Wide Range Of Structural Diversity Research Articles

Lineage-Specific CYP80 Expansion and Benzylisoquinoline Alkaloid Diversity in Early-Diverging Eudicots.

Menispermaceae species, as early-diverging eudicots, can synthesize valuable benzylisoquinoline alkaloids (BIAs) like bisbenzylisoquinoline alkaloids (bisBIAs) and sinomenines with a wide range of structural diversity. However, the evolutionary mechanisms responsible for their chemo-diversity are not well understood. Here, a chromosome-level genome assembly of Menispermum dauricum is presented and demonstrated the occurrence of two whole genome duplication (WGD) events that are shared by Ranunculales and specific to Menispermum, providing a model for understanding chromosomal evolution in early-diverging eudicots. The biosynthetic pathway for diverse BIAs in M. dauricum is reconstructed by analyzing the transcriptome and metabolome. Additionally, five catalytic enzymes - one norcoclaurine synthase (NCS) and four cytochrome P450 monooxygenases (CYP450s) - from M. dauricum are responsible for the formation of the skeleton, hydroxylated modification, and C-O/C-C phenol coupling of BIAs. Notably, a novel leaf-specific MdCYP80G10 enzyme that catalyzes C2'-C4a phenol coupling of (S)-reticuline into sinoacutine, the enantiomer of morphinan compounds, with predictable stereospecificity is discovered. Moreover, it is found that Menispermum-specific CYP80 gene expansion, as well as tissue-specific expression, has driven BIA diversity in Menispermaceae as compared to other Ranunculales species. This study sheds light on WGD occurrences in early-diverging eudicots and the evolution of diverse BIA biosynthesis.

Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002-2020).

The tetrahydroisoquinoline (THIQ) natural products constitute one of the largest families of alkaloids and exhibit a wide range of structural diversity and biological activity. Ranging from simple THIQ natural products to complex trisTHIQ alkaloids such as the ecteinascidins, the chemical syntheses of these alkaloids and their analogs have been thoroughly investigated due to their intricate structural features and functionalities, as well as their high therapeutic potential. This review describes the general structure and biosynthesis of each family of THIQ alkaloids as well as recent advancements of the total synthesis of these natural products from 2002 to 2020. Recent chemical syntheses that have emerged harnessing novel, creative synthetic design, and modern chemical methodology will be highlighted. This review will hopefully serve as a guide for the unique strategies and tools used in the total synthesis of THIQ alkaloids, as well as address the longstanding challenges in their chemical and biosynthesis.

Multifunctional Carbon-Based Nanoparticles: Theranostic Applications in Cancer Therapy and Diagnosis

Cancer diagnosis and treatment are the most critical challenges in modern medicine. Conventional cancer treatments no longer meet the needs of the health field due to the high rate of mutations and epigenetic factors that have caused drug resistance in tumor cells. Hence, the search for unique methods and factors is quickly expanding. The development of nanotechnology in medicine and the search for a system to integrate treatment and diagnosis to achieve an effective approach to overcome the known limitations of conventional treatment methods have led to the emergence of theranostic nanoparticles and nanosystems based on these nanoparticles. An influential group of these nanoparticles is carbon-based theranostic nanoparticles. These nanoparticles have received significant attention due to their unique properties, such as electrical conductivity, high strength, excellent surface chemistry, and wide range of structural diversity (graphene, nanodiamond, carbon quantum dots, fullerenes, carbon nanotubes, and carbon nanohorns). These nanoparticles were widely used in various fields, such as tissue engineering, drug delivery, imaging, and biosensors. In this review, we discuss in detail the recent features and advances in carbon-based theranostic nanoparticles and the advanced and diverse strategies used to treat diseases with these nanoparticles.

Profiling of Plant Derived Natural Constituents by Using Magnetic Resonance Techniques

