Similar Natural Products Research Articles

A 3D-QSAR Study on the Antitrypanosomal and Cytotoxic Activities of Steroid Alkaloids by Comparative Molecular Field Analysis.

As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R2, Q2, and P2 for partial least squares (PLS) regression, internal cross-validation (leave-one-out), and external predictions (test set), respectively, as well as the corresponding standard deviation error in prediction (SDEP) and F-values). With R2 = 0.99, Q2 = 0.83 and P2 = 0.79 for anti-Tbr activity and R2 = 0.94, Q2 = 0.64, P2 = 0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common structure–activity relationship (SAR) and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization.

The Swinholide Biosynthesis Gene Cluster from a Terrestrial Cyanobacterium, Nostoc sp. Strain UHCC 0450.

ABSTRACTSwinholides are 42-carbon ring polyketides with a 2-fold axis of symmetry. They are potent cytotoxins that disrupt the actin cytoskeleton. Swinholides were discovered from the marine sponge Theonella sp. and were long suspected to be produced by symbiotic bacteria. Misakinolide, a structural variant of swinholide, was recently demonstrated to be the product of a symbiotic heterotrophic proteobacterium. Here, we report the production of swinholide A by an axenic strain of the terrestrial cyanobacterium Nostoc sp. strain UHCC 0450. We located the 85-kb trans-AT polyketide synthase (PKS) swinholide biosynthesis gene cluster from a draft genome of Nostoc sp. UHCC 0450. The swinholide and misakinolide biosynthesis gene clusters share an almost identical order of catalytic domains, with 85% nucleotide sequence identity, and they group together in phylogenetic analysis. Our results resolve speculation around the true producer of swinholides and demonstrate that bacteria belonging to two distantly related phyla both produce structural variants of the same natural product. In addition, we described a biosynthesis cluster from Anabaena sp. strain UHCC 0451 for the synthesis of the cytotoxic and antifungal scytophycin. All of these biosynthesis gene clusters were closely related to each other and created a group of cytotoxic macrolide compounds produced by trans-AT PKSs of cyanobacteria and proteobacteria.IMPORTANCE Many of the drugs in use today originate from natural products. New candidate compounds for drug development are needed due to increased drug resistance. An increased knowledge of the biosynthesis of bioactive compounds can be used to aid chemical synthesis to produce novel drugs. Here, we show that a terrestrial axenic culture of Nostoc cyanobacterium produces swinholides, which have been previously found only from marine sponge or samples related to them. Swinholides are polyketides with a 2-fold axis of symmetry, and they are potent cytotoxins that disrupt the actin cytoskeleton. We describe the biosynthesis gene clusters of swinholide from Nostoc cyanobacteria, as well as the related cytotoxic and antifungal scytophycin from Anabaena cyanobacteria, and we study the evolution of their trans-AT polyketide synthases. Interestingly, swinholide is closely related to misakinolide produced by a symbiotic heterotrophic proteobacterium, demonstrating that bacteria belonging to two distantly related phyla and different habitats can produce similar natural products.

Structural Searching of Biosynthetic Enzymes to Predict Protein Targets of Natural Products.

Recently, we have demonstrated that site comparison methodology using flavonoid biosynthetic enzymes as the query could automatically identify structural features common to different flavonoid-binding proteins, allowing for the identification of flavonoid targets such as protein kinases. With the aim of further validating the hypothesis that biosynthetic enzymes and therapeutic targets can contain a similar natural product imprint, we collected a set of 159 crystallographic structures representing 38 natural product biosynthetic enzymes by searching the Protein Databank. Each enzyme structure was used as a query to screen a repository of approximately 10 000 ligandable sites by active site similarity. We report a full analysis of the screening results and highlight three retrospective examples where the natural product validates the method, thereby revealing novel structural relationships between natural product biosynthetic enzymes and putative protein targets of the natural product. From a prospective perspective, our work provides a list of up to 64 potential novel targets for 25 well-characterized natural products.

Two-dimensional mathematical model for simulation of the drying process of thick layers of natural materials in a conveyor-belt dryer

This paper presents the mathematical model and numerical analysis of the convective drying process of thick slices of colloidal capillary-porous materials slowly moving through conveyor-belt dryer. A flow of hot moist air was used as drying agent. The drying process has been analyzed in the form of a 2-D mathematical model, in two directions: along the conveyor and perpendicular on it. The mathematical model consists of two non-linear differential equations and one equation with a transcendent character and it is based on the mathematical model developed for drying process in a form of a 1-D thin layer. The appropriate boundary conditions were introduced. The presented model is suitable for the automated control of conveyor-belt dryers. The obtained results with analysis could be useful in predicting the drying kinetics of potato slices and similar natural products.

Application of Mixture Analysis to Crude Materials from Natural Resources (V) [1]: Discrimination of Glycyrrhiza uralensis and G. glabra by EI mass spectrometry

The roots and stolons of some Glycyrrhiza species are used worldwide for traditional folk medicines and commercial pharmaceuticals. Phenolic constituents such as flavonoids and coumarins are medicinal and vary according to species. Therefore, species identification is important for quality analysis. In order to identify Glycyrrhiza species by chemical fingerprinting, methanol extracts of the root bark of Glycyrrhiza uralensis Fischer and G. glabra Linn6 were analyzed using EI-MS. Differences in kinds and quantity of components are reflected in complex EI-MS data and determining characteristic peaks for each species is straightforward.. The chaiacteristic peaks were determined statistically by volcano plot, a multivariate analysis method. EI-MS data of G. uralensis and G. glabra showed differential patterns, and the notable peaks in each pattern were identified. Peaks at m/z 153 and 221 are signature peaks of G. uralensis, and at 11/z 173, 309, and 324 are those of G. glabra. In conclusion, we found species-specific patterns by EI-MS that distinguish G. uralensis and G. glabra. This method based on chemical constituent patterns can be applied to identify other Glycyrrhiza species and similar natural products.

Transcriptional Regulation and Transport of Terpenoid Indole Alkaloid in Catharanthus roseus: Exploration of New Research Directions.

As one of the model medicinal plants for exploration of biochemical pathways and molecular biological questions on complex metabolic pathways, Catharanthus roseus synthesizes more than 100 terpenoid indole alkaloids (TIAs) used for clinical treatment of various diseases and for new drug discovery. Given that extensive studies have revealed the major metabolic pathways and the spatial-temporal biosynthesis of TIA in C. roseus plant, little is known about subcellular and inter-cellular trafficking or long-distance transport of TIA end products or intermediates, as well as their regulation. While these transport processes are indispensable for multi-organelle, -tissue and -cell biosynthesis, storage and their functions, great efforts have been made to explore these dynamic cellular processes. Progress has been made in past decades on transcriptional regulation of TIA biosynthesis by transcription factors as either activators or repressors; recent studies also revealed several transporters involved in subcellular and inter-cellular TIA trafficking. However, many details and the regulatory network for controlling the tissue-or cell-specific biosynthesis, transport and storage of serpentine and ajmalicine in root, catharanthine in leaf and root, vindoline specifically in leaf and vinblastine and vincristine only in green leaf and their biosynthetic intermediates remain to be determined. This review is to summarize the progress made in biosynthesis, transcriptional regulation and transport of TIAs. Based on analysis of organelle, tissue and cell-type specific biosynthesis and progresses in transport and trafficking of similar natural products, the transporters that might be involved in transport of TIAs and their synthetic intermediates are discussed; according to transcriptome analysis and bioinformatic approaches, the transcription factors that might be involved in TIA biosynthesis are analyzed. Further discussion is made on a broad context of transcriptional and transport regulation in order to guide our future research.

Jamaicensamide A, a Peptide Containing β-Amino-α-keto and Thiazole-Homologated η-Amino Acid Residues from the Sponge Plakina jamaicensis.

A new cyclic peptide, jamaicensamide A, composed of six amino acids, including a thiazole-homologated amino acid, was isolated from the Bahamian sponge Plakina jamaicensis, along with known compounds bitungolide A and franklinolide A. The structure of the title peptide was solved by integrated analysis of MS, 1D and 2D NMR data, oxidation-hydrolyses to α-amino acids, and their stereodetermination by Marfey's method. The close structural resemblance of Western Atlantic-derived jamaicensamide A to known Western Pacific-derived peptides of lithistid sponges in the genus Theonella and Discodermia suggests a common origin: the symbiotic bacterium Entotheonella sp., a so-called "talented producer" responsible for biosynthesis of most Theonella-associated peptides. Similar natural products from sponges of disparate genera evince the likelihood that these invertebrates harbor the same or a very similar symbiont.

A mathematical model and simulation of the drying process of thin layers of potatoes in a conveyor-belt dryer

This paper presents a mathematical model and numerical analysis of the convective drying process of small particles of potatoes slowly moving through the flow of a drying agent - hot moist air. The drying process was analyzed in the form of a one-dimensional thin layer. The mathematical model of the drying process is a system of two ordinary nonlinear differential equations with constant coefficients and an equation with a transcendent character. The appropriate boundary conditions of the mathematical model were given. The presented model is suitable in the automated control. The presented system of differential equations was solved numerically. The analysis presented here and the obtained results could be useful in predicting the drying kinetics of potatoes and similar natural products in a conveyor-belt dryer.

Preconcentration of Indigotin and Indirubin from Indigowoad Roots with Novel Quinoline Ionic Liquids with Determination by High-Performance Liquid Chromatography

Five novel ionic liquids based on quinoline and hexafluorophosphate, including one acidic ionic liquid and four neutral polyethylene glycol-based dicationic ionic liquids, were synthesized and used as extractants for the preconcentration of indigotin and indirubin from Indigowoad roots for the first time. The structures of the ionic liquids were characterized by spectral data. Their solubilities and viscosities were measured, and the latter were correlated with the Litovitz and Arrhenius equations. In the preconcentration of indigotin and indirubin, the type of ionic liquid, concentration of ionic liquid, solid-liquid ratio, temperature, and duration time on the preconcentration efficiency for indigotin and indirubin were investigated. Furthermore, high-performance liquid chromatography was used to determine indigotin and indirubin in Indigowoad roots. High selectivity and enhancement were obtained, and the method was validated for linearity, precision, repeatability, stability, recovery, and accuracy. The limits of detection were 0.0192 microgram per milliliter for indigotin and 0.0236 microgram per milliliter for indirubin, while the limits of quantification were 0.084 microgram per milliliter for indigotin and 0.040 microgram per milliliter for indirubin. This study provides a useful reference for the design and synthesis of task-specific ionic liquids, which may be applied for the separation of similar natural products.

Antimicrobial compounds from endophytic fungi

Endophytes are microorganisms (primarily fungi) that live in a tissue of plants in a mutualistic symbiosis with their host causing asymptotic infections. In fact, endophytes use plant nutrients for their survivals and in turn produce natural products that help plants in their growth and competitiveness in nature. These microorganisms are found in all plants that have been tested for their presence suggesting their ubiquitous nature. Endophytes are relatively unexplored compared to other natural product sources. It is also documented in the literature that the endophytes and host plants produce similar natural products. For instance Taxomyces andreanae, an endophyte isolated from a yew tree (a taxol producing plant) produces taxol, an anticancer agent. We have identified a few endophytic fungi exhibiting antibacterial and antifungal activities. In this poster presentation, antimicrobial activity directed chemical investigation of fungal extracts will be presented.

Structure of a sedoheptulose 7-phosphate cyclase: ValA from Streptomyces hygroscopicus.

