Parent Skeleton Research Articles

The Synthesis of 1H‐Pyrazolo[3,4‐b]quinoxaline Derivatives Oriented towards Modification of Carbocyclic Ring in the Parent Skeleton

AbstractPalladium catalyzed aminoarylation reactions are widely used to create new C−N bonds. It has been proved that the method of synthesis of 1H‐pyrazolo[3,4‐b]quinoxaline derivatives (PQX), consisting of the reductive cyclization of the corresponding pyrazole derivative, is the most universal method of PQX synthesis among the known and is regiospecific. The obtained x‐chloro‐1‐methyl‐3‐phenyl‐1H‐pyrazolo[3,4‐b]quinoxaline isomers were starting materials for the synthesis of N,N‐diethylamine derivatives. The position differentiation of these substituents strongly impact the emissive properties of the final compounds.

Probing Sialidases or Siglecs with Sialic Acid Analogues, Clusters and Precursors

AbstractSialic acids have recently gathered interests of many researchers. Sialidases and Siglecs are two important sialic acids‐related proteins that exist in biological systems, and aberrant sialoside‐Siglec or sialoside‐sialidase interactions are associated with many diseases, including autoimmunity, infection and cancer. Probing sialidase and Siglec effectively can enable the studies on the complex physiological functions of sialic acids. Over the last few decades, many sialic acid derivatives with modifications of parent skeleton and aglycon have been designed to increase the binding affinity with sialidase/Siglec or improve their detection efficiency. At the same time, in‐situ detection has also been aided by metabolic oligosaccharide engineering, in which incubating cells with sialic acid precursors could result in unnatural sialylated glycans incorporated into cellular membrane. In this minireview, we will predominantly highlight the development of sialidase and Siglec probing strategies using sialic acid analogues, clusters and precursors, which may further lay foundation for new diagnostics and treatments.

A Review on Bioactivities of Tobacco Cembranoid Diterpenes.

Cembranoids are carbocyclic diterpenes comprising four isoprene units and are natural products with a parent skeleton consisting of a 14-membered ring. They have gained wide interest in recent years and are a major hotspot in the research of natural product chemistry. Since 1962, various tobacco cembranoid diterpenes have been identified. This review systematically discusses and summarises the excellent antimicrobial, insecticidal, cytotoxic and neuroprotective activities of tobacco cembranoid diterpenes. These compounds show potential to be developed as botanical fungicides, cytotoxic drugs and drugs for the treatment of human immunodeficiency virus, Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. However, there are relatively few studies on the structure–activity relationship (SAR) of tobacco cembranoid diterpenes. Therefore, future studies should focus on their structural modification, SAR and biogenic relationships.

Ultra-Tuning of the Aperture Size in Stiffened ZIF-8_Cm Frameworks with Mixed-Linker Strategy for Enhanced CO2 /CH4 Separation.

ZIF-8 membrane has the potential for CO2 /CH4 separation based on size exclusion. But if traditionally prepared by solvothermal methods, it shows only negligible selectivity due to the linker mobility. Here, ≈500 nm-thin hybrid ZIF-7x -8 membranes with suppressed linker mobility and narrowed window aperture are prepared by a fast current-driven synthesis (FCDS) within 20 min. The in situ electric field during FCDS allows the formation of stiffened ZIF-8_Cm as parent skeleton and the mixed-linker strategy is applied to narrow the aperture size simultaneously. The ZIF-722 -8 membrane shows significantly sharpened molecular sieving for CO2 /CH4 with a separation factor above 25, which soared tenfold compared with other unmodified ZIF-8 membranes. Additionally, the membrane shows exceptional separation performance for H2 /CH4 and CO2 /N2 , with separation factors of 71 and 20, respectively. After 180 h temperature swing operation, it still maintains the excellent separation performance.

Steroidal Oximes: Useful Compounds with Antitumor Activities.

