Enhancing structural diversity through chemical engineering of Ambrosia tenuifolia extract for novel anti-glioblastoma compounds.

Natural products are an unsurpassed source of leading structures in drug discovery. The biosynthetic machinery of the producing organism offers an important source for modifying complex natural products, leading to analogs that are unattainable by chemical semisynthesis or total synthesis. In this report, through the combination of natural products chemistry and diversity-oriented synthesis, a diversity-enhanced extracts approach is proposed using chemical reactions that remodel molecular scaffolds directly on extracts of natural resources. This method was applied to subextract enriched in sesquiterpene lactones from Ambrosia tenuifolia (Fam. Asteraceae) using acid media conditions (p-toluenesulfonic acid) to change molecular skeletons. The chemically modified extract was then fractionated by a bioguided approach to obtain the pure compounds responsible for the anti-glioblastoma (GBM) activity in T98G cell cultures. Indeed, with the best candidate, chronobiological experiments were performed to evaluate temporal susceptibility to the treatment on GBM cell cultures to define the best time to apply the therapy. Finally, bioinformatics tools were used to supply qualitative and quantitative information on the physicochemical properties, chemical space, and structural similarity of the compound library obtained. As a result, natural products derivatives containing new molecular skeletons were obtained, with possible applications as chemotherapeutic agents against human GBM T98G cell cultures.

Expanding Diterpene Complexity and Diversity via Photoinduced Ring Distortions.

Natural products and their semi-synthetic derivatives undoubtedly constitute an important source of therapeutic agents. Their importance lies in their own origin and evolution, since they have great chemical diversity, biochemical specificity, and pharmacological properties. Currently, there is a renewed interest in the development of methodologies capable of efficiently modifying the chemical structure of these bioactive platforms. In this work, the photoderivatization of the diterpene solidagenone was performed using a complexity-to-diversity-oriented approach. By exploring [2+2]-photocycloaddition, photoinduced-hydrogen abstraction, and photoxygenation reactions, a set of solidagenone derivatives was obtained, showing different ring fusions, side chain rearrangements, and modifications of the original furan ring's substitution pattern. The derivatives obtained were characterised by NMR methodologies. To evaluate the structural diversity of the labdane-derived compounds, their physicochemical properties, structural similarity, and chemical space were analysed. These results suggest that photochemical reactions are a useful tool for performing ring distortion transformations, generating derivatives of natural compounds with wide diversity, structural complexity, and with potential biological properties.

Antibacterial activity of withanolides and their structure-activity relationship.

Two new withanolides, (17R,20S,22R)-4ß-acetoxy-5ß,6ß-epoxy-19,27-dihydroxy-1-oxo-witha-2,24-dienolide (withalongolide A 4-acetate (5) and (17R,20S,22R)-5ß,6ß-epoxy-27-hydroxy-1,4-dioxo-witha-24-enolide (9), and seven known withanolides with normal structure (1-4, 6-8) were isolated from aerial parts of Cuatresia colombiana. Several semisynthetic derivatives were prepared from the natural metabolites withaferin A and jaborosalactone 38. The compounds were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS). The compounds isolated from C. colombiana, sixteen withanolides previously isolated from different Solanaceae species with different skeletons and semisynthetic derivatives were evaluated for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. According to the bioactivity against S. aureus and E. faecalis, the compounds evaluated were divided into three groups: compounds with high activity (MIC 0.063 mM), compounds with moderate activity (0.5 mM > MIC > 0.125 mM) and non-active compounds (MIC ≥1 mM); in addition, some structure-activity relationship keys could be inferred.

Identification of potential biological target for trypanocidal sesquiterpene lactones derivatives.

Sesquiterpene lactones are natural products of the Asteraceae family that have shown trypanocidal activity against Trypanosoma cruzi, even exceeding the effectiveness of drugs used in the treatment of American trypanosomiasis. However, there is no agreement on their mechanism of action and their specificity to interact with parasite proteins. For this reason, we aimed to find biological targets that can interact with these compounds by reverse virtual screening with ligand pharmacophores and putative binding sites and the use of bioinformatic databases. Therefore, 41 possible biological targets were found, and four of them (with crystallized proteins), interfering directly or indirectly in the trypanosomatid redox system, were studied in detail. As a first approach, we focused on the study of trypanothione reductase, and protein-ligand interaction fingerprint analyses were performed to find binding site determinants that promote a possible inhibition of the enzyme. This study contributes to the understanding of one of the putative mechanisms of action of sesquiterpene lactones on one of the numerous suggested targets.Communicated by Ramaswamy H. Sarma.

Identification of chia, flax and sesame seeds authenticity markers by NMR-based untargeted metabolomics and their validation in bakery products containing them.

Chia, flax, and sesame seeds are considered superseeds due to their beneficial nutritional properties, and they are frequently included as functional ingredients in foods. Authenticity markers of these seeds, including bakery products containing them, have been identified by both liquid and gas chromatography coupled to mass spectrometry (LC-MS/MS and GC-MS/MS, respectively) targeted metabolomics. However, there are no reports describing the use of nuclear magnetic resonance (NMR) spectroscopy based metabolomics to identify authenticity markers in either the raw seeds or foods containing them. We herein report the application of an untargeted NMR-based metabolomics workflow to the identification of authenticity markers for the three seeds. Seven markers, belonging to the families of polyphenols and cyanogenic glycosides, allowed good differentiation of the raw materials. Validation in cookies containing different seed percentages showed that two markers resisted the processing stage, making them feasible authenticity markers for the food trade.

Psilostachyins as trypanocidal compounds: Bioguided fractionation of Ambrosia tenuifolia chemically modified extract.

This work focusses on the chemical diversification of an Ambrosia tenuifolia extract and its bioguided fractionation, aiming to unveil the chemical entity responsible for the trypanocidal activity. Besides, a revision of the phytochemical study of this species, based on previous reports of the antiparasitic psilostachyins A and C as main compounds, was conducted. To improve the biological properties of a plant extract through a simple chemical reaction, the oxidative diversification of the dichloromethane extract of this plant species was carried out. A bioguided fractionation of a chemically modified extract was performed by evaluating the inhibitory activity against Trypanosoma cruzi trypomastigotes. This experiment led to the isolation of one of the most active compounds. In general terms, epoxidized metabolites were obtained as a result of the oxidation of the major metabolite of the species. The trypanocidal activity of some tested metabolites overperformed the reference drug, benznidazole, displaying no cytotoxicity at trypanocidal concentrations. Key structure-activity relationships were obtained for designing previously undescribed antiparasitic sesquiterpene lactones.

Design, synthesis and evaluation of cholinesterase hybrid inhibitors using a natural steroidal alkaloid as precursor.

To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase. In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area. Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure-activity relationship analysis.

An activity prediction model for steroidal and triterpenoidal inhibitors of Acetylcholinesterase enzyme.

Nowadays, the importance of computational methods in the design of therapeutic agents in a more efficient way is indisputable. Particularly, these methods have been important in the design of novel acetylcholinesterase enzyme inhibitors related to Alzheimer's disease. In this sense, in this report a computational model of linear prediction of acetylcholinesterase inhibitory activity of steroids and triterpenes is presented. The model is based in a correlation between binding energies obtained from molecular dynamic simulations (after docking studies) and [Formula: see text] values of a training set. This set includes a family of natural and semi-synthetic structurally related alkaloids reported in bibliography. These types of compounds, with some structural complexity, could be used as building blocks for the synthesis of many important biologically active compounds Therefore, the present study proposes an alternative based on the use of conventional and easily accessible tools to make progress on the rational design of molecules with biological activity.

Synthetic Lethal Activity of Benzophenanthridine Alkaloids From Zanthoxylum coco Against BRCA1-Deficient Cancer Cells.

Several plants from South America show strong antitumoral properties based on anti-proliferative and/or pro-apoptotic activities. In this work we aimed to identify selective cytotoxic compounds that target BRCA1-deficient cancer cells by Synthetic Lethality (SL) induction. Using a high-throughput screening technology developed in our laboratory, we analyzed a collection of extracts from 46 native plant species from Argentina using a wide dose-response scheme. A highly selective SL-induction capacity was found in an alkaloidal extract from Zanthoxylum coco (Fam. Rutaceae). Bio-guided fractionation coupled to HPLC led to the identification of active benzophenanthridine alkaloids. The most potent SL activity was found with the compound oxynitidine, which showed a remarkably low relative abundance in the active fractions. Further validation experiments were performed using the commercially available and closely related analog nitidine, which showed SL-induction activity against various BRCA1-deficient cell lines with different genetic backgrounds, even in the nanomolar range. Exploration of the underlying mechanism of action using BRCA1-KO cells revealed AKT and topoisomerases as the potential targets responsible of nitidine-triggered SL-induction. Taken together, our findings expose an unforeseen therapeutic activity of alkaloids from Zanthoxylum-spp. that position them as novel lead molecules for drug discovery.

Clinanthus microstephium, an Amaryllidaceae Species with Cholinesterase Inhibitor Alkaloids: Structure-Activity Analysis of Haemanthamine Skeleton Derivatives.

Plants of the Amaryllidaceae family are well-known (not only) for their ornamental value but also for the alkaloids that they produce. In this report, the first phytochemical study of Clinanthus genus was carried out. The chemical composition of alkaloid fractions from Clinanthus microstephium was analyzed by GC/MS and NMR. Seven known compounds belonging to three structural types of Amaryllidaceae alkaloids were identified. An epimeric mixture of a haemanthamine-type compound (6-hydroxymaritidine) was tested as an inhibitor against acetyl- and butyrylcholinesterase enzymes (AChE and BChE, respectively), two enzymes relevant in the treatment of Alzheimer's disease, with good results. Structure-activity relationships through molecular docking studies with this alkaloid and other structurally related compounds were discussed.

