Tricyclic Structure Research Articles

Treatment of Substandard Rocket Fuel 1,1-Dimethylhydrazine via Its Methylene Derivative into Heterocycles Based on Pyrrolo-[3,4c]Quinolines, Cyclododeca[b]piran and Pyrrole.

1,1-Dimethylhydrazine (Heptil, rocket fuel (UDMH)) is characterized by extremely high toxicity, teratogenicity and the ability to constantly absorb water from the atmosphere, losing its energy characteristics. In this regard, as well as due to the alternative fuel ("Angara") transition, there is a need for UDMH utilization in huge amounts. A more benign approach involves its immediate reaction with a formalin solution to form 1,1-dimethyl-2-methylene hydrazone (MDH), which is significantly less toxic by an order of magnitude. MDH can then be polymerized under acidic conditions, and the resulting product can be burned, yielding a substantial amount of nitrogen oxides. We propose an alternative to incineration by involving MDH in organic synthesis. We studied the reactions of MDH and its analog N,N-dimethyl-2-(methylenamino)ethane-1-amine (MDEA) with available CH-acids: tetracyanoethylated ketones (TCEKs) based on cyclohexanone, 4-propylcyclohexanone, 2-methylcyclohexanone, cyclododecanone and tetracyanoethane. The structures synthesized were confirmed by IR, 1H, 13C NMR and mass spectroscopy methods. MDH-based adducts were also identified by X-ray structural analysis. TCEKs and MDH, as well as TCEK based on cyclohexanone and MDEA, form bi- and tricyclic structures: pyrrolo [3,4c]-quinolines (using TCEKs based on cyclohexanone and 4-propylcyclohexanone), epiminomethanoquinoline-3,4-dicarbonitrile (using TCEK based on 2-methylcyclohexanone) and cyclododec[b]pyran-3,4-dicarbonitrile (using TCEK based on cyclododecanone). MDH and TCNEH2 formed a pyrrole derivative. Thus, we synthesized the structures that are of interest for molecular design and pharmaceutical chemistry.

Synthesis and Properties of Backbone Silylated Imidazol‐2‐thiones

AbstractImidazole‐2‐thiones have attracted considerable interest in the past as materials for potential applications in the pharmaceutical and chemical industries. Herein, the synthesis of a series of backbone silylated 1,3‐dialkylimidazol‐2‐thiones is reported. The developed synthesis protocol involves the silylation of N,N‐dimethylimidazol‐2‐thione 1 followed by the addition of organochlorosilanes RnSiCl4–n (R=Me, Ph; n=0–4) and enabled the synthesis of the C‐silylated derivatives with monocyclic, silyl‐bridged or fused tricyclic structures. Reactivity studies performed with N,N‐dimethyl‐4,5‐bistrimethylsilylimidazole‐2‐thione as a model substance showed surprisingly stable silicon‐vinyl bonds and reactivity patterns closely related to those observed for the unsilylated species 1. Combined UV‐spectroscopic and computational studies revealed only minor impