Biological Importance Research Articles

Current Advances in Synthesis and Therapeutic Applications of Thiazole and its Derivatives

Thiazole, a five-membered heterocyclic compound with sulfur and nitrogen atoms, serves as a fundamental scaffold in medicinal chemistry. The aromatic nature and diverse substitution patterns of the thiazole ring system enable its extensive applications in drug development. Multiple synthetic routes, from classical Hantzsch synthesis to modern methods, yield varied thiazole derivatives under specific reaction conditions. The biological importance of thiazole-containing compounds extends to anticancer, antimicrobial, and antidepressant activities. Several thiazole-based drugs have demonstrated significant therapeutic effects - dasatinib and dabrafenib as antitumor agents target specific kinases to inhibit cancer cell growth, while ampicillin and myxothiazole exhibit broad-spectrum antimicrobial properties. Structure-activity relationship studies have revealed that substituents at different positions of the thiazole ring significantly influence the biological activity. For instance, attachment of thiourea linker at position 2 enhances anticancer properties, while aryl/alkyl substitutions affect chemical stability and pharmacokinetic properties. The mechanistic understanding of thiazole-based compounds has led to targeted drug development. Recent synthetic methods have produced novel thiazole derivatives with enhanced therapeutic properties, particularly in antimalarial activity where thiazolyl benzenesulfonamide carboxylates show promising results against Plasmodium falciparum

Ethnomedicinal uses, Pharmacological activity, and Analytical aspects of Galuteolin: A Natural Flavonoid of Medicinal Importance

Background: Nature is the best source of all raw materials that we need for growth, development, and better health. Flavonoids are an important class of phytochemicals found to be present in plants and their derived byproducts. Lonicera japonica and its active phytochemicals possess antiviral, anti-endotoxin, anti-pyretic, and blood fat-reducing properties in medicine. Moreover, Galuteolin is a natural flavonoid that has anti-oxidant, anti-tumor, anti-infective, and antiinflammatory potential. Methods: In the present review article, we have collected all scientific information on galuteolin from different scientific databases and analyzed it to know the biological importance and therapeutic benefit of galuteolin in medicine against human disorders. Scientific data on galuteolin were collected from numerous literature databases, such as Google, Google Scholar, PubMed, Scopus and Science Direct. Detailed pharmacological data on galuteolin were collected from these scientific sources and analyzed in the present work to know the health-beneficial aspects of galuteolin in medicine. In addition, scientific data on analytical techniques of galuteolin were also collected and analyzed in the present work to know their importance in the separation, isolation, and identification of galuteolin in different plant materials. Results: The present work signified the biological importance of galuteolin in medicine and other allied health sectors. Pharmacological data analysis revealed the health-beneficial aspects of galuteolin on rheumatoid arthritis, cerebral ischemia, carcinoma, COVID-19, Atherosclerosis, and melanin biosynthesis. Further, intestinal absorption and pharmacokinetic parameters of galuteolin were also discussed in the present work. Analytical data signified the importance of newer and modern analytical techniques in medicine for the qualitative and quantitative analysis of galuteolin in different biological samples. Conclusion: Scientific data analysis of galuteolin revealed its biological importance and therapeutic benefit in medicine.

Hypo-osmolarity promotes naive pluripotency by reshaping cytoskeleton and increasing chromatin accessibility

IntroductionCell fate determination and transition are of paramount importance in biology and medicine. Naive pluripotency could be achieved by reprogramming differentiated cells. However, the mechanism is less clear. Osmolarity is an essential physical factor that acts on living cells, especially for pluripotent cells, but its significance in cell fate transition remains unexplored. ObjectivesTo investigate the role of osmolarity in cell fate transition and its underlying mechanism. MethodsFlow cytometry, quantitative PCR, teratoma and chimeric mice assays were performed to assess reprogramming efficiency and characterize iPSCs. TEM, immunofluorescence staining, western blot, chemical treatment and genetic modification were utilized to evaluate cell morphology, signaling pathways, cytoskeleton and nuclear structure. Multiomic sequencings were applied to unveil the transcriptome, histone markers and chromatin accessibility of EpiSCs in hypo-osmotic condition. ResultIn hypo-osmotic condition, the reprogramming efficiency of hypo-osmotic EpiSCs increased over 60-fold than that of iso-osmotic cells (1100 vs 18 colonies per 3 × 105 cells), whereas no colony formed in hyper-osmotic cells. The converted cells displayed naive pluripotency. The hypo-osmotic EpiSCs exhibited larger cell size, nuclear area and less heterochromatin; ATAC-seq and ChIP-seq confirmed the increased accessibility of naive pluripotent gene loci with more H3K27ac. Mechanistically, hypo-osmolarity activated PI3K-AKT-SP1 signaling in EpiSCs, which reshaped cytoskeleton and nucleoskeleton, resulting in genome reorganization and pluripotent gene expression. In contrast, hypo-osmolarity delayed the ESCs’ exit from naive pluripotency. Moreover, in MEFs reprograming, hypo-osmolarity promoted the conversion to naive pluripotency. ConclusionHypo-osmolarity promotes cell fate transition by remodeling cytoskeleton, nucleoskeleton and genome via PI3K-AKT-SP1 pathway.

Phosphorus Heterocycles and Their Biological Applications

AbstractLife of the living organism is based on phosphorous, and it is involved in almost all important biological and biochemical processes such as energy transfer, bone development and storing genetic information. Many of the therapeutic agents having C─P bond, isolated naturally as well and widely used in daily clinical practices are phosphorus‐containing drugs (e.g: phosphotriesters, phosphonates, phosphinates, phosphine oxides, phosphoric amides, bisphosphonates, phosphoric anhydrides, etc.) and growing further. The phosphorus heterocycles (PHs) integrate the merits of both phosphorus atom and heterocyclic scaffolds representing an important class of organophosphorus compounds, which are constantly drawing the attention among both industrial and scientific society as these compounds have shown varieties of related applications. Owing to its seminal biological importance PHs have inspired a whole generation of medicinal chemists to come up with novel scaffolds containing phosphorous atom. This review is focused mainly on the compilation of different classes of bioactive phosphorus containing heterocyclic skeletons (which includes phosphorus atom within the heterocyclic ring system or as substituted phosphorus atom attached with another heterocyclic ring system) having both therapeutic and other material chemistry applications since the year 2000 onwards barring their synthetic routes.

Computational Studies and Antimicrobial Activity of 1-(benzo[d]oxazol-2- yl)-3,5-diphenylformazan Derivatives.

Due to the biological importance of the benzoxazole derivatives, some 1- (benzo[d]oxazol-2-yl)-3,5-diphenyl-formazans 4a-f were synthesized and screened for in-silico studies and in-vitro antibacterial activity. The benzo[d]oxazole-2-thiol (1) was prepared by reacting with 2-aminophenol and carbon disulfide in the presence of alcoholic potassium hydroxide. Then 2-hydrazinylbenzo[d] oxazole (2) was synthesized from the reaction of compound 1 with hydrazine hydrate in the presence of alcohol. Compound 2 was reacted with aromatic aldehydes to give Schiff base, 2-(2- benzylidene-hydrazinyl)benzo[d]oxazole derivatives 3a-f. The title compounds, formazan derivatives 4a-f, were prepared by a reaction of benzene diazonium chloride. All compounds were confirmed by their physical data, FTIR, 1H-NMR, and 13CNMR spectral data. All the prepared title compounds were screened for in-silico studies and in-vitro antibacterial activity on various microbial strains. Molecular docking against the 4URO receptor demonstrated that molecule 4c showed a maximum dock score of (-) 8.0 kcal/mol. MD simulation data reflected the stable ligand-receptor interaction. As per MM/PBSA analysis, the maximum free binding energy of (-) 58.831 kJ/mol was exhibited by 4c. DFT calculation data confirmed that most of the molecules were soft molecules with electrophilic nature. The synthesized molecules were validated using molecular docking, MD simulation, MMPBSA analysis, and DFT calculation. Among all the molecules, 4c showed maximum activity. The activity profile of the synthesized molecules against tested micro-organisms was found to be 4c>4b>4a>4e>4f>4d.

Theory of epigenetic switching due to stochastic histone mark loss during DNA replication

How much information does a cell inherit from its ancestors beyond its genetic sequence? What are the epigenetic mechanisms that allow this? Despite the rise in available epigenetic data, how such information is inherited through the cell cycle is still not fully understood. Often, epigenetic marks can display bistable behaviour and their bistable state is transmitted to daughter cells through the cell cycle, providing the cell with a form of memory. However, loss-of-memory events also take place, where a daughter cell switches epigenetic state (with respect to the mother cell). Here, we develop a framework to compute these epigenetic switching rates, for the case when they are driven by DNA replication, i.e. the frequency of loss-of-memory events due to replication. We consider the dynamics of histone modifications during the cell cycle deterministically, except at DNA replication, where nucleosomes are randomly distributed between the two daughter DNA strands, which is therefore implemented stochastically. This hybrid stochastic-deterministic approach enables an analytic derivation of the replication-driven switching rate. While retaining great simplicity, this framework can explain experimental switching rate data, establishing its biological importance as a framework to quantitatively study epigenetic inheritance.

A Bioinspired Cu2+-Responsive Magnetic Resonance Imaging Contrast Agent with Unprecedented Turn-On Response and Selectivity.

Imaging extracellular Cu2+ in vivo is of paramount interest due to its biological importance in both physiological and pathological states. Magnetic resonance imaging (MRI) is a powerful technique to do so. However, the development of efficient MRI contrast agents selective for Cu2+, particularly versus the more abundant Zn2+ ions, is highly challenging. We present here an innovative Cu2+-responsive MRI contrast agent that contains a bioinspired Cu2+ binding site. This sensor shows a remarkable increase in relaxivity of nearly 400% in the presence of Cu2+, which could be rationalized in terms of an increase in the hydration number of the Ln3+ ion, as demonstrated by spectroscopic and relaxometric studies and supported by density functional theory calculations. Importantly, the system also shows an unprecedented selectivity for Cu2+, in particular over Zn2+. Phantom MRI images were recorded at 9.4 T to highlight the potential of such probes, which lies directly in their bioinspired design.

UniBioPAN: A Novel Universal Classification Architecture for Bioactive Peptides Inspired by Video Action Recognition.

The classification of bioactive peptides is of great importance in protein biology, but there is still a lack of a universal and effective classifier. Inspired by video action recognition, we developed the UniBioPAN architecture to create a universal peptide classifier to solve this problem. The architecture treats the peptide sequence as a video sequence and the molecular image of each amino acid in the peptide sequence as a video frame, enabling feature extraction and classification using convolutional neural networks, bidirectional long short-term memory networks, and fully connected networks. As a novel peptide classification architecture, UniBioPAN significantly outperforms other universal architecture in ACC, AUC and MCC across 11 data sets, and F1 score in 9 data sets. UniBioPAN is available in three ways: python script, jupyter notebook script and web server (https://gzliang.cqu.edu.cn/software/UniBioPAN.html). In summary, UniBioPAN is a universal, convenient, and high-performance peptide classification architecture. UniBioPAN holds significant importance in the discovery of bioactive peptides and the advancement of peptide classifiers. All the codes and data sets are publicly available at https://github.com/sanwrh/UniBioPAN.

Striking Departures from Polygenic Architecture in the Tails of Complex Traits.

Understanding the genetic architecture of human traits is of key biological, medical and evolutionary importance[1]. Despite much progress, little is known about how genetic architecture varies across the trait continuum and, in particular, if it differs in the tails of complex traits, where disease often occurs. Here, applying a novel approach based on polygenic scores, we reveal striking departures from polygenic architecture across 148 quantitative trait tails, consistent with distinct concentrations of high-impact rare alleles in one or both tails of most of the traits. We demonstrate replication of these results across ancestries, cohorts, repeat measures, and using an orthogonal family-based approach[2]. Furthermore, trait tails with inferred enrichment of rare alleles are associated with more exome study hits, reduced fecundity, advanced paternal age, and lower predictive accuracy of polygenic scores. Finally, we find evidence of ongoing selection consistent with the observed departures in polygenicity and demonstrate, via simulation, that traits under stabilising selection are expected to have tails enriched for rare, large-effect alleles. Overall, our findings suggest that while common variants of small effect likely account for most of the heritability in complex traits[3], rare variants of large effect are often more important in the trait tails, particularly among individuals at highest risk of disease. Our study has implications for rare variant discovery, the utility of polygenic scores, the study of selection in humans, and for the relative importance of common and rare variants to complex traits and diseases.

Evaluation of the antitrypanosomal activity, cytotoxicity and phytochemistry of red Brazilian propolis.

Recently, the growth in the consumption of functional foods with potential nutritional and health benefits revealed rapid progress in phytochemical analysis to assure quality and profile the chemical composition. Bee propolis, a gummy exudate produced in beehives after harvesting from different plant species and showed to contain bioactive secondary metabolites with biological importance. The main goal of the current study is to profile the chemical composition of red propolis samples from the Brazilian stingless bee Tetragonula biroi for the first time using HPLC-UV-ELSD and NMR analysis for assignment of the abundant metabolites' classes as well as extraction and isolation of the major compounds. Column chromatography and size exclusion chromatography were applied for the purification of the major compounds in red Brazilian propolis. Further, testing the antitrypanosomal and cytotoxic activities against Trypanosoma brucei and human leukemia cell lines (U937) was performed. A total of 29 secondary metabolites were identified as two anthocyanins, 6 flavonoids, 8 isoflavonoids, 10 phenolics, two phenolic acids, and one triterpenoid. Two phenolic compounds were purified and identified using 1D and 2D NMR analysis along with MS analysis as liquiritigenin and calycosin. Red Brazilian propolis FB-3 fraction showed the highest inhibitory activity against T. brucei at 1.6 μg/ml, compared to 12.4 μg/ml of the crude extract. The isolated compounds showed moderate activity with an MIC of 8.5 μg/ml for liquiritigenin and 8.7 μg/ml for calycosin. Moreover, FB-3 fraction and calycosin were showed the potent cytotoxic effect with IC50 = 45.1 and 35.8μg/ml, respectively compared to IC50 = 29.5 μg/ml of the standard diminazen. Hence, red Brazilian propolis is rich source of polyphenols with myriad biological importance. Propolis fractions and purified compounds showed moderate antiprotozoal activity and potent cytotoxic activity against human leukemia cell lines.

Biological Importance of Complex Sphingolipids and Their Structural Diversity in Budding Yeast Saccharomyces cerevisiae.

Complex sphingolipids are components of eukaryotic biomembranes and are involved in various physiological functions. In addition, their synthetic intermediates and metabolites, such as ceramide, sphingoid long-chain base, and sphingoid long-chain base 1-phosphate, play important roles as signaling molecules that regulate intracellular signal transduction systems. Complex sphingolipids have a large number of structural variations, and this structural diversity is considered an important molecular basis for their various physiological functions. The budding yeast Saccharomyces cerevisiae has simpler structural variations in complex sphingolipids compared to mammals and is, therefore, a useful model organism for elucidating the physiological significance of this structural diversity. In this review, we focus on the structure and function of complex sphingolipids in S. cerevisiae and summarize the response mechanisms of S. cerevisiae to metabolic abnormalities in complex sphingolipids.

Length and Sequence-Selective Polymer Synthesis Templated by a Combination of Covalent and Noncovalent Base-Pairing Interactions.