Steroids play an important role in life because they can regulate a variety of biological processes and have been widely used in medicine namely as antiinflammatory, anabolic, contraceptives and anticancer drugs. In recent years, there has been an increasing interest in the introduction of the oxime group in a large variety of molecules in order to increase their biological effects. This review highlights steroidal oximes with anticancer properties and their potential mechanisms of action, as well as data on their relative potencies reported in literature in the last few years. To prepare this review, an extensive literature search was performed on three databases, PubMed, ISI Web of Knowledge and Science Direct, to generate a critical but comprehensive overview of the potential antitumor activities of steroidal oximes. The main keywords used for the search consisted of combinations of the following terms or their synonyms: steroidal oximes, anticancer activity and enzymatic inhibitory activity. The abstracts and full texts were evaluated for their clarity and scientific merit and to further help on the selection of other articles. Over the last decades the introduction of oxime groups in the steroid scaffold is originating molecules with relevant antitumor activities, as well as steroid sulfatase, aromatase, 17α-hydroxylase-17,20-lyase, 5α-reductase and 17β-hydroxysteroid dehydrogenase type 1 inhibitory activities. As relevant examples, pregnenolone 20-oximes showed high activity as 17α-hydroxylase-17,20-lyase and 5α-reductase inhibitors and the introduction of an oxime group at C-6 in androstane series also led to relevant results as aromatase inhibitors. Interestingly, the introduction of this functional group frequently improves the bioactivity when compared with non-oxime analogous compounds, which can be due to extra interactions with biological targets. In addition, it has been observed that varying the position of the hydroximino group on the parent skeleton leads to remarkable changes in the antitumor activity. The recent advances in synthesis and in vitro bioactivity studies of steroidal oximes contributed to understand the potential interest of the introduction of this functional group in the steroidal nucleus in the development of anticancer molecules. Moreover, the cytotoxic/enzyme inhibitory activity usually depends on the position of the oxime group in different steroid scaffolds. However, despite the promising results, it is necessary to perform more in vitro and in vivo assays not only to better explore the mechanisms of action but also to confirm the potential effectiveness and safety of this interesting family of compounds in clinical practice.

Stolonial Movement: A New Type of Whole-Organism Behavior in Porifera.

Sponges (phylum Porifera) traditionally are represented as inactive, sessile filter-feeding animals devoid of any behavior except filtering activity. However, different time-lapse techniques demonstrate that sponges are able to show a wide range of coordinated but slow whole-organism behavior. The present study concerns a peculiar type of such behavior in the psychrophilic demosponge Amphilectus lobatus: stolonial movement. During stolonial movement, sponges produce outgrowths (stolons) that crawl along a substrate with a speed of 4.4 ± 2.2 μm min-1 and branch, thus forming a complex net covering a considerable area of a substrate. This net is used by sponges to search for new points with appropriate environmental conditions for individual relocation. After such points are found, all cells of the parental sponge migrate through stolons, leaving a naked parental skeleton, forming one or several filial sponges in the new location. Thus, stolonial movement combines traits of crawling along the substrate and asexual reproduction. This behavior relies on massive cell dedifferentiation followed by coordinated cell migration to the point of new sponge body formation and their subsequent differentiation into specialized cell types.

Total Synthesis of Desmethyl Jahanyne and Its Lipo-Tetrapeptide Conjugates Derived from Parent Skeleton as BCL-2-Mediated Apoptosis-Inducing Agents.

The total synthesis of highly potent and scarcely available marine natural product (−)-jahanyne was attempted resulting in a solution-phase synthesis of pruned versions with comparable activity. A simple and facile synthetic route was employed for the preparation of pruned congeners and would be scalable. The lipophilic tail of the natural product was synthesized from R-(+)-citronellol, utilizing easily available chemicals. All the synthesized compounds were screened for apoptotic activity against a panel of cell lines. These compounds depicted marked binding to B cell lymphoma 2 till 50 °C in cellular thermal shift analysis.

