High Structural Diversity Research Articles

Unusual structures of CCTG repeats and their participation in repeat expansion.

CCTG repeat expansion in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene has been identified to be the genetic cause of myotonic dystrophy type 2 (DM2). Yet the underlying reasons for the genetic instability in CCTG repeats remain elusive. In recent years, CCTG repeats have been found to form various types of unusual secondary structures including mini-dumbbell (MDB), hairpin and dumbbell, revealing that there is a high structural diversity in CCTG repeats intrinsically. Upon strand slippage, the formation of unusual structures in the nascent strand during DNA replication has been proposed to be the culprit of CCTG repeat expansions. On the one hand, the thermodynamic stability, size, and conformational dynamics of these unusual structures affect the propensity of strand slippage. On the other hand, these structural properties determine whether the unusual structure can successfully escape from DNA repair. In this short overview, we first summarize the recent advances in elucidating the solution structures of CCTG repeats. We then discuss the potential pathways by which these unusual structures bring about variable sizes of repeat expansion, high strand slippage propensity and efficient repair escape.

Evaluation of Organoselenium Based Compounds as Co‐Catalysts in Rhodium‐Catalyzed Hydroformylation

AbstractHerein we report the synthesis of new organoselenium compounds and their evaluation as co‐catalysts in rhodium‐catalyzed hydroformylation. Simple low molecular weight selenium compounds as well as more complicated organoselenium phosphites with a high structural diversity were involved in the study. Some of the new structures (e. g. phosphites) were related to well established mono‐ and bi‐dendate phosphorus ligands commonly used in hydroformylation. In the catalytic trials in most cases serious inhibition effects were observed due to the presence of the selenium additive. Moreover, our results show that selena compounds may differ in the behavior in comparison to other chalcogenides such as oxygen or sulfur.

ChemInform Abstract: Diastereoselective Synthesis of Structurally and Stereochemically Diversified 2‐Oxa‐7‐azabicyclo[4.1.0]hept‐3‐enyl Carboxylates and Their Potential Application Toward the Synthesis of Functionalized Pyranooxazolone and Pyrrole Derivatives Through Skeletal Transformations.

An advanced protocol for the diastereoselective intramolecular aziridination reaction has been developed to synthesize 2-oxa-7-azabicyclo[4.1.0]hept-3-en-1-yl carboxylates from their corresponding 4-H-pyrans and spiropyrans analogues employing iodosylbenznene as the exclusive oxidant in the presence of carboxylic acid and triethylamine. High structural and stereochemical diversity of these pyran fused NH-azridine scaffolds makes them useful in evaluating their biological and pharmacological activities by SAR studies. Additionally, their potential synthetic application has been uncovered by efficient transformation into biologically relevant novel pyranooxazolone and pyrrole derivatives.

Nrf2 activation as a key event triggered by skin sensitisers: The development of the stable KeratinoSens reporter gene assay.

The 21st century paradigm for toxicology and the adverse outcome pathway concept envisage a future toxicology largely based on mechanistic in vitro assays and relying mainly on cellular models. In the skin sensitisation field, this concept was not intuitive at the beginning. Given the high structural diversity of skin sensitising molecules, classical receptor binding as the molecular initiating event in a cell-based assay could be excluded from the start, leaving the question of how cells could sense potential skin sensitising chemicals and be able to differentiate them from non-sensitisers. When we entered this field in 2006, we realised that, in another emerging field of toxicology, detailed work on the antioxidant/electrophile sensing pathway Keap1/Nrf2/ARE was being performed. We postulated that, based on their intrinsic electrophilicity, a large structural variety of skin sensitisers would activate this pathway. This was demonstrated in a preliminary pilot study with an existing, breast cancer-derived reporter cell line. Broader confirmation of this initial hypothesis then came from a multitude of genome-wide studies, in which sensitiser-induced changes to the transcriptome were investigated. The results showed that this regulatory pathway is indeed the most common regulatory pathway activated by sensitisers at the gene expression level, and the underlying event in keratinocytes has become formalised as a Key Event in the Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway for sensitisation. These studies led to the development of the KeratinoSens® assay, which became the first cell-based in vitro test for skin sensitisation to be endorsed by a European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) statement and an OECD Test Guideline. More recently, a number of studies have further developed this approach into 3-D skin models. Here, we review the underlying mechanism and the development of the KeratinoSens assay. We also present data on the stability of the assay over time, which is a key requirement for a cell-based biological assay to be endorsed in a regulatory context.

Synthesis of complex head-to-side-chain cyclodepsipeptides.

Cyclodepsipeptides are cyclic peptides in which at least one amide link on the backbone is replaced with an ester link. These natural products present a high structural diversity that corresponds to a broad range of biological activities. Therefore, they are very promising pharmaceutical candidates. Most of the cyclodepsipeptides have been isolated from marine organisms, but they can also originate from terrestrial sources. Within the family of cyclodepsipeptides, 'head-to-side-chain' cyclodepsipeptides have, in addition to the macrocyclic core closed by the ester bond, an arm terminated with a polyketide moiety or a branched amino acid, which makes their synthesis a challenge. This protocol provides guidelines for the synthesis of 'head-to-side-chain cyclodepsipeptides' and includes-as an example-a detailed procedure for preparing pipecolidepsin A. Pipecolidepsin was chosen because it is a very complex 'head-to-side-chain cyclodepsipeptide' of marine origin that shows cytotoxicity in several human cancer cell lines. The procedure begins with the synthesis of the noncommercial protected amino acids (2R,3R,4R)-2-{[(9H-fluoren-9-yl)methoxy]carbonylamino}-3-hydroxy-4,5-dimethylhexanoic acid (Fmoc-AHDMHA-OH), Alloc-pipecolic-OH, (4R,5R)-5-((((9H-fluoren-9-yl)methoxy)carbonylamino)-4-oxo-4-(tritylamino)butyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (Fmoc-DADHOHA(acetonide, Trt))-OH and the pseudodipeptide (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid ((HTMHA)-D-Asp(OtBu)-OH). It details the assembly of the depsipeptidic skeleton using a fully solid-phase approach (typically on an amino polystyrene resin coupled to 3-(4-hydroxymethylphenoxy)propionic acid (AB linker)), including the key ester formation step. It concludes by describing the macrocyclization step performed on solid phase, and the global deprotection and cleavage of the cyclodepsipeptide from the resin using a trifluoroacetic acid-H2O-triisopropylsilane (TFA-H2O-TIS; 95:2.5:2.5) cocktail, as well as the final purification by semipreparative HPLC. The entire procedure takes ∼2 months to complete.

Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer’s disease

This paper describes the synthesis and evaluation of new dihydropyrimidinone (DHPM)-derived selenoesters as potential multi-targeted agents for the treatment of Alzheimer’s disease. A series of DHPM-derived selenoesters were obtained with high structural diversity through a short and modular synthetic route. The antioxidant activity was evaluated by TBARS and iron chelation assays. These compounds were also evaluated as acetylcholinesterase inhibitors (AChEi). The compounds demonstrated good antioxidant activity, since they presented excellent lipid peroxidation inhibition and good iron chelation activity. In addition, they showed acetylcholinesterase inhibition activity and some of them presented activity superior to that of the standard drug galantamine. The in silico predictions showed that the compound 1h may present a good pharmacokinetic profile. Therefore, the series of DHPM-derived selenoesters described herein displayed good potential for the development of antioxidant and anticholinesterasic agents in the search for new multi-targeted therapeutics for the treatment of Alzheimer’s disease.

