Synthesis of Novel Pyran Fragments to Incorporate into Peloruside Analogues

<p>Cancer is currently the second largest cause of death globally, leading to a high demand for new and effective chemotherapeutics. For years, natural products have been used as a source of new bioactive compounds; of particular interest in this context, as a source of new chemotherapeutics. One chemotherapeutic candidate which has attracted significant attention in synthetic and medicinal chemistry communities, is peloruside A. Peloruside A is a bioactive secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli. Since its discovery, peloruside A has shown great promise in cancer studies both in vivo and in vitro with effects observed even at nanomolar concentrations. These chemotherapeutic effects have been shown to occur by halting cell division at the G2/M checkpoint via microtubule stabilisation. Of particular interest is that this stabilisation occurs in a manner distinct from that of the already established taxane class of microtubule stabilising drugs. This means that peloruside A is able to offer both inhibition of cell division in Taxol® resistant cells and synergistic inhibition alongside the current taxane drugs. Since peloruside A is not abundantly available from its natural source, there is a strong incentive for the development of new synthetic strategies for peloruside A production. Unfortunately attempts at aquaculture and attempts at developing an industrial scale synthesis have both proven unsuccessful thus far. In an attempt to overcome some of the difficulties with the scale up of peloruside, analogues have been developed that are intended to have similar bioactivity to peloruside A but simpler, more concise, synthetic routes. These analogues will also enable further elucidation of the binding properties of peloruside A. This project focuses on the generation of a functionalised pyran fragment, starting from a simple carbohydrate, that may be incorporated into the proposed analogues.</p>

Synthesis of Novel Pyran Fragments to Incorporate into Peloruside Analogues

<p>Cancer is currently the second largest cause of death globally, leading to a high demand for new and effective chemotherapeutics. For years, natural products have been used as a source of new bioactive compounds; of particular interest in this context, as a source of new chemotherapeutics. One chemotherapeutic candidate which has attracted significant attention in synthetic and medicinal chemistry communities, is peloruside A. Peloruside A is a bioactive secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli. Since its discovery, peloruside A has shown great promise in cancer studies both in vivo and in vitro with effects observed even at nanomolar concentrations. These chemotherapeutic effects have been shown to occur by halting cell division at the G2/M checkpoint via microtubule stabilisation. Of particular interest is that this stabilisation occurs in a manner distinct from that of the already established taxane class of microtubule stabilising drugs. This means that peloruside A is able to offer both inhibition of cell division in Taxol® resistant cells and synergistic inhibition alongside the current taxane drugs. Since peloruside A is not abundantly available from its natural source, there is a strong incentive for the development of new synthetic strategies for peloruside A production. Unfortunately attempts at aquaculture and attempts at developing an industrial scale synthesis have both proven unsuccessful thus far. In an attempt to overcome some of the difficulties with the scale up of peloruside, analogues have been developed that are intended to have similar bioactivity to peloruside A but simpler, more concise, synthetic routes. These analogues will also enable further elucidation of the binding properties of peloruside A. This project focuses on the generation of a functionalised pyran fragment, starting from a simple carbohydrate, that may be incorporated into the proposed analogues.</p>

In-silico ADMET predicated Pharmacoinformatics of Quercetin-3-Galactoside, polyphenolic compound from Azadirachta indica, a sacred tree from Hill Temple in Alagarkovil Reserve Forest, Eastern Ghats, INDIA

Quercetin (3,3′,4′,5,7-Pentahydroxyflavone) is the one among the bioactive secondary metabolite (BASM) in neem seed of Azadirachta indica A. Juss. Quercetin (Que) and its derivatives hold promising pharmacological effects. Antidiabetic, anti-inflammatory, antioxidant, antimicrobial, anti-Alzheimer’s, antiarthritic, cardiovascular, and wound-healing effects of Que have been extensively investigated, recently lot of work has been carried out on its anticancer activity against different cancer cell lines. Recently, in silico/ in vitro studies have demonstrated that Que interferes with different stages of coronavirus entry and replication cycle (PLpro, 3CLpro, and NTPase/helicase). Due to its pleiotropic effects in human health and disease and lack of systemic toxicity, Que and its derivatives could be tested for their efficacy on human target system in future clinical trials. In the present study, an attempt has been made to evaluate the physicochemical, druggable properties of Que from A. indica to prospect its ADMET properties. Keywords: NEEM; Azadirachta indica; Quercetin; Pharmacoinformatics; ADMET; Drug-Likeness; Toxicology