Plants are reservoirs of naturally occurring chemical constituents with a wide range of structural diversity. These biological compounds can be derived from different parts of plants such as leaves, barks, seeds, seed coats, flowers, and roots. A broad array of secondary metabolic compounds is present in the plants such as antibiotics, alkaloids, antimicrobials, food-grade pigments, and phenolics which have been reported to possess numerous health-related benefits, including antioxidant, anti-inflammatory, anticancer, and antiobesity activities. Therefore, the identification and detection of these compounds are of utmost importance in order to utilise their benefits into various fields. Wherein, magnetic resonance techniques, such as NMR (nuclear magnetic resonance), MRI (magnetic resonance imaging), and EPR (electron paramagnetic resonance), being far more reproducible, nondestructive, than other analytical techniques such as liquid chromatography, mass spectroscopy, and high-performance liquid chromatography cover a much wider dynamic range of metabolites with easy sample preparation techniques with high speed and fidelity. Hence, these magnetic resonance techniques have been proven to be extremely useful in plant metabolite profiling and disease metabolomics, along with structural elucidation of bioactive compounds from plant sources. Therefore, the present review focuses on the effectiveness of magnetic resonance for the detection of plant-derived metabolites that may lead to new areas of research in various fields such as drug discovery and development, metabolomics, combinatorial chemistry, and assessing overall food safety and quality.

A Retrospective Look at the Impact of Binding Site Environment on the Optimization of TRPA1 Antagonists.

Transient receptor potential ankyrin 1 (TRPA1) antagonists have generated broad interest in the pharmaceutical industry for the treatment of both pain and asthma. Over the past decade, multiple antagonist classes have been reported in the literature with a wide range of structural diversity. Our own work has focused on the development of proline sulfonamide and hypoxanthine-based antagonists, two antagonist classes with distinct physicochemical properties and pharmacokinetic (PK) trends. Late in our discovery program, cryogenic electron microscopy (cryoEM) studies revealed two different antagonist binding sites: a membrane-exposed proline sulfonamide transmembrane site and an intracellular hypoxanthine site near the membrane interface. A retrospective look at the discovery program reveals how the different binding sites, and their location relative to the cell membrane, influenced the optimization trajectories and overall drug profiles of each antagonist class.

Nickel-Catalyzed C(sp3)-H Functionalization of Benzyl Nitriles: Direct Michael Addition to Terminal Vinyl Ketones.

An efficient nickel(0)-catalyzed addition of benzyl nitriles to terminal vinyl ketones via C(sp3)-H functionalization has been developed. The reaction provides a novel and efficient protocol for the synthesis of α-functionalized benzyl nitriles with a wide range of structural diversity under mild reaction conditions while obviating the use of a strong base. The work might be potentially useful toward the development of an enantioselective variant using chiral nitrogen ligands.

The Existing Methods and Novel Approaches in Mycotoxins' Detection.

Mycotoxins represent a wide range of secondary, naturally occurring and practically unavoidable fungal metabolites. They contaminate various agricultural commodities like cereals, maize, peanuts, fruits, and feed at any stage in pre- or post-harvest conditions. Consumption of mycotoxin-contaminated food and feed can cause acute or chronic toxicity in human and animals. The risk that is posed to public health have prompted the need to develop methods of analysis and detection of mycotoxins in food products. Mycotoxins wide range of structural diversity, high chemical stability, and low concentrations in tested samples require robust, effective, and comprehensible detection methods. This review summarizes current methods, such as chromatographic and immunochemical techniques, as well as novel, alternative approaches like biosensors, electronic noses, or molecularly imprinted polymers that have been successfully applied in detection and identification of various mycotoxins in food commodities. In order to highlight the significance of sampling and sample treatment in the analytical process, these steps have been comprehensively described.

Building trans-bicyclo[4.4.0]decanes/decenes in complex multifunctional frameworks: the case for antibiotic development.

Covering: 2000 to 2020. trans-Bicyclo[4.4.0]decane/decene (such as trans-decalin and trans-octalin)-containing natural products display a wide range of structural diversity and frequently exhibit potent and selective antibacterial activities. With one of the major factors in combatting antibiotic resistance being the discovery of novel scaffolds, the efficient construction of these natural products is an attractive pursuit in the development of novel antibiotics. This highlight aims to provide a critical analysis on how the presence of dense architectural and stereochemical complexity necessitated special strategies in the synthetic pursuits of these natural trans-bicyclo[4.4.0]decane/decene antibiotics.

The Physiological Functions of Universal Stress Proteins and Their Molecular Mechanism to Protect Plants From Environmental Stresses.