Insight into the aroma profile of Bulgarian tobacco absolute oil

The tobacco absolute usually obtained from tobacco waste, generated at various stages of post-harvest processing of the tobacco leaves and the cigarettes production, can be an important source of natural additives for tobacco compositions and cosmetics. Therefore, the chemical profile of Bulgarian tobacco absolutes derived from the three main type tobacco, grown in Bulgaria (Burley, Virginia and Oriental) was studied by means of gas chromatography-mass spectrometry (GC/MS) and gas chromatography with flame ionization detection (GC-FID). A protocol for simultaneous analysis of compounds with high structural diversity and volatility was developed involving a multistep temperature gradient and trimethylsilyl derivatives. As a result 90 compounds, mainly terpenes, but also organic acids, waxes and steroids were identified. The main constituents, representing 94.5-97.5% of the total content of the detected compounds, were quantified by means of GC-FID. Although the most important terpenoid classes, forming the heart of tobacco flavour, were found in all three samples, significant differences were observed as a reflection of the tobacco type. In Virginia and Burley absolutes only cembranoids were detected, while in Oriental compounds representative for both cembranoids and labdanoids were found. This defines a specific chromatographic fingerprint pattern that could be used for a fast identification of the tobacco absolute type.

Membrane re-arrangements and rippled phase stabilisation by the cell penetrating peptide penetratin

Cell penetrating peptides are promising vectors for molecular drug delivery in eukaryotic cells. Despite of their discovery 20years ago, the mechanisms of peptide membrane crossing are still controversial. The different suggested penetration mechanisms reflect the high sequence and structural diversity of cell penetrating peptides. The fundamental step for peptide penetration into the cytosol is the crossing of the membrane lipid barrier at the level of the plasma membrane or the endosomes. Therefore, the study of the peptide-lipid interaction is the key for peptide penetration mechanisms understanding. In order to study the changes in lipid organisation induced by the cell penetrating peptide penetratin, several experiments by three different physicochemical approaches were performed. X-ray diffraction data shows that penetratin is able to induce membrane phase separation and lipid rearrangements observed by inter-lipid distances. These changes are accompanied by a temperature stable behaviour of some of the induced membrane domains. The membrane environment fluorescent probe laurdan showed that, in DMPC and DMPC/DMPG membranes, the peptide induces de-packing of lipids. Calorimetric analyses show that penetratin favours the gel phase to gel-like rippled phase transition. Overall, the data suggest both, that the rippled phase is a heterogeneous structure formed by gel-like and fluid-like coexisting components, and that the penetratin-induced membrane heterogeneity could be important for membrane destabilisation during cell penetration.

Soluble monomers, dimers and HLA-G-expressing extracellular vesicles: the three dimensions of structural complexity to use HLA-G as a clinical biomarker.

The HLA-G molecule belongs to the family of nonclassical human leukocyte antigen (HLA) class I. At variance to classical HLA class I, HLA-G displays (i) a low number of nucleotide variations within the coding region, (ii) a high structural diversity, (iii) a restricted peptide repertoire, (iv) a limited tissue distribution and (v) strong immune-suppressive properties. The physiological HLA-G surface expression is restricted to the maternal-fetal interface and to immune-privileged adult tissues. Soluble forms of HLA-G (sHLA-G) are detectable in various body fluids. Cellular activation and pathological processes are associated with an aberrant or a neo-expression of HLA-G/sHLA-G. Functionally, HLA-G and its secreted forms are considered to be key players in the induction of short- and long-term tolerance. Thus, its unique expression profile and tolerance-inducing functions render HLA-G/sHLA-G an attractive biomarker to monitor the systemic health/disease status and disease activity/progression for clinical approaches in disease management and treatments. Here, we place emphasis on (i) the current status of the tolerance-inducing functions by HLA-G/sHLA-G, (ii) the current complexity to implement this molecule as a meaningful clinical biomarker regarding the three dimensions of structural diversity (monomers, dimers and HLA-G-expressing extracellular vesicles) with its functional implications, and (iii) novel and future approaches to detect and quantify sHLA-G structures and functions.

Glycolipid biosurfactants: main properties and potential applications in agriculture and food industry.