Evaluation of the Antibacterial Activity of Crude Extracts Obtained From Cultivation of Native Endophytic Fungi Belonging to a Tropical Montane Rainforest in Colombia

Bioactive secondary metabolite production from endophytic fungi has gained a recurring research focus in recent decades as these microorganisms represent an unexplored biological niche for their diverse biotechnological potential. Despite this focus, studies involving tropical endophytes remain scarce, particularly those isolated from medicinal plants of these ecosystems. In addition, the state of the art of the pharmaceutical industry has experienced stagnation in the past 30years, which has pushed pathogenic infections to get one step ahead, resulting in the development of resistance to existing treatments. Here, five fungal endophytes were isolated from the medicinal plant Otoba gracilipes (Myristicaceae), which corresponded to the genera Xylaria and Diaporthe, and screened to demonstrate the promissory potential of these microorganisms for producing bioactive secondary metabolites with broad-spectrum antibacterial activities. Thus, the evaluation of crude organic extracts obtained from the mycelia and exhaust medium allowed the elucidation of Xylaria sp. and Diaporthe endophytica potential toward providing crude extracellular extracts with promising bioactivities against reference strains of Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 25923), according to the determined half-maximum inhibitory concentration (IC50) with values down to 3.91 and 10.50mg/ml against each pathogen, respectively. Follow-up studies provided insights into the polarity nature of bioactive compounds in the crude extracts through bioactivity guided fractionation using a polymeric resin absorbent alternative extraction procedure. In addition, evaluation of the co-culturing methods demonstrated how this strategy can enhance endophytes biosynthetic capacity and improve their antibacterial potential with a 10-fold decrease in the IC50 values against both pathogens compared to the obtained values in the preliminary evaluations of Xylaria sp. and D. endophytica crude extracts. These results support the potential of Colombian native biodiversity to provide new approaches concerning the global emergence of antibiotics resistance and future production of undiscovered compounds different from the currently used antibiotics classes and simultaneously call for the value of preserving native habitats due to their promising ecosystemic applications in the biotechnological and pharmaceutical industries.

Physicochemical, Druggable, ADMET Pharmacoinformatics and Therapeutic Potentials of Azadirachtin - a Prenol Lipid (Triterpenoid) from Seed Oil Extracts of Azadirachta indica A. Juss.

Azadirachtin (AZA) is the most abundant bioactive secondary metabolite (BASM) in neem seed oil extract (NSOE) of Azadirachta indica A. Juss. AZA is localised in different parts of the plant (seeds, fruits, flowers, leaves, stem, bark and root) however, with varying degree of concentration. It has been documented that maximum concentration of AZA is present to the tune of 48000 μg g-1 in the seeds. It has been established that the environmental conditions determines the overall content and composition of BASM in different parts of the plant. Neem plant parts are most commonly used as therapeutic agents in remote villages in India for its ethnomedicinal therapeutic potentials; however, its physicochemical, druggable and pharmacological properties inadequately described. In the present study an attempt has been made to evaluate the physicochemical, druggable and pharmacological properties of Azadirachtin in NSOE of A. indica from ADMET perspectives. Keywords: NEEM; Azadirachta indica; Azadirachtin; Pharmacoinformatics; ADMET; Drug-Likeness; Toxicology

Quercetin: A Bioactive Compound Imparting Cardiovascular and Neuroprotective Benefits: Scope for Exploring Fresh Produce, Their Wastes, and By-Products

Quercetin, a bioactive secondary metabolite, holds incredible importance in terms of bioactivities, which has been proved by in vivo and in vitro studies. The treatment of cardiovascular and neurological diseases by quercetin has been extensively investigated over the past decade. Quercetin is present naturally in appreciable amounts in fresh produce (fruits and vegetables). However, today, corresponding to the growing population and global demand for fresh fruits and vegetables, a paradigm shift and focus is laid towards exploring industrial food wastes and/or byproducts as a new resource to obtain bioactive compounds such as quercetin. Based on the available research reports over the last decade, quercetin has been suggested as a reliable therapeutic candidate for either treating or alleviating health issues, mainly those of cardiovascular and neurological diseases. In the present review, we have summarized some of the critical findings and hypotheses of quercetin from the available databases foreseeing its future use as a potential therapeutic agent to treat cardiovascular and neurological diseases. It is anticipated that this review will be a potential reference material for future research activities to be undertaken on quercetin obtained from fresh produce as well as their respective processing wastes/byproducts that rely on the circular concept.

