Tricyclic System Research Articles

Eremophilane Sesquiterpenoids with Antibacterial and Anti-inflammatory Activities from the Endophytic Fungus Septoria rudbeckiae.

Fourteen eremophilane sesquiterpenoids (1-14), including nine new congeners, septoreremophilanes A-I (1-9), together with three known sesquiterpenes (15-17), two known tetralone derivatives (18, 19), and two known cholesterol analogues (20, 21), were isolated from the endophytic fungus Septoria rudbeckiae. Compounds 1-6 and 7a belong to the family of the highly oxygenated eremophilane sesquiterpenoids with a 6/6/5 tricyclic system and bearing a hemiacetal moiety. The inhibitions of all metabolites against eight bacteria were estimated in vitro, and nine new metabolites (1-9) were tested for antineuroinflammatory activity. Notably, the effects of 4 against Pseudomonas syringae pv. actinidae and 20 against Bacillus cereus displayed potent inhibitory, with the MIC values of 6.25 and 6.25 μM, respectively. Further, scanning electron microscopy analyses indicated that 4 and 20 were to change the outer configuration of bacterial cells, respectively, and the investigations demonstrated that 4 and 20 may act as potential structure templates for the development of the agrochemical bactericides. Additionally, compound 6 displayed potent inhibition of NO generation in lipopolysaccharide-induced BV-2 microglial cells (IC50 = 12.0 ± 0.32 μM), and the conceivable anti-inflammatory mechanisms implicated were also investigated by molecular docking. Thus, the bioactive metabolites of the strain S. rudbeckiae may serve as a novel resource to be developed.

SYNTHESIS AND BROMINATION OF 2-METALLYLTHIO-3-HYDROXYIMINOMETHYLQUINOLINE

Quinoline and its condensed analogues are an important class of heterocycles with a wide range of biological activity. Many quinoline derivatives are used as substrates in organic synthesis and molecular design of pharmacologically active substances with different effects. Its reported a number of natural compounds containing a quinoline fragment are used as drugs. The annulation of azole and azine heterocycles to the quinoline backbone expands the search for biologically active compounds in this series. The most convenient and most effective method of annulation of additional cycles to quinoline is the reaction of electrophilic intramolecular cyclization of its unsaturated derivatives with various electrophilic reagents. Therefore, the synthesis of previously unknown polycyclic quinoline derivatives is an urgent problem.
 The purpose of this work is to study of the regio-selectivity of the process of electrophilic intramolecular cyclization of 2-methallylthio-3-(hydroxyiminomethyl)quinoline.
 The model oxime was obtained by the condensation reaction of 3-formyl-2-methalylthioquinoline with hydroxylamine hydrochloride in an alcohol-alkaline medium. 2-Methallylthio-3-(hydroxyiminomethyl)quinoline has several nucleophilic centers for studying of the regioselectivity of electrophilic heterocyclization - a multiple bond of a methallyl fragment, an endocyclic nitrogen atom of quinolone cycle, an exocyclic nitrogen atom of an imino group and an exocyclic atom oxygen of ОН- group. During the bromination of such an oxime, the formations of both a linear and angular tricyclic system are possible. It was found that when brominated with a double excess of bromine in chloroform medium, the thiazole cycle is annealed to the quinoline backbone to form 1-bromomethyl-4-((hydroxyimino)methyl)-1-methyl-1,2-dihydrothiazolo[3,2-a]-quinolin-10-ium tribromide.
 Thus, as a result of the performed research, the 2-methallylthio-3-(hydroxyiminomethyl) quinoline was obtained and its bromination was carried out. It is proved that the bromocyclization of the model oxime occurs regio-selectively with the formation of angular tribromide of 1-bromomethyl-4 -((hydroxyimino)methyl) -1-methyl-1,2-dihydrothiazolo [3,2-a] quinolin-10-ium. This tricyclic salt has the potential to have high biological activity.

Synthesis of Three-Dimensional (Di)Azatricyclododecene Scaffold and Its Application to Peptidomimetics.