Phytochemical Study of Senecio volckmannii Assisted by CASE-3D with Residual Dipolar Couplings and Isotropic 1H/13C NMR Chemical Shifts.

Nine new eremophilanolides, with seven known sesquiterpenoids, and 4-hydroxyacetophenone were isolated from the aerial parts of Senecio volckmannii var. volckmannii. The structures of these compounds were fully characterized using a combination of spectroscopic techniques including multinuclear and multidimensional NMR and mass spectrometry. The recently published Computer Assisted 3D Structure Elucidation (CASE-3D) protocol was applied in the configurational and conformational analysis of many of these eremophilanolides on the basis of Residual Dipolar Couplings (RDCs) and/or DFT predicted 1H/13C chemical shifts.

Di(ethylene glycol) methyl ether methacrylate (DEGMEMA)-derived gels align small organic molecules in methanol.

Residual dipolar couplings (RDCs) constitute an important NMR parameter for structural elucidation in all areas of chemistry. In this study, di(ethylene glycol) methyl ether methacrylate (DEGMEMA)-based gels are introduced as alignment media for the measurement of RDCs of small organic molecules in polar solvents such as methanol. The low viscosity of methanol permits the execution of J-scaled BIRD HSQC experiments that yield very sharp lines in anisotropic conditions. The gels have excellent mechanical properties, and their compression and expansion in the swollen state can be reversed and performed multiple times. This process enables the easy loading and release of analytes. The excellent performance of these new aligning gels is demonstrated by analyzing the structure of the alkaloid retrorsine. Copyright © 2016 John Wiley & Sons, Ltd.

Solanocapsine derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular docking and biological studies.

The investigation of natural products in medicinal chemistry is essential today. In this context, acetylcholinesterase (AChE) inhibitors comprise one type of the compounds most actively studied in the search for an effective treatment of symptoms of Alzheimer's disease. This work describes the isolation of a natural compound, solanocapsine, the preparation of its chemical derivatives, the evaluation of AChE inhibitory activity, and the structure-activity analysis of relevant cases. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different reactive parts of the parent molecule. A theoretical study was also carried out into the binding mode of representative compounds to the enzyme through molecular modeling. The biological properties of the series were investigated. Through this study valuable information was obtained of steroidal alkaloid-type compounds as a starting point for the synthesis of AChE inhibitors.

Antiproliferative and quinone reductase-inducing activities of withanolides derivatives.

Two new and five known withanolides (jaborosalactones 2, 3, 4, 5, and 24) were isolated from the leaves of Jaborosa runcinata Lam. We also obtained some derivatives from jaborosalactone 5, which resulted to be the major isolated metabolite. The natural compounds as well as derivatives were evaluated for their antiproliferative activity and the induction of quinone reductase 1 (QR1; NQ01) activity. Structure-activity relationships revealed valuable information on the pharmacophore of withanolide-type compounds. Three compounds of this series showed significantly higher antiproliferative activity than jaborosalactone 5. The effect of these compounds on the cell cycle was determined. Furthermore, the ability of major compounds to induce QR1 was evaluated. It was found that all the active test compounds are monofunctional inducers that interact with Keap1. The most promising derivatives prepared from jaborosalactone 5 include (23R)-4ß,12ß,21-trihydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen-26,23-olide (18) and (23R)-21-acetoxy-12ß-hydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen-26,23-lactame (20).

Agarofuran sesquiterpenes from Schaefferia argentinensis.

Sixteen dihydro-ß-agarofuran sesquiterpenes were isolated from the aerial parts of Schaefferia argentinensis Speg. Their structures were determined by a combination of 1D and 2D NMR and MS techniques. The in vitro antiproliferative activity of the major sesquiterpenes was examined in T47D, MCF7, and MDA-MB231 human cancer cell lines, but was found to be marginal.

Antiproliferative activity of withanolide derivatives from Jaborosa cabrerae and Jaborosa reflexa. Chemotaxonomic considerations.

Three withanolides were isolated from the aerial parts of Jaborosa reflexa Phil. Jaborosa cabrerae Barboza yielded five sativolide withanolides (including jaborosalactones R, S, 38, and 39) and two trechonolide withanolides epimeric at C-23 (trechonolide A and jaborosalactone 32). In addition, five derivatives were obtained by chemical derivatization of jaborosalactone 38, and all compounds were fully characterized by 1D and 2D NMR spectroscopic studies. The in vitro antiproliferative activities of the major natural withanolides and the semisynthetic derivatives were examined against HBL-100, HeLa, SW1573, T-47D, and WiDr human solid tumor cancer cell lines. Some chemotaxonomic considerations are discussed.