Sedoheptulose 7-phosphate cyclases (SH7PCs) encompass three enzymes involved in producing the core cyclitol structures of pseudoglycosides and similar bioactive natural products. One such enzyme is ValA from Streptomyces hygroscopicus subsp. jinggangensis 5008, which makes 2-epi-5-epi-valiolone as part of the biosynthesis of the agricultural antifungal agent validamycin A. We present, as the first SH7PC structure, the 2.1 Å resolution crystal structure of ValA in complex with NAD+ and Zn2+ cofactors. ValA has a fold and active site organization resembling those of the sugar phosphate cyclase dehydroquinate synthase (DHQS) and contains two notable, previously unrecognized interactions between NAD+ and Asp side chains conserved in all sugar phosphate cyclases that may influence catalysis. Because the domains of ValA adopt a nearly closed conformation even though no sugar substrate is present, comparisons with a ligand-bound DHQS provide a model for aspects of substrate binding. One striking active site difference is a loop that adopts a distinct conformation as a result of an Asp → Asn change with respect to DHQS and alters the identity and orientation of a key Arg residue. This and other active site differences in ValA are mostly localized to areas where the ValA substrate differs from that of DHQS. Sequence comparisons with a second SH7PC making a product with distinct stereochemistry lead us to postulate that the product stereochemistry of a given SH7PC is not the result of events taking place during catalysis but is accomplished by selective binding of either the α or β pyranose anomer of the substrate.

Synthesis of zearalenone-16-β,D-glucoside and zearalenone-16-sulfate: A tale of protecting resorcylic acid lactones for regiocontrolled conjugation.

The development of a reliable procedure for the synthesis of the 16-glucoside and 16-sulfate of the resorcylic acid lactone (RAL) type compound zearalenone is presented. Different protective group strategies were considered and applied to enable the preparation of glucosides and sulfates that are difficult to access up to now. Acetyl and p-methoxybenzyl protection led to undesired results and were shown to be inappropriate. Finally, triisopropylsilyl-protected zearalenone was successfully used as intermediate for the first synthesis of the corresponding mycotoxin glucoside and sulfate that are highly valuable as reference materials for further studies in the emerging field of masked mycotoxins. Furthermore, high stability was observed for aryl sulfates prepared as tetrabutylammonium salts. Overall, these findings should be applicable for the synthesis of similar RAL type and natural product conjugates.

On the biosynthesis and optical activity of the flinderoles

A proposed biosynthesis of the flinderoles described herein would produce racemic compounds through nonenzymatic dimerization of borrerine. However, an initial report of optical activity for natural flinderoles is inconsistent with that hypothesis as well as the racemic production of similar natural products. Herein, pure enantiomers of flinderole B were obtained and the specific rotations thereof were found to be significantly different from those in the original report, which were taken at low concentrations. These new data remove the inconsistency arising from the original data.