A novel sp3 carbon-rich tricyclic 3D scaffold-based peptide mimetic compound library was constructed to target protein-protein interactions. Tricyclic framework 7 was synthesized from 9-azabicyclo[3,3,1]nonan-3-one (11) via a gold(I)-catalyzed Conia-ene reaction. The electron-donating group on the pendant alkyne of cyclization precursor 12 b-e was the key to forming 6-endo-dig cyclized product 7 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 7, a diazatricyclododecene 3D-scaffold 8 a, which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 21 a-u were synthesized via step-by-step installation of three substituents on diazatricyclododecene scaffold 8 a. Compounds 21 a-h were synthesized as α-helix peptide mimics of hydrophobic ZZxxZ and ZxxZZ sequences (Z=Leu or Phe) and subjected to cell-based assays: antiproliferative activity, HIF-1 transcriptional activity which is considered to affect cancer malignancy, and antiviral activity against rabies virus. Compound 21 a showed the strongest inhibitory activity of HIF-1 transcriptional activity (IC50 =4.1±0.8 μM), whereas compounds 21 a-g showed antiviral activity with IC50 values of 4.2-12.4 μM, suggesting that the 3D-scaffold 8 a has potential as a versatile peptide mimic skeleton.

Interaction of new tri-, tetra-, and pentacyclic azaphenothiazine derivatives with calf thymus DNA: Spectroscopic and molecular docking studies

Azaphenothiazines (AZA), modified phenothiazine derivatives, have been reported to exhibit a wide spectrum of biological activities, including anticancer activities, but the mechanisms of their interactions with biomolecules are not fully recognized. In this work, the mode of interaction of selected AZA with calf thymus DNA was investigated using UV–Vis absorption, fluorescence spectroscopy (competition experiment with ethidium bromide, quenching of fluorescence) and molecular docking. The investigated AZA represent dipyrido[3,4-b;3′4′-e][1,4]thiazine, quino[3,2-b]benzo[1,4]thiazine and diquino[3,2-b;2′,3′-e][1,4]thiazine possessing tricyclic, tetracyclic and pentacyclic ring system with the additional N,N-dimethylaminopropyl group at the nitrogen atom in the 1,4 thiazine ring. The results obtained from spectroscopic studies showed that AZA bind to DNA by insertion of a fragment of the fused rings system between the base pair stack in the double helix of DNA. In addition, the number of rings in the AZA structures seemed to be related to the strength of the interaction, because pentacyclic AZA (binding constant Kb = 6.31 × 106 L/mol) demonstrated 10-fold higher affinity towards DNA than the tetracyclic AZA and about 100-fold higher affinity than that of tricyclic AZA. The molecular docking results showed that the binding mode of AZA to DNA helix was an intercalation mode with the partial insertion of one planar part of the AZA structure (the pyridine or quinoline ring) into the neighboring bases of one of the DNA chains with additional hydrogen bonding with the minor groove through the positively charged N,N-dimethylaminopropyl group. Chemical potential (μ), chemical hardness (ƞ), electronegativity (χ) and the value of electrons transferred from one system to another (ΔN) calculated from the HOMO and LUMO energies by the density functional theory method indicated that AZA acted as the electron acceptors to the DNA bases.

Highly Diastereoselective Intramolecular Asymmetric Oxidopyrylium-olefin [5 + 2] Cycloaddition and Synthesis of 8-Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems.

We have the investigated base mediated asymmetric intramolecular oxidopyrylium-alkene [5 + 2]-cycloaddition reaction which resulted in the synthesis of functionalized tricyclic ring systems containing an 8-oxabicyclo[3.2.1]octane core. Intramolecular cycloaddition constructed two new rings, three new stereogenic centers, and provided a tricyclic cycloadduct with high diastereoselectivity and isolated yield. We incorporated an α-chiral center and an alkoxy alkene tether on the substrates and examined the effect of the size of alkyl groups and alkene tether length on diastereoselectivity. The requisite substrates for the oxidopyrylium-alkene cycloaddition reaction were synthesized in a few steps involving alkylation of optically active α-hydroxy amide, furyllithium addition, reduction of resulting ketone, and Achmatowicz reaction followed by acylation of a lactol intermediate. We have proposed stereochemical models for the [5 + 2] cycloaddition reaction via the oxidopyrylium ylide. Interestingly, the alkoxy substituent on the stereocenter and the chain length are responsible for the degree of stereoselectivity of the cycloadduct.

