenistein ( 6), and 4-prenylcoumestrol ( 7). Compounds ( 2– 6) are reported for the first time in soybean, as are the 13C chemical shift assignments for compound ( 7). Formation of these six prenylated compounds was also induced by the primary defense glucan elicitor from the cell wall of the pathogen Phytophthora sojae (Kauf. and Gerde.), further suggesting a potential role in soybean defense. These results highlight the metabolic flexibility within soybean secondary product pathways and suggest that prenylation may be associated with defense responses. Moreover, this study demonstrates a promising future approach using metabolomics on elicitor-induced plants for discovery of unknown compounds even in relatively well studied plants.

Mild RIP — an alternative method for in vivo mutagenesis of thealbino-3 gene inNeurospora crassa

We have used a biological phenomenon that occurs in Neurospora crassa, termed Repeat-Induced Point mutation (RIP), to create partially functional mutant alleles of the albino-3 (al-3) gene encoding geranylgeranyl pyrophosphate synthase, an enzyme involved in the biosynthesis of carotenoids and diverse prenylated compounds. A total of 70 RIP-induced al-3 mutants were identified by their pale albino phenotype, resulting from inactivation of carotenoid bio-synthesis. Nucleotide sequence analysis of the al-3 gene in five of the RIP-induced mutants revealed that in each case RIP had introduced no more than six point mutations. The low frequency of RIP mutants (0.42%) and the isolation of only leaky mutants with very few mutations suggest that ascospores containing a heavily mutated al-3 gene do not survive. These results are evidence that the RIP phenomenon, used to inactivate and silence duplicated genes in N. crassa, may be exploited in its mild version as a method of sequence-specific in vivo mutagenesis to obtain functional mutant alleles of Neurospora genes. This mild form of mutagenesis may be particularly advantageous in selecting for leaky mutations in essential Neurospora genes.