Human neutrophil elastase inhibitory potential of flavonoids from Campylotropis hirtella and their kinetics

Campylotropis hirtella is used as a food supplement in the subtropical region of China. In an intensive hunt for human neutrophil elastase inhibitors, we isolated eight flavonoids from C. hirtella three of which (1–3) emerged to be elastase inhibitors. Geranylated flavonoids (1–3) displayed significant inhibitory activity with IC50s between 8.5 and 30.8 μM. The most striking example was geranylated isofavanone 3 that inhibited elastase significantly (IC50 = 30.8 μM) but its parent compound (dalbergioidin) and isoflavone analog (5) were inactive (IC50 > 200 μM). Compounds (1–3) displayed different kinetic mechanisms (noncompetitive, competitive, and mixed type, respectively) that were dependent upon the parent skeleton. The competitive inhibitor, isoflavan-3-ol-4-one 2 manifested an inhibition of isomerization profile for elastase with kinetic parameters K5 = 0.0386 M−1S−1, K6 = 0.0244 μM−1S−1 and Kiapp = 16.3427 μM. The specific identification of metabolites was accomplished by LC-DAD-ESI/MS that was also used to analyze abundance of active components (1–3) within the plant.

ST09, a Novel Thioester Derivative of Tacrine, Alleviates Cognitive Deficits and Enhances Glucose Metabolism in Vascular Dementia Rats

Chemical entities containing mercapto group have been increasingly attractive in the therapy of central nerve system (CNS) diseases. In the recent study, we screened a series of mercapto-tacrine derivatives with synergistic neuropharmacological profiles in vitro. We investigated the effect and mechanism of ST09, a thioester derivative of tacrine containing a potential mercapto group, on the vascular dementia (VaD) model of rat induced by bilateral common carotid arteries occlusion (2-VO). ST09 and its active metabolite ST10 retained excellent inhibition on acetylcholinesterase (AChE) activity. ST09 significantly attenuated the 2-VO-induced impairment in spatial acquisition performance and inhibited the 2-VO-induced rise of AChE activity. In the VaD model, ST09 attenuated the oxidative stress and decreased the apoptosis in the cortex and hippocampus. Compared with donepezil, ST09 exhibited a better effect on the regeneration of free thiols in 2-VO rats. Interestingly, ST09, not donepezil, greatly improved glucose metabolism in various brain regions of 2-VO rats using functional imaging of (18) F-labeled fluoro-deoxyglucose (FDG) positron emission tomography (PET). ST09 may serve as a more promising agent for the therapy of VaD than tacrine owing to the introduction of a potential mercapto group into the parent skeleton.

ChemInform Abstract: Sidearm as a Control in the Asymmetric Ring Opening Reaction of Donor—Acceptor Cyclopropane.

AbstractTrisoxazoline and bisthiazoline based ligands with a chiral backbone on the sidearm and without chiral motif on the parent skeleton efficiently promote the amine nucleophilic ring opening reaction of 1,1‐cyclopropane diesters to γ‐amino acid derivatives.

Synthesis, structure and properties of C3-symmetric heterosuperbenzene with three BN units.

The parent skeleton of BN heterocoronene with three BN units and C3 symmetry was synthesized as a model compound of BN-doped graphene. Further investigation of this graphene-type molecule revealed the important role of BN doping in opening the bandgap and modulating the electronic properties.

Sidearm as a Control in the Asymmetric Ring Opening Reaction of Donor‐Acceptor Cyclopropane

AbstractA new type of trisoxazoline and bisthiazoline based ligands have been developed,which are absent of chiral motif on the parent skeleton and containa chiral backbone on sidearm. The ligands promote the amine nucleophilic ring opening reaction of 1,1‐cyclopropane diesters smoothly, furnishing the γ‐amino acid derivatives in high yield with moderate to good enantioselectivity.

Enumeration of substitutional isomers with restrictive mutual positions of ligands. II. Counts with restrictions on (sub)symmetry

The present paper extends our previous discussion of paper I on “Overall Counts”, still focusing on enumerations of substitutional isomers with restrictive positioning of ligands. But now, we address the counts of such isomers with a specified subsymmetry of the symmetry of the parent skeleton. Constrained analogs of Polya’s cycle index still appear, but now we introduce more powerful technical tools to include subsymmetry-specified generalizations of the cycle index. This involves differential-operator approach for analytically treating newly derived hybrids of the the generalized cycle index and suitable F-polynomials. As a simple illustration of the general mathematical exposition, a specific problems are solved and some tasks for possible further consideration are also stated, where again the Maple symbolic manipulation package proves useful.