Crystal structure and Hirshfeld surface analysis of 4,5-di-bromo-2-(4-meth-oxy-phen-yl)-2,3,4,4a,5,6,7,7a-octa-hydro-1H-4,6-ep-oxy-1H-cyclo-penta-[c]pyridin-1-one.

The mol-ecule of the title compound, C15H15Br2NO3, comprises a fused tricyclic system consisting of two five-membered rings (cyclo-pentane and tetra-hydro-furan) and one six-membered ring (tetra-hydro-pyridinone). Both five-membered rings of the tricyclic system have envelope conformations, and the conformation of the six-membered cycle is inter-mediate between chair and half-chair. In the crystal, the mol-ecules are linked by C-H⋯O hydrogen bonds and C-H⋯π, C-Br⋯π and C⋯O inter-actions into double layers. The layers are connected into a three-dimensional network by van der Waals inter-actions.

Synthesis and structure-activity relationships of hydroxylated and halogenated 2,4-diaryl benzofuro[3,2-b]pyridin-7-ols as selective topoisomerase IIα inhibitors

The objective of this study was to discover potential topoisomerase (topo) targeting anticancer agents. Novel series of hydroxylated and halogenated(-F, -Cl, and -CF3) 2,4-diaryl benzofuro[3,2-b]pyridin-7-ols were systematically designed and synthesized by faster, economic, and environmentally friendly l-proline catalyzed and microwave-assisted one pot reaction method. The synthesized compounds were assessed for topo I and IIα inhibitory and anti-proliferative activities. The in vitroevaluation displayed that most of the compounds have selective topo IIα inhibitoryactivity as well as selectivity towards T47D human cancer cell line. Structure-activity relationship study suggested that the introduction of additional hydroxyl functionality at 7-positon of benzofuro[3,2-b]pyridine skeleton is crucial for selective topo IIα inhibitory activity. Placement of phenolic moiety on the 4-position of the tricyclic system imparts better topo IIα inhibitory and anti-proliferative activity.

Fast and efficient regioselective synthesis of a novel eight membered ring system, 5H-benzo[f]pyrimido[4,5-b][1,5]oxazocine

An efficient two-steps strategy for the regioselective synthesis of the benzo[f]pyrimido[4,5-b][1,5]oxazocine as a novel tricyclic system has been developed via inter- and intramolecular heterocyclization of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine and 2-aminobenzylalcohol in room temperature and short reaction times under mild conditions, followed amination with some secondary amines. 2D-NOESY and HMBC NMR spectroscopy was performed to gain the true regioisomer of the reaction, as well.

Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin**

AbstractStreptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B1, using a rhodium‐catalyzed distal selective allene‐ynamide Pauson–Khand reaction. A regio‐ and enantioselective epoxidation under chiral phase‐transfer catalytic conditions directly afforded streptazone A in 8 steps overall. In one additional step, a chemoselective, iridium‐catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazone A towards a cysteine mimic, N‐acetylcysteamine, was studied and revealed unanticipated transformations, including bis‐thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.

Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin*.

Streptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B1 , using a rhodium-catalyzed distal selective allene-ynamide Pauson-Khand reaction. A regio- and enantioselective epoxidation under chiral phase-transfer catalytic conditions directly afforded streptazone A in 8 steps overall. In one additional step, a chemoselective, iridium-catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazone A towards a cysteine mimic, N-acetylcysteamine, was studied and revealed unanticipated transformations, including bis-thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.