Since the original discovery of a Universal Stress Protein (USP) in Escherichia coli, a number of USPs have been identified from diverse sources including archaea, bacteria, plants, and metazoans. As their name implies, these proteins participate in a broad range of cellular responses to biotic and abiotic stresses. Their physiological functions are associated with ion scavenging, hypoxia responses, cellular mobility, and regulation of cell growth and development. Consistent with their roles in resistance to multiple stresses, USPs show a wide range of structural diversity that results from the diverse range of other functional motifs fused with the USP domain. As well as providing structural diversity, these catalytic motifs are responsible for the diverse biochemical properties of USPs and enable them to act in a number of cellular signaling transducers and metabolic regulators. Despite the importance of USP function in many organisms, the molecular mechanisms by which USPs protect cells and provide stress resistance remain largely unknown. This review addresses the diverse roles of USPs in plants and how the proteins enable plants to resist against multiple stresses in ever-changing environment. Bioinformatic tools used for the collection of a set of USPs from various plant species provide more than 2,100 USPs and their functional diversity in plant physiology. Data from previous studies are used to understand how the biochemical activity of plant USPs modulates biotic and abiotic stress signaling. As USPs interact with the redox protein, thioredoxin, in Arabidopsis and reactive oxygen species (ROS) regulates the activity of USPs, the involvement of USPs in redox-mediated defense signaling is also considered. Finally, this review discusses the biotechnological application of USPs in an agricultural context by considering the development of novel stress-resistant crops through manipulating the expression of USP genes.

Effect of surface hydroxyl groups on heat capacity of mesoporous silica

This paper quantifies the effect of surface hydroxyl groups on the effective specific and volumetric heat capacities of mesoporous silica. To achieve a wide range of structural diversity, mesoporous silica samples were synthesized by various methods, including (i) polymer-templated nanoparticle-based powders, (ii) polymer-templated sol-gel powders, and (iii) ambigel silica samples dried by solvent exchange at room temperature. Their effective specific heat capacity, specific surface area, and porosity were measured using differential scanning calorimetry and low-temperature nitrogen adsorption-desorption measurements. The experimentally measured specific heat capacity was larger than the conventional weight-fraction-weighted specific heat capacity of the air and silica constituents. The difference was attributed to the presence of OH groups in the large internal surface area. A thermodynamic model was developed based on surface energy considerations to account for the effect of surface OH groups on the specific and volumetric heat capacity. The model predictions fell within the experimental uncertainty.

ChemInform Abstract: Asymmetric Synthesis of Isoquinoline Alkaloids: 2004—2015

AbstractReview: 308 refs.

Asymmetric Synthesis of Isoquinoline Alkaloids: 2004-2015.

In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet-Spengler, the Bischler-Napieralski, and the Pomeranz-Fritsch-Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1-N2, N2-C3, C1-N2/N2-C3, and C1-N2/C4-C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis.

A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.

The carbon balance pivot point of southwestern U.S. semiarid ecosystems: Insights from the 21st century drought

AbstractGlobal‐scale studies indicate that semiarid regions strongly regulate the terrestrial carbon sink. However, we lack understanding of how climatic shifts, such as decadal drought, impact carbon sequestration across the wide range of structural diversity in semiarid ecosystems. Therefore, we used eddy covariance measurements to quantify how net ecosystem production of carbon dioxide (NEP) differed with relative grass and woody plant abundance over the last decade of drought in four Southwest U.S. ecosystems. We identified a precipitation “pivot point” in the carbon balance for each ecosystem where annual NEP switched from negative to positive. Ecosystems with grass had pivot points closer to the drought period precipitation than the predrought average, making them more likely to be carbon sinks (and a grass‐free shrubland, a carbon source) during the current drought. One reason for this is that the grassland located closest to the shrubland supported higher leaf area and photosynthesis at the same water availability. Higher leaf area was associated with a greater proportion of evapotranspiration being transpiration (T/ET), and therefore with higher ecosystem water use efficiency (gross ecosystem photosynthesis/ET). Our findings strongly show that water availability is a primary driver of both gross and net semiarid productivity and illustrate that structural differences may contribute to the speed at which ecosystem carbon cycling adjusts to climatic shifts.

ChemInform Abstract: Gold‐Catalyzed Multiple Cascade Reaction of 2‐Alkynylphenylazides with Propargyl Alcohols.

AbstractThe title reaction allows the step‐economical synthesis of pyrroloindolone derivatives, such as (III), (VI), and (VIII), with a wide range of structural diversity.

Gold-catalyzed multiple cascade reaction of 2-alkynylphenylazides with propargyl alcohols.

An unprecedented gold-catalyzed multiple cascade reaction between 2-alkynyl arylazides and alkynols has been developed, allowing for the step-economical synthesis of pyrroloindolone derivatives with a wide range of structural diversity. In this reaction, the gold complex participates in triple catalysis in tandem fashion. Moreover, the efficient chirality transfer from optically pure alkynol substrates enables facile access to chiral pyrroloindolone derivatives with two stereogenic centers, including a quaternary one, with excellent levels of optical purity.

Unsaturated Lactams: New Inputs for Povarov-Type Multicomponent Reactions

Unsaturated lactams with endo- or exocyclic C-C double bonds constitute a set of reactive inputs that serve as the electron-rich olefin component in Povarov reactions. These substrates afford the multicomponent adducts in convenient yields and offer a wide range of structural diversity. Postcondensation transformations allow direct access to a variety of lactam-fused and amide-substituted quinoline derivatives.

Strategies for the Total Synthesis of C2−C11 Cyclized Cembranoids

The C2-C11 cyclized cembranoids, which include the eunicellins (also known as the cladiellins), briarellins, asbestinins, and sarcodictyins, are secondary metabolites isolated from gorgonian octocorals and soft corals. An unusual oxatricyclic ring system containing a hydroisobenzofuran and an oxonene unit with stereogenic centers residing at C1-3, 9, 10, and 14 is common to the eunicellins, briarellins, and asbestinins. However, the location of the cyclohexyl methyl groups (C11 versus C12) and the oxidation level of the sixand nine-membered rings differ among the three classes. Faulkner has proposed that the cyclization of the cembranoid diterpene skeleton initiates a biosynthetic pathway that leads to all four subclasses of these unusual molecules (Figure 1). Beginning with the cembrane skeleton, C2-C11 cyclization provides the cladiellin framework. An intramolecular etherification of the cladiellin tricycle affords the tetracyclic framework of the briarellin subclass, and a subsequent 1,2-suprafacial methyl shift of the briarellin structure is postulated to deliver the asbestinins as the class that is furthest evolved from the cembrane skeleton. The presence of multiple structural types in a common organism provides circumstantial evidence for Faulkner’s proposed biosynthetic pathway. The isolation of a cembrane metabolite with cladiellin metabolites in Alcyonium molle and with asbestinin metabolites in Briareum steckii are specific examples. The sarcodictyins are also proposed to arise from a C2-C11 cyclization of the cembrane skeleton; however, in these systems, the cyclization results in a fused cyclohexane and oxonane in place of the hydroisobenzofuran of the cladiellins, briarellins, and asbestinins. As a result of this significant structural variation of the sarcodictyins, the synthetic approaches to these molecules are quite different than those for the other three related subclasses. This review will cover efforts toward the eunicellins, briarellins, and asbestinins but will not cover efforts toward the total synthesis of the sarcodictyins. Eunicellin was the first reported member of the C2-C11 cyclized cembranoid natural products, isolated in 1968 by Djerassi and co-workers from the soft coral Eunicella stricta found off the coast of Banyuls-sur-Mer in France. Since this discovery, over 100 unique secondary metabolites of gorgonian octocorals have been characterized, including the first asbestinin in 1980 and the first briarellin in 1995. A wide range of structural diversity is displayed by this group of marine natural products. The natural role of these cembranoids is proposed, based upon mollusk and fish lethality assays, to involve predation deterrence. Upon further investigation, several of the members of these subclasses have demonstrated significant pharmacological potential. Particularly, these diterpenes have been shown to exhibit in vitro cytotoxicity against various cancer cell lines, anti-inflammatory properties, antimicrobial activities, and histamine and acetylcholine antagonism. The fascinating molecular architecture of these cembranoids, as well as their potential as therapeutic agents, has sparked much interest in the synthetic community over the past decade. A variety of approaches toward these challenging structural motifs have been investigated and several total syntheses have been accomplished. Efforts toward the total synthesis of the cladiellins, briarellins, and asbestinins are the subject of this review.

Therapeutic potential of mitotic kinesin inhibitors in cancer

Background: Mitotic kinesins are attractive targets in cancer chemotherapy. A large number of small-molecule inhibitors of kinesin spindle protein (KSP) and centromere-associated protein E (CENP-E) have been discovered. Objective: To estimate the therapeutic potential of mitotic kinesin inhibitors. Methods: We comprehensively summarized and analysed the trend among recent patents and conducted a literature review of clinical trials performed since July 2004. Results/conclusion: More than 80 patent applications have been made, spanning a wide range of structural diversity. Five KSP inhibitors and one CENP-E inhibitor have advanced to the early clinical stage, and some of the results for these clinical trials have been disclosed. The therapeutic potential for mitotic kinesin inhibitors is likely to become obvious within the next few years.

Synthesis of Naturally Occurring Polyynes

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