INTRODUCTION - Mechanism-based Development of Natural Products for Human Health

This Special Issue of the Journal of Pharmacy and Pharmaceutical Sciences arises from an inaugural conference on “Mechanism-Based Natural Product Development” held at Whistler Mountain, Canada on September 21-22, 2012. The aim of the conference was to bring together scientists from various disciplines to discuss the development of new therapeutic products from natural medicines based on mechanistic and related scientific studies. It provided an opportunity to explore new directions in natural medicine research and development, with the ultimate objective of leading to greater integration of natural and conventional synthetic pharmaceutical medicines for the health of the community worldwide. The concept for this conference and the Special Issue has come from the growing interest internationally in traditional and natural medicinal health products in recent years. It may, at first, appear surprising that developed countries are re-embracing natural product research and development. There are of course many reasons for this, including growing community interest in natural products providing improved health and wellbeing, the growing difficulty and cost of maintaining a pipeline of effective and, above all, safe new products for chronic diseases in the mainstream pharmaceutical industry, and the knowledge that many of our small drug pharmaceutical medicines have come from plants and other organisms. But as traditional natural product medicines increasingly enter the mainstream, the call for evidence to support their use also grows louder. Essential to the acceptance of natural medicines are the validation of their traditional uses and identification, isolation and structural characterization of their active components, together with the elucidation of their mechanisms of biological action, adverse effects, and identification of their molecular targets. These requirements provide the focus of this Special Issue. Scientific investigation and development of new health products requires the joining together of many disciplines, including chemistry, pharmacology, pharmacognosy and cell and molecular biology, as well as integration with clinical medicine. Natural product medicines are expected to be multi-component and multi-targeted. Are they effective, safe and properly standardized in their existing formulations? Are there opportunities to isolate single active components for standardization and conventional drug discovery and development? Answering these questions requires collaboration between scientific disciplines focused on a common goal. In line with the aims of the conference, the Special Issue has incorporated review and original research articles related to mechanisms of action in a number of therapeutic areas, mostly from invited speakers at the Whistler conference. Other articles were unsolicited submissions to the Journal that satisfy the scope of the issue. Articles range from reports on efforts to work with traditional owners in the appropriate cultural context, to develop new therapeutics based on traditional literature, to discover new medicinal products, to develop new pharmaceuticals based on the isolation of active chemical components, to develop new methods of delivery, and to identify mechanisms of action. The medical 'territory' includes cancer, heart disease, diabetes and related chronic inflammatory diseases, pain pathways, deafness and infertility. Other articles investigate the quality and safety of products by the application of current analytical methods, the potential for interactions of natural products (e.g., cranberry) with pharmaceutical medicines and the variability of a selection of similar natural product medicines with regard to their contents of therapeutically beneficial and marker compounds, as claimed on the product labels. In addition, the issue includes the abstracts of posters that formed an important part of the conference, especially from postgraduate students and postdoctoral fellows. These are included as Proceedings. We are indebted to the scientists who willingly gave their time and resources to attend the Whistler conference and, in many cases, submitted manuscripts for inclusion in this Special Issue. The delegates and contributors came from many places, near and far, to make this inaugural conference on mechanism-based natural product development a success. Such a conference and the subsequent proceedings in the Special issue are not possible without the work of many. We thank the organizing and scientific committee for their support and valuable suggestions. A conference of this scope would not be possible without sponsorship; this includes especially the National Health Products Research Society of Canada, the Canadian Society for Pharmaceutical Sciences and several Universities. Major support, without program or editorial input, was provided by SOHO Flordis International (SFI). We commend them for believing in the quest for clinically proven and research-based products based on an understanding of underlying mechanisms. The support of Purapharm International is also gratefully acknowledged. We would like to dedicate this Special Issue to Professor Allan SY Lau of the University of Hong Kong, who contributed enthusiastically to the organization of the conference and its program, but was ultimately unable to attend due to his untimely passing. Professor Lau was a pioneer in the integration of natural and orthodox medical studies and his inspiration will be greatly missed. Basil D Roufogalis, Arthur D Conigrave and Emanuel E Strehler Co-Guest Editors

Extraction optimization approach to improve accessibility of functional fraction based on combination of total polyphenol, chromatographic profiling and antioxidant activity evaluation: Pyracantha fortuneana fruit as an example

Optimized solid–liquid extraction conditions by response surface methodology (RSM) and optimal solvent selectivity liquid–liquid fractionation by mixture design were studied for process of Pyracantha fortuneana fruits (PFF) healthy products. A combination of total polyphenolic content (TPC), total antioxidant activity (TAA) and chromatographic profiling was used to evaluate the optimization. RSM results were ethanol concentration, 71%; extraction temperature, 51°C; and pH solution, 3.2. The mixture design indicated that the fraction with the highest TAA and TPC was directed to ethyl-acetate phase. The fractions of water-soluble and n-butylalcohol-soluble were rich in TAA and TPC compared with the starting row of PFF. Twenty-seven polyphenols were detected in chromatographic profilings, most of which were reported for the first time in this study. The improvements of accessibility in the optimized fractions suggest their flexible applicabilities for nutraceutical food industries. This study may be crucial approach for all similar natural functional product optimization.