Glycolipids, consisting of a carbohydrate moiety linked to fatty acids, are microbial surface active compounds produced by various microorganisms. They are characterized by high structural diversity and have the ability to decrease the surface and interfacial tension at the surface and interface, respectively. Rhamnolipids, trehalolipids, mannosylerythritol lipids and cellobiose lipids are among the most popular glycolipids. They have received much practical attention as biopesticides for controlling plant diseases and protecting stored products. As a result of their antifungal activity towards phytopathogenic fungi and larvicidal and mosquitocidal potencies, glycolipid biosurfactants permit the preservation of plants and plant crops from pest invasion. Also, as a result of their emulsifying and antibacterial activities, glycolipids have great potential as food additives and food preservatives. Furthermore, the valorization of food byproducts via the production of glycolipid biosurfactant has received much attention because it permits the bioconversion of byproducts on valuable compounds and decreases the cost of production. Generally, the use of glycolipids in many fields requires their retention from fermentation media. Accordingly, different strategies have been developed to extract and purify glycolipids. © 2016 Society of Chemical Industry.

Diastereoselective Synthesis of Structurally and Stereochemically Diversified 2-Oxa-7-azabicyclo[4.1.0]hept-3-enyl Carboxylates and Their Potential Application toward the Synthesis of Functionalized Pyranooxazolone and Pyrrole Derivatives through Skeletal Transformations.

An advanced protocol for the diastereoselective intramolecular aziridination reaction has been developed to synthesize 2-oxa-7-azabicyclo[4.1.0]hept-3-en-1-yl carboxylates from their corresponding 4-H-pyrans and spiropyrans analogues employing iodosylbenznene as the exclusive oxidant in the presence of carboxylic acid and triethylamine. High structural and stereochemical diversity of these pyran fused NH-azridine scaffolds makes them useful in evaluating their biological and pharmacological activities by SAR studies. Additionally, their potential synthetic application has been uncovered by efficient transformation into biologically relevant novel pyranooxazolone and pyrrole derivatives.

Multicomponent Coupling Reaction and Intramolecular Nitrile Oxide–Alkyne Cycloaddition towards Isoxazolo[3,4]‐pyrrolizines

AbstractThis study reports an efficient four‐step method to synthesize a series of new (4S,8aS)‐3,4‐diphenyl‐6,7,8,8a‐tetrahydro‐4H‐isoxazolo[3,4‐a]pyrrolizines. The first step involves a copper(II) acetylacetonate catalyzed three component coupling of aldehyde, (S)‐pyrrolidin‐2‐ylmethanol, and alkynes (A3 coupling) to form propargylamines (4 a–4 n). The coupling reaction is applicable to various aldehydes, amines, and alkynes and provides the propargylamines in good to excellent yields with excellent distereoselectivities. Products (4 a–4 n) were converted into aldehydes (5 a–5 n) by Swern oxidation, aldehydes (5 a–5 n) were reacted with hydroxyl amine hydrochloride to form aldoxime (6 a–6 n), respectively. Further aldoximes (6 a–6 n) underwent an intramolecular 1,3‐dipolar cycloaddition to form tricyclic‐fused isoxazoles (7 a–7 n). The 1,3‐dipolar cycloaddition reaction tolerates high structural diversity and generated desired products (7 a–7 n) in moderate to good yields and excellent diastereoselectivities. A proposed mechanism for synthesis of 7 a is reported.

Covalent and non-covalent binding of metal complexes to RNA

Targeting nucleic acids with metal complexes is an exciting and widely explored field of research. Following the discovery of the anticancer drug cisplatin, a number of metal complexes have been designed, synthesised, and tested for their DNA binding properties. On the contrary, the interaction of metal complexes with RNA has been much less investigated. RNA is an essential biomolecule, involved in a variety of crucial cellular functions, which offers a much wider structural diversity than DNA. As such, RNA represents an attractive target for the design and the development of structure-selective therapeutic and diagnostic agents. A few recent publications describe the ability of various metal complexes to interact with RNA, and the binding of cisplatin and derivatives to RNA is being currently investigated. This short review offers an overview of some recent advances on both covalent and non-covalent interactions of metal complexes with RNA and addresses the potential of targeting RNA non-duplex structures.