Identification and Characterization of the Linalool/Nerolidol Synthase from Streptomyces clavuligerus

No cyclization: To produce the parent skeletons of diverse terpenoids, linear isoprenyl diphosphate precursors are usually cyclized by terpenoid cyclases. However, some terpenoid synthases produce acyclic terpenoids from the linear substrates. The linalool/nerolidol synthase reported here is the first example of a bacterial acyclic terpenoid synthase that shows significant homology to bacterial terpenoid cyclases.

The membrane transport of flavonoids from Crossostephium chinense across the Caco‐2 monolayer

The permeation and efflux of six polysubstituted flavonoids isolated from Crossostephium chinense, a Chinese traditional and herbal drug for the treatment of diabetes, were investigated using the Caco-2 cell monolayer. The six flavonoids (selagin, apometzgerin, tricetin-3',4',5'-trimethylether, quercetagetin-3,6,7-trimethylether, hispidulin and quercetagetin) sharing a similar parent skeleton structure with varied substituents in the heterocyclic ring B were selected for the study. Quercetagetin exhibited a low bi-directional permeability comparable to that of atenolol, suggesting a paracellular diffusion mechanism. The remaining compounds exhibited time- and concentration- dependent permeation with apparent permeability coefficient (P(app)) values in the range 10⁻⁶-10⁻⁵ cm/s, suggesting transcellular diffusion pathways. Selagin exhibited significantly larger basolateral to apical P(app) than that of the reverse direction, suggesting the existence of efflux mechanisms. ATP-depletion and probenecid pretreatment led to a significant inhibition of the efflux of selagin, whereas verapamil had no effect on the basolateral to apical transport of selagin, suggesting that multidrug resistance proteins (MRPs) and not P-glycoprotein play a role in the intestinal efflux of selagin. Based on present and previous results, the structure-permeation relationship and the role of MRPs in mediating the efflux of flavonoids are discussed. Experimental results in this study provide useful information for pharmacological applications of the flavonoids from C. chinense.

Synthesis and Antineoplastic Activity of O‐Alkylated Derivatives of 7‐Hydroximinoandrost‐5‐ene Steroids

Varied positioning of the hydroximino group on the parental steroid skeleton results in remarkable changes in the antineoplastic activity profile of the compounds. Here, the compound 7-oximino-5-androstene and its O-alkylated derivatives have been prepared and screened for cytotoxic and aromatase inhibitory activity. The steroidal 7-oximino ether derivatives exhibited insignificant cytotoxic effects when screened against three cancer cell lines, MCF-7 (breast), NCl-H460 (lung), and SF-268 (CNS) at 100 microM. However, the imidazolyl-substituted steroidal oxime ethers displayed moderate inhibition of cytochrome P450 aromatase.

Asymmetry of the craniofacial skeleton in the parents of children with a cleft lip, with or without a cleft palate, or an isolated cleft palate

The objective of this study was to evaluate asymmetry of the parental craniofacial skeleton of subjects with a cleft lip, with or without cleft palate [CL(P)], and isolated cleft palate (CP). The postero-anterior (PA) cephalograms of 52 parents of children with CL(P) and 40 parents of children with CP from a sample of 196 children with non-syndromic clefts in the west of Scotland were analysed. A conventional cephalometric asymmetry analysis was used to evaluate size-related right:left asymmetry comprising eight linear distances, nine angular, and three facial area measurements. Right:left ratios of the mean values identified the direction of the asymmetry and two-sample t-tests determined statistical significance. A shape-related asymmetry analysis was also undertaken. The configurations of landmarks were optimally superimposed and scaled using Procrustes algorithms. Euclidean distance matrix analysis (EDMA) was then compared and the shape of the left and the right landmark configurations were statistically tested using a non-parametric bootstrap technique. For the parents of CL(P) children, size-related asymmetry was identified and the area of the craniofacial polygon was statistically significantly larger on the right than on the left side. EDMA detected the presence of shape-related asymmetry (T statistic = 1.304; P = 0.003). For the parents of CP children, although size-related asymmetry was identified, EDMA did not identify shape-related asymmetry (T statistic = 1.281; P = 0.065). Size and shape directional asymmetries are characteristic features of the parental craniofacial skeleton in CL(P). Although directional size asymmetry is present in the parental craniofacial skeleton in CP, shape asymmetry is not a characteristic feature.