Caerulomycins and Collismycins Share a Common Paradigm for 2,2′-Bipyridine Biosynthesis via an Unusual Hybrid Polyketide–Peptide Assembly Logic

Caerulomycins (CAEs) and collismycins (COLs), which mainly differ in sulfur decoration, are two groups of structurally similar natural products containing a 2,2'-bipyridine (2,2'-BP) core, derivatives of which have been widely used in chemistry. The biosynthetic pathways of CAEs and COLs remain elusive. In this work, cloning of the CAE biosynthetic gene cluster allowed us to mine a highly conserved gene cluster encoding COL biosynthesis in a Streptomyces strain that was previously unknown as a 2,2'-BP producer. In vitro and in vivo investigations into the biosynthesis revealed that CAEs and COLs share a common paradigm featuring an atypical hybrid polyketide synthase/nonribosomal peptide synthetase system that programs the 2,2'-BP formation. This likely involves an unusual intramolecular cyclization/rearrangement sequence, and a difference in processing of the sulfhydryl group derived from the same precursor cysteine drives the biosynthetic route toward CAEs or COLs.

ChemInform Abstract: The Cylindrospermopsin Alkaloids

AbstractReview: 209 refs.

Synthetic Studies Towards Caulophyllumine and its Derivatives

Caulophyllum thalictroides (L.) Michx. (Blue Cohosh) is a popular herb, roots and rhizomes of which have been extensively used for women's health [1] and it is also considered a poisonous plant. A detailed phytochemical analysis revealed that alkaloids and saponins are the major components responsible for its pharmacological effects. In addition to their biological activity, recently we have demonstrated that the piperidine alkaloid isolated from Blue Cohosh, Caulophyllumine B inhibits the major drug metabolizing P450 (Cyp450) enzymes [2]. In continuation of our efforts in safety and efficacy of dietary supplements, we need Caulophyllumine B and its analogs. To achieve these piperidine based alkaloids here we propose and demonstrate a four step synthesis starting from commercially available 2-piperidinone. Furthermore, the flexibility of the current strategy to introduce any substituted aromatic ring attached to piperidine scaffold allows construction of various structurally similar natural products and its analogs. Our synthetic strategy and the full chemical details will be presented.

A practical synthesis of (all- Z)-eicosa-3,6,9,12-tetraene, a pheromone component isolated from emerald moths

A short and practical synthesis of (all- Z)-eicosa-3,6,9,12-tetraene, a component of the emerald moth pheromone is reported. Two different methodologies are used both starting with the natural polyunsaturated fatty acid (all- Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA). The methodology can be used for the syntheses of a homologous series of analogues of the pheromone that may be practical for analytical purposes of similar natural products.

Structure and Dynamics of Dinucleosomes Assessed by Atomic Force Microscopy

Dynamics of nucleosomes and their interactions are important for understanding the mechanism of chromatin assembly. Internucleosomal interaction is required for the formation of higher-order chromatin structures. Although H1 histone is critically involved in the process of chromatin assembly, direct internucleosomal interactions contribute to this process as well. To characterize the interactions of nucleosomes within the nucleosome array, we designed a dinucleosome and performed direct AFM imaging. The analysis of the AFM data showed dinucleosomes are very dynamic systems, enabling the nucleosomes to move in a broad range along the DNA template. Di-nucleosomes in close proximity were observed, but their population was low. The use of the zwitterionic detergent, CHAPS, increased the dynamic range of the di-nucleosome, facilitating the formation of tight di-nucleosomes. The role of CHAPS and similar natural products in chromatin structure and dynamics is also discussed.