Information can be encoded and stored in sequences of monomer units organized in linear synthetic polymers. Replication of sequence information is of fundamental importance in biology; however, it represents a challenge for synthetic polymer chemistry. A combination of covalent and noncovalent base pairs has been used to achieve high-fidelity templated synthesis of synthetic polymers that encode information as a sequence of different side-chain recognition units. Dialkyne building blocks were attached to the template by using ester base pairs, and diazide building blocks were attached to the template by using H-bond base pairs. Copper-catalyzed azide-alkyne cycloaddition reactions were used to zip up the copy strand on the template, and the resulting duplex was cleaved by hydrolyzing the covalent ester base pairs. By using recognition-encoded melamine oligomers with either three phosphine oxide or three 4-nitrophenol recognition units to form the noncovalent base pairs, exceptionally high affinities of the diazides for the template were achieved, allowing the templated polymerization step to be carried out at low concentrations, which promoted on-template intramolecular reactions relative to competing intermolecular processes. Two different templates, a 7-mer and an 11-mer, were used in the three-step reaction sequence to obtain the sequence-complementary copy strands with minimal amounts of side reaction.

The Two Sides of Indoleamine 2,3-Dioxygenase 2 (IDO2).

Indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 originated from gene duplication before vertebrate divergence. While IDO1 has a well-defined role in immune regulation, the biological role of IDO2 remains unclear. Discovered in 2007, IDO2 is located near the IDO1 gene. Because of their high sequence similarity, IDO2 was initially thought to be a tryptophan (Trp)-degrading enzyme like IDO1. Differently from what expected, IDO2 displays extremely low catalytic activity toward Trp. Nevertheless, many studies, often contradictory, have tried to demonstrate that IDO2 modulates immune responses by catabolizing Trp into kynurenine, an unconvincing hypothesis linked to an incomplete understanding of IDO2's activity. In this study, we review IDO2's functional role beyond Trp metabolism. IDO2's evolutionary persistence across species, despite being almost inactive as an enzyme, suggests it has some relevant biological importance. IDO2 expression in human normal cells is poor, but significant in various cancers, with two prevalent SNPs. Overall, the comparison of IDO2 to IDO1 as a Trp-degrading enzyme may have led to misunderstandings about IDO2's true physiological and pathological roles. New insights suggest that IDO2 might function more as a signaling molecule, particularly in cancer contexts, and further studies could reveal its potential as a target for cancer therapy.

Biological importance and environmental quality of the Laguna Santa Ana in Zacatecas, Mexico

Objective: To determine the environmental quality and diversity of the waterfowl species of the Laguna Santa Ana, located in the municipality of Fresnillo, Zacatecas. Design/Methodology/Approach: A physicochemical analysis of the water was carried out to determine its organic matter pollution. In addition, the Bradford method was applied to establish protein levels, and an optical emission spectrometry was conducted to detect heavy metals. The Shannon-Weiner diversity index (H’) was carried out to identify and count the populations of the lagoon. Results: The physicochemical analysis of water recorded 55 and 230.6 mg/L BOD5 and COD, respectively. High protein levels (0.27-2.95 mL/mL) indicated organic pollution and high arsenic levels. The Shannon-Weiner index (2.7) recorded a high waterfowl diversity. Study Limitations/Implications: Biological abundance was not determined, as a result of the sample size. The changes regarding waterfowl diversity may be the consequence of the seasonal conditions. Findings/Conclusions: The Laguna de Santa Ana has a high waterfowl diversity, including species of international interest; however, organic pollution has caused a a significant environmental deterioration.

A long straight square microchannel in viscoelastic fluid for focusing submicron-sized particles and bacteria.