Antibiotics and RNase P.

RNase P is an essential endonuclease in tRNA biogenesis, which generates the mature 5′-termini of tRNAs. Most forms of RNase P are ribonucleoproteins, i.e., they consist of an essential RNA and protein subunits. The catalytic function of ribonucleoprotein RNase P enzymes resides entirely in the RNA subunit. Its high structural and functional diversity among representatives of a vast variety of phylogenetic domains indicates that RNase P could serve as a molecular target and a useful screening system for the development of new drugs in the battle against bacterial drug resistance.

Stability of Zirconium Metal Organic Frameworks with 9,10- Dicarboxylic Acid Anthracene as Ligand

With high specific surface area and pore structural diversity, MOFs show important applications in gas storage, catalysis, sensing, separation, and biomedicine. However, the stability of the structure of MOFs has restricted their application and development. In this study, zirconium metal organic frameworks with 9,10-dicarboxylic acid anthracene as ligand, named UIO-66 (H2DCA), were synthesized and their properties and structures were characterized by XRD, SEM, and N2 adsorption. We focus on the stability of the structure of UIO-66 (H2DCA) under different conditions (acid, alkali, and water). The structural changes or ruins of UIO-66 (H2DCA) were traced by means of XRD, TG, and FT-IR under different conditions. The results show that the UIO-66 (H2DCA) materials are stable at 583 K, and that this structural stability is greatly influenced by different types of acid and alkali compounds. Importantly, we found that the structures maintain their stability in environments of nitric acid, triethylamine, and boiling water. Key words: Zirconium metal organic framework materials, UIO-66, Structure stability, Ligands, 9,10- dicarboxylic acid anthracene

Atmospheric carbon removal capacity of a mangrove ecosystem in a micro-tidal basin estuary in Sri Lanka

Characterization of the micro-tidal mangrove forests in Negombo estuary, located on the west coast of Sri Lanka, with respect to its capacity to remove atmospheric carbon and sequestration in above and below ground plant components is the objective of this study. These mangroves constitute both natural stands (e.g. Kadolkele) and woodlots planted, protected and managed by fishermen (e.g. Wedikanda) to extract twigs and branches to construct “brush parks”, a traditional method of fishing in this estuary. Both types of mangrove stands support high species richness and structural diversity, indicating planted mangrove areas have reached a semi-natural state. Allometric relationships were used to calculate biomass increment. Differences in litterfall, above and below ground biomass increment and net primary productivity (NPP) of the two types of mangrove areas were statistically insignificant, thus indicating that they are structurally and functionally comparable. Average rate of mangrove litterfall in Negombo estuary was 802 ± 25 g m−2y−1. The average above ground biomass increment was 1213 ± 95 gm−2y−1 and below ground increment was 267 ± 18 gm−2y−1, thus the average NPP of these mangroves was 2282 ± 125 g m−2y−1. NPP showed a decreasing trend from water towards land, in line with plant density and leaf area index. A statistically significant relationship was found between vegetation structure (represented by complexity index), NPP and rate of organic carbon accumulation in mangroves. Potential carbon accumulation capacity of mangroves of Negombo estuary was estimated to be approximately 12 t ha−1y−1, which is equivalent to the amount of carbon emitted as CO2 through combustion of 19,357 L of diesel or 22,212 L of gasoline in motor vehicles. Potential atmospheric carbon removal capacity of Negombo estuarine mangroves (350 ha in extent) therefore was estimated to be 4143 t y−1, which is equivalent to removal of CO2 emitted through combustion of 6,779,000 L of diesel or 7,779,000 L of gasoline within a year.