A new route to BCD tricyclic fragment of C19-diterpenoid alkaloids via intramolecular Pauson-Khand reaction followed by anionic 1,2-migration rearrangement

A robust synthetic approach for the rapid assembly of the bridged tricyclic BCD ring system of C19-diterpenoid alkaloids bearing a characteristic hydroxy group on ring C has been developed. The synthesis features an efficient intramolecular Pauson-Khand reaction and an exclusive anionic 1,2-migration rearrangement to generate the unique bicyclo[3.2.1]octane moiety of the CD-ring on the seven-membered B-ring.

9-Borafluorenes: Synthesis, Properties, and Reactivity.

This review covers all aspects of 9-borafluorene chemistry, from the first attempted synthesis in 1960 to the present. This class of molecules consists of a tricyclic system featuring a central antiaromatic BC4 ring with two fused arene groups. The synthetic routes to all 9-borafluorenes and their adducts are presented. The Lewis acidity and photophysical properties outlined demonstrate potential utility as sensors and in electronic materials. The reactivity of borafluorenes reveals their prospects as reagents for the synthesis of other boron-containing molecules. The appealing traits of 9-borafluorenes have stimulated investigations into analogues that bear different aromatic groups fused to the central BC4 ring. Finally, we offer our views on the challenges and future of borafluorene chemistry.

Synthesis of 6H-Benzo[c]chromene Scaffolds from O-Benzylated Phenols through a C–H Sulfenylation/Radical Cyclization Sequence

S-Aryl dibenzothiophenium salts, obtained through a highly regioselective C–H sulfenylation of o-benzyl-protected phenols, are used as precursors of 6H-benzo[c]chromenes. The reaction starts with a photocatalytically triggered single-electron transfer to the sulfonium salt, which promotes the formation of an aryl radical via selective mesolitic cleavage of the S–Arexo bond. Mechanistic studies reveal that this initial radical species cyclizes following a kinetically favored 5-exo-trig pathway. Subsequent ring expansion, favored by rearomatization, delivers the desired tricyclic systems.

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein.

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named “correctors”. So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.

Hydrazides in the reaction with hydroxypyrrolines: less nucleophilicity – more diversity

Expedient protocols for the synthesis of three types of highly functionalized azaheterocyclic scaffolds (dihydropyridazines, tetrahydropyridazines, and partially saturated tricyclic systems) from readily available hydroxypyrrolines and hydrazides are described. The directions of the transformation of a common initial intermediate, namely a Brønsted acid-activated hydroxypyrroline, depend on the reaction conditions and the structure of the hydrazides.

Synthesis, molecular docking, antibacterial, and anti‐inflammatory activities of benzimidazole‐containing tricyclic systems

AbstractIn the present study, we reported the synthesis of benzimidazole‐containing tricyclic systems and evaluated their antimicrobial efficacy against some Gram‐positive, Gram‐negative strains, and their anti‐inflammatory activity as well as a hemolytic assay in terms of percentage. The antimicrobial study of the synthesized compounds revealed that most of them showed significant activity, and compound 5b displayed excellent antimicrobial efficacy among all. Results showed that the hydroxyl group at the fourth position on the aromatic ring has a substantial role in the biological activity. Synthesized compounds showed promising minimum inhibitory concentration (μg/mL) values in the range of 1.2–12.8 μg/mL against the tested strains. The in vitro anti‐inflammatory activity of these compounds was evaluated by denaturation of bovine serum albumin method and showed the inhibition in the range of IC50 value 31.16–94.63 μg/mL. Among all the tested compounds, compound 5b has a significant IC50 value. The percentage of hemolysis of the target compounds ranged from 1.14 to 52.8 at a concentration of 100 μg/mL. Molecular docking study revealed the good binding interactions against Escherichia coli, and it is best suited with in vitro studies. Pharmacokinetic studies showed the safe profiles for the title compounds.

Metabolites with Anti-Inflammatory Activity from the Mangrove Endophytic Fungus Diaporthe sp. QYM12.