Aviscoelastic flow focusing device is presentedthat enables simple and robust focusing of submicron-sized particles in the channel center by optimizing operating conditions such as channel length, flow rate and poly(ethylene oxide) (PEO) concentration. Submicron-sized particles (up to 100nm) can be easily focused to the channel center under viscoelastic fluid flow without any external force via a simply fabricated microchannel with a long channel length and a large square cross-section. The device was fabricated using a common soft lithography technique for the polydimethylsiloxane (PDMS) channel, which has a width of 50μm, a height of 50μm and a channel length of 27cm. The extralong channel enabled submicron-sized particle focusing, even in a channel of a relatively large size with high flow rate, which can realize flow cytometric applications. The focusing performance was first demonstrated using submicron-sized polystyrene (PS) beads ranging from 870nm to 50nm and then using biological particles such as E. coli bacteria to demonstrate the biological feasibility of the device. The PS beads, which ranged in diameter from 870nm to 100nm, were focused to the center of the channel, achieving over 90% focusing efficiency for beads as small as 510nm and 62% focusing efficiency for 100-nm beads. The device could also align a bacterial suspension in the center of the channel at flow rates up to 30 µL/min, demonstrating its biological importance. The ability of the developed device to align submicron-sized particles within a narrow flow stream in a highly robust manner is promising for various biological and clinical applications, such as distinguishing pathogenic bacteria and evaluating individual antibiotic responses in a single experiment.

Evaluation of ploidy and the DNA index by flow cytometry in central nervous system tumors: a review.

Research on central nervous system tumors (CNSTs) has a significant impact on the diagnosis and prognosis of patients. Currently, CNSTs are classified according to the schema proposed by the World Health Organization (WHO), which considers clinical, histopathological, and molecular characteristics, highlighting the importance of tumor biology for accurate diagnosis and optimal treatment approaches. Despite these advances, assessing DNA ploidy-a marker of tumor aggressiveness-remains complex in CNSTs. This review investigates the utility of DNA index (DNAi) and DNA ploidy analysis by flow cytometry in diagnosing CNSTs and prognosing their outcomes. We systematically reviewed studies in the PubMed database from 1990 to the present using the keywords "DNA Index", "Brain", "Flow cytometry", and "Ploidy". We identified 151 studies, 36 of which met our inclusion criteria. We found considerable variation in sample sizes and methodological variation across the studies. Discrepancies between the reported DNAi and ploidy values were observed. Aneuploidy is generally associated with more aggressive tumors, although exceptions exist. Higher DNAi levels correlate with increased malignancy, notably in glioblastomas, astrocytomas, and meningiomas, whereas diploid astrocytomas and oligodendrogliomas are associated with shorter survival rates. DNA ploidy assessment via flow cytometry could predict CNST behavior, yet methodological issues with tissue selection, adequate control samples, and technique variability remain. DNAi and ploidy assessments show promise as prognostic markers in CNSTs. However, the standardization of flow cytometry protocols and alignment with the current WHO classification schema are essential steps to integrate ploidy analysis in routine CNST assessment.

Machine learning unveils key Redox signatures for enhanced breast Cancer therapy

BackgroundBreast cancer remains a leading cause of mortality among women worldwide, necessitating innovative prognostic models to enhance treatment strategies.MethodsOur study retrospectively enrolled 9,439 breast cancer patients from 12 independent datasets and single-cell data from 12 patients (64,308 cells). Moverover, 30 in-house clinical cohort were collected for validation. We employed a comprehensive approach by combining ten distinct machine learning algorithms across 108 different combinations to scrutinize 88 pre-existing signatures of breast cancer. To affirm the efficacy of our developed model, immunohistochemistry assays were performed. Additionally, we investigated various potential immunotherapeutic and chemotherapeutic interventions.ResultsThis study introduces an Artificial Intelligence-aided Redox Signature (AIARS) as a novel prognostic tool, leveraging machine learning to identify critical redox-related gene signatures in breast cancer. Our results demonstrate that AIARS significantly outperforms existing prognostic models in predicting breast cancer outcomes, offering a robust tool for personalized treatment planning. Validation through immunohistochemistry assays on samples from 30 patients corroborated our results, underscoring the model’s applicability on a wider scale. Furthermore, the analysis revealed that patients with low AIARS expression levels are more responsive to immunotherapy. Conversely, those exhibiting high AIARS were found to be more susceptible to certain chemotherapeutic agents, including vincristine.ConclusionsOur study underscores the importance of redox biology in breast cancer prognosis and introduces a powerful machine learning-based tool, the AIARS, for personalized treatment strategies. By providing a more nuanced understanding of the redox landscape in breast cancer, the AIARS paves the way for the development of redox-targeted therapies, promising to enhance patient outcomes significantly. Future work will focus on clinical validation and exploring the mechanistic roles of identified genes in cancer biology.