Identification and characterization of toxins in the venom gland of the Chinese bird spider, Haplopelma hainanum, by transcriptomic analysis.

Tarantula venoms provide a model system for studying toxin selectivity, structure-activity relationships and molecular evolution of peptide toxins. Previous studies have identified a large number of peptide toxins in the venom of the Chinese bird spider Haplopelma hainanum, generally regarded as a highly venomous spider. However, the lack of available RNA-seq transcriptomic and genomic data is an obstacle to understanding its venom at the molecular level. In this study, we investigated the venom gland transcriptome of H. hainanum by RNA-seq, in the absence of an available genomic sequence. We identified 201 potential toxins among 57181 de novo assembled transcripts, including knottins, Kunitz-type toxins, enzymes and other proteins. We systematically identified most of the knottins and Kunitz-type toxins, some of which showed strongly biased expression in the venom gland, including members of the huwentoxin-1, huwentoxin-2 and magi-1 families. We also discovered several novel potential toxins. These data demonstrate the high molecular and structural diversity in the venom toxins of H. hainanum. This study offers a useful strategy for exploring the complex components of spider venoms.

Nucleoside Analogues: Synthesis from Strained Rings

AbstractNucleoside analogues are widely employed as bioactive compounds against cancer and viral infections. Consequently, it is important to develop efficient synthetic methods to access them with high efficiency and structural diversity. Herein, we present a full account of our work on the synthesis of nucleoside analogues via annulations of donor acceptor aminocyclopropanes and aminocyclobutanes. Thymine‐ and uracil‐derived diester cyclopropanes were accessed from the corresponding nucleobases via vinylation and rhodium‐catalyzed cyclopropanation, and were then used in (3+2) annulations with aldehydes, ketones and enol ethers. The obtained analogues could be transformed into important hydroxymethyl derivatives. Thymine and fluoro‐uracil‐derived diester cyclobutanes obtained from the nucleobases via vinylation and (2+2) cycloaddition could also be used in a (4+2) annulation with aldehydes. Finally, purine‐derived diester cyclopropanes could be accessed using the condensation of nucleobases with chloromethyl ethylidene malonates, but annulation reactions with this class of substrates were not successful.

ChemInform Abstract: Design of Chiral Urea‐Quaternary Ammonium Salt Hybrid Catalysts for Asymmetric Reactions of Glycine Schiff Bases.

AbstractThe new catalysts are tested in asymmetric Michael addition reactions and aldol‐initiated cascade reactions.

Surface-active biopolymers from marine bacteria for potential biotechnological applications

Surface-active agents are amphiphilic chemicals that are used in almost every sector of modern industry, the bulk of which are produced by organo-chemical synthesis. Those produced from biological sources (biosurfactants and bioemulsifiers), however, have gained increasing interest in recent years due to their wide structural and functional diversity, lower toxicities and high biodegradability, compared to their chemically-synthesised counterparts. This review aims to present a general overview on surface-active agents, including their classification, where new types of these biomolecules may lay awaiting discovery, and some of the main bottlenecks for their industrial-scale production. In particular, the marine environment is highlighted as a largely untapped source for discovering new types of surface-active agents. Marine bacteria, especially those living associated with micro-algae (eukaryotic phytoplankton), are a highly promising source of polymeric surface-active agents with potential biotechnological applications. The high uronic acids content of these macromolecules has been linked to conferring them with amphiphilic qualities, and their high structural diversity and polyanionic nature endows them with the potential to exhibit a wide range of functional diversity. Production yields (e.g. by fermentation) for most microbial surface-active agents have often been too low to meet the volume demands of industry, and this principally remains as the most important bottleneck for their further commercial development. However, new developments in recombinant and synthetic biology approaches can offer significant promise to alleviate this bottleneck. This review highlights a particular biotope in the marine environment that offers promise for discovering novel surface-active biomolecules, and gives a general overview on specific areas that researchers and the industry could focus work towards increasing the production yields of microbial surface-active agents.