Growth inhibition of Spodoptera frugiperda larvae by camptothecin correlates with alteration of the structures and gene expression profiles of the midgut

Background Spodoptera frugiperda is a serious pest that causes devastating losses to many major crops, including corn, rice, sugarcane, and peanut. Camptothecin (CPT) is a bioactive secondary metabolite of the woody plant Camptotheca acuminata, which has shown high toxicity to various pests. However, the effect of CPT against S. frugiperda remains unknown. Results In this study, bioassays have been conducted on the growth inhibition of CPT on S. frugiperda larvae. Histological and cytological changes were examined in the midgut of larvae fed on an artificial diet supplemented with 1.0 and 5.0 µg/g CPT. The potential molecular mechanism was explored by comparative transcriptomic analyses among midgut samples obtained from larvae under different treatments. A total of 915 and 3560 differentially expressed genes (DEGs) were identified from samples treated with 1.0 and 5.0 µg/g CPT, respectively. Among the identified genes were those encoding detoxification-related proteins and components of peritrophic membrane such as mucins and cuticle proteins. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that part of DEGs were involved in DNA replication, digestion, immunity, endocrine system, and metabolism. Conclusions Our results provide useful information on the molecular basis for the impact of CPT on S. frugiperda and for future studies on potential practical application.

Rutin: A Potential Antiviral for Repurposing as a SARS-CoV-2 Main Protease (Mpro) Inhibitor

Various computational studies, including in silico ones, have identified several existing compounds that could serve as effective inhibitors of the SARS-CoV-2 main protease (Mpro), and thus preventing replication of the virus. Among these, rutin has been identified as a potential hit, having prominent binding affinity to the virus. Moreover, its presence in several traditional antiviral medicines prescribed in China to infected patients with mild to moderate symptoms of COVID-19 justify its promise as a repurposed bioactive secondary metabolite against SARS-CoV-2.

Distribution of ε-Poly-L-Lysine Synthetases in Coryneform Bacteria Isolated from Cheese and Human Skin

ABSTRACT ε-Poly-l-lysine is a potent antimicrobial produced through fermentation of Streptomyces and used in many Asian countries as a food preservative. It is synthesized and excreted by a special nonribosomal peptide synthetase (NRPS)-like enzyme called Pls. In this study, we discovered a gene from cheese bacterium Corynebacterium variabile that showed high similarity to the Pls from Streptomyces in terms of domain architecture and gene context. By cloning it into Streptomyces coelicolor with a Streptomyces albulus Pls promoter, we confirmed that its product is indeed ε-poly-l-lysine. A comprehensive sequence analysis suggested that Pls genes are widely spread among coryneform actinobacteria isolated from cheese and human skin; 14 out of 15 Brevibacterium isolates and 10 out of 12 Corynebacterium isolates contain it in their genomes. This finding raises the possibility that ε-poly-l-lysine as a bioactive secondary metabolite might be produced and play a role in the cheese and skin ecosystems. IMPORTANCE Every year, microbial contamination causes billions of tons of food wasted and millions of cases of illness. ε-Poly-l-lysine has potent, wide-spectrum inhibitory activity and is heat stable and biodegradable. It has been approved for food preservation by an increasing number of countries. ε-Poly-l-lysine is produced from soil bacteria of the genus Streptomyces, also producers of various antibiotic drugs and toxins and not considered to be a naturally occurring food component. The frequent finding of pls in cheese and skin bacteria suggests that ε-poly-l-lysine may naturally exist in cheese and on our skin, and ε-poly-l-lysine producers are not limited to filamentous actinobacteria.