One new diterpenoid, diaporpenoid A (1), two new sesquiterpenoids, diaporpenoids B–C (2,3) and three new α-pyrone derivatives, diaporpyrones A–C (4–6) were isolated from an MeOH extract obtained from cultures of the mangrove endophytic fungus Diaporthe sp. QYM12. Their structures were elucidated by extensive analysis of spectroscopic data. The absolute configurations were determined by electronic circular dichroism (ECD) calculations and a comparison of the specific rotation. Compound 1 had an unusual 5/10/5-fused tricyclic ring system. Compounds 1 and 4 showed potent anti-inflammatory activities by inhibiting the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cells with IC50 values of 21.5 and 12.5 μM, respectively.

Consecutive reactions to construct tricarbonyl compounds and synthetic applications thereof.

Lithium anions derived from O-carbonate-protected cyanohydrins undergo conjugate addition to cycloalkenones with the concomitant transfer of the alkoxycarbonyl group to produce tricarbonyl compounds. These products offer numerous possibilities for further elaboration. The synthetic potential of the cascade products was demonstrated by forming bicyclic and tricyclic systems through intramolecular condensation reactions.

Intramolecular Friedel-Crafts alkylation with a silylium-ion-activated cyclopropyl group: formation of tricyclic ring systems from benzyl-substituted vinylcyclopropanes and hydrosilanes.

A trityl-cation-initiated annulation of benzyl-substituted vinylcyclopropanes (VCPs) with hydrosilanes is reported. Two Si–C(sp3) bonds and one C(sp2)–C(sp3) bond are formed in this process where an intramolecular 6-endo-tet Friedel–Crafts alkylation of a silylium-ion-activated cyclopropane ring is the rate-determining key step. The reaction mechanism is proposed based on computations and is in agreement with experimental observations. The new reaction leads to an unprecedented silicon-containing 6/6/5-fused ring system. A phenethyl-substituted VCP derivative yields another unknown tricycle having 6/6/6 ring fusion by reacting in a related but different way involving a 6-exo-tet ring closure.

Impact of symmetry-breaking of non-fullerene acceptors for efficient and stable organic solar cells.

The concurrent enhancement of short-circuit current (JSC) and open-circuit voltage (VOC) is a key problem in the preparation of efficient organic solar cells (OSCs). In this paper, we report efficient and stable OSCs based on an asymmetric non-fullerene acceptor (NFA) IPC-BEH-IC2F. The NFA consists of a weak electron-donor core dithienothiophen[3,2-b]-pyrrolobenzothiadiazole (BEH) and two kinds of strong electron-acceptor (A) units [9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (IPC) with a tricyclic fused system and 2-(5,6-difluoro-3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (IC2F)]. For comparison, the symmetric NFAs IPC-BEH-IPC and IC2F-BEH-IC2F were characterised. The kind of flanking A unit significantly affects the light absorption features and electronic structures of the NFAs. The asymmetric IPC-BEH-IC2F has the highest extinction coefficient among the three NFAs owing to its strong dipole moment and highly crystalline feature. Its highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) levels lie between those of the IPC-BEH-IPC and IC2F-BEH-IC2F molecules. The IPC group also promotes molecular packing through the tricyclic π-conjugated system and achieves increased crystallinity compared to that of the IC2F group. Inverted-type photovoltaic devices based on p-type polymer:NFA blends with PBDB-T and PM6 polymers as p-type polymers were fabricated. Among all these devices, the PBDB-T:IPC-BEH-IC2F blend device displayed the best photovoltaic properties because the IPC unit provides balanced electronic and morphological characteristics. More importantly, the PBDB-T:IPC-BEH-IC2F-based device exhibited the best long-term stability owing to the strongly interacting IPC moiety and the densely packed PBDB-T:IPC-BEH-IC2F film. These results demonstrate that asymmetric structural modifications of NFAs are an effective way for simultaneously improving the photovoltaic performance and stability of OSCs.