Understanding complex systems through differential causal networks

In the evolving landscape of data science and computational biology, Causal Networks (CNs) have emerged as a robust framework for modelling causal relationships among elements of complex systems derived from experimental data. CNs can efficiently model causal relationships emerging in a single system while comparing multiple systems, allowing to understand rewiring in different cells, tissues, and physiological states with a deeper perspective. Despite the existence of network models, namely differential networks, that have been used to compare coexpression and correlation structures, causality needs to be introduced in differential analysis to robustly provide direction to the edges of such networks, in order to better understand the flows of information, and also to better intervene in their functioning, for example for agricultural or pharmacological purposes. Resolved to reach this ambitious goal, we introduce Differential Causal Networks (DCNs), a novel framework that represents differences between two existing CNs. A DCN is obtained from experimental data by comparing two CNs, and it is a power tool for highlighting differences in causal relations. After a careful definition and design of DCNs, we test our algorithm to model possible differential causal relationships between genes responsible for the onset of type 2 diabetes mellitus-related pathologies considering patients’ sex at the tissue level. DCNs allowed us to shed light on causal differences between sexes across nine tissues. We also compare differences among three possible definitions of DCNs to highlight similarities and differences of biological importance. Code, Data and Supplementary Information are available at https://github.com/hguzzi/DifferentialCausalNetworks.

Exploring Bioactive Fungal RiPPs: Advances, Challenges, and Future Prospects.

Fungal ribosomally synthesized and post-translationally modified peptides (RiPPs) are a vital class of natural products known for their biological activities including anticancer, antitubulin, antinematode, and immunosuppressant properties. These bioactive fungal RiPPs play key roles in chemical ecology and have a significant therapeutic potential. Their structural diversity, which arises from intricate post-translational modifications of precursor peptides, is particularly remarkable. Despite their biological and ecological importance, the discovery of fungal RiPPs has been historically challenging and only a limited number have been identified. To date, known fungal RiPPs are primarily grouped into three groups: cycloamanides and borosins from basidiomycetes and dikaritins from ascomycetes. Recent advancements in bioinformatics have revealed the vast untapped potential of fungi to produce RiPPs, offering new opportunities for their discovery. This review highlights recent progress in fungal RiPP biosynthesis and genome-guided discovery strategies. We propose that combining the knowledge of fungal RiPP biosynthetic pathways with advanced gene-editing technologies and bioinformatic tools will significantly accelerate the discovery of novel bioactive fungal RiPPs.

Reaction Kinetics of the Benzylation of Adenine in DMSO: Regio-Selectivity Guided by Entropy.

The factors governing the regio-selectivity of the alkylation of adenine have been of interest for many years due to the biological importance of adenine derivatives, however, no reaction kinetic studies have been conducted. Herein, we report the rate constants and activation parameters of the benzylation of adenine under basic conditions in DMSO in the absence and presence of 15-crown-5 ether using real-time 1H NMR spectroscopy. The reaction is second-order for the formation of the N9- and N3-benzyladenine products, with a regio-selectivity factor 2.3 in favour of the N9-adduct. The Gibbs free energy of activation amounts to 87±2 kJ mol-1 for both reactions. The formation of the N9-adduct is more activated by 7 kJ mol-1, but its effect is offset by a less negative activation entropy, demonstrating that the long-contested reason for the regioselectivity in the benzylation of adenine is dominated by compensation of entropy and enthalpy in the transition state. The kinetic parameters obtained in the presence of the 15-crown-5 ether indicate that the crown ether forms a complex with an adenine-sodium ion-pair, increasing the activation barrier. However, the Gibbs free energy in the absence and presence of the crown ether remains constant.