Crystal Structure Analysis and in Silico pKa Calculations Suggest Strong pKa Shifts of Ligands as Driving Force for High‐Affinity Binding to TGT

A novel ligand series is presented to inhibit tRNA-guanine transglycosylase (TGT), a protein with a significant role in the pathogenicity mechanism of Shigella flexneri, the causative agent of Shigellosis. The enzyme exchanges guanine in the wobble position of tRNA(Asn,Asp,His,Tyr) against a modified base. To prevent the base-exchange reaction, several series of inhibitors have already been designed, synthesized, and tested. One aim of previous studies was to address a hydrophobic pocket with different side chains attached to the parent skeletons. Disappointingly, no significant increase in binding affinity could be observed that could be explained by the disruption of a conserved water cluster. The ligand series examined in this study are based on the known scaffold lin-benzoguanine. Different side chains were introduced leading to 2-amino-lin-benzoguanines, which address a different pocket of the protein and avoid disruption of the water cluster. With the introduction of an amino group in the 2-position, a dramatic increase in binding affinity can be experienced. To explain this significant gain in binding affinity, Poisson-Boltzmann calculations were performed to explore pK(a) changes of ligand functional groups upon protein binding, they can differ significantly on going from aqueous solution to protein environment. For all complexes, a permanent protonation of the newly designed ligands is suggested, leading to a charge-assisted hydrogen bond in the protein-ligand complex. This increased strength in hydrogen bonding takes beneficial effect on binding affinity of the ligands, resulting in low-nanomolar binders. Crystal structures and docking emphasize the importance of the newly created charge-assisted hydrogen bond. A detailed analysis of the crystal structures in complex with substituted 2-amino-lin-benzoguanines indicate pronounced disorder of the attached side chains addressing the ribose 33 binding pocket. Docking suggests multiple orientations of these side chains. Obviously, an entropic advantage of the residual mobility experienced by these ligands in the bound state is beneficial and reveals an overall improved protein binding.

Discovery of the First Selective Inhibitor of Excitatory Amino Acid Transporter Subtype 1

The discovery of the first class of subtype-selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rat orthologue GLAST is reported. An opening structure-activity relationship of 25 analogues is presented that addresses the influence of substitutions at the 4- and 7-positions of the parental skeleton 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. The most potent analogue 1o displays high nanomolar inhibitory activity at EAAT1 and a >400-fold selectivity over EAAT2 and EAAT3, making it a highly valuable pharmacological tool.

Studies of intestinal permeability of 36 flavonoids using Caco-2 cell monolayer model

To investigate the structure–permeability relationship of dietary/nutriceutic flavonoids, the transepithelial transport and cellular uptake of 36 flavonoids (including flavones, flavonols, dihydroflavones, dihydroflavonols, isoflavones, chalcones, flavanes, flavanols, methylated and glycosidic derivatives) were investigated using the Caco-2 cell monolayer. The apparent permeability coefficients ( P app) of the flavonoids were calculated from bilateral transport assays in the Transwell system with flavonoid determination using a high performance liquid chromatography (HPLC) coupled with a UV detector. The most flavonoids exhibited concentration-independent P app values and a ratio of 0.5–1.8 for P app AB to BL/ P app BL to AB, suggesting passive diffusion pathways. However, certain flavonoids e.g. morin and some flavonoid glycosides may involve the efflux mechanisms. For isoflavones, flavones, and dihydroflavones, the oil/water partition coefficients (additionally modified by the number and position of the three hydroxyl groups) was the key determinant for Caco-2 cell permeation. However, the permeability of flavonols is more complex with their structure possibly related to their high rate of cell accumulation. Overall, the parental skeleton structure, the number and position of free hydroxyl groups, accumulation and efflux in Caco-2 cell play the key roles in the transport of flavonoids across Caco-2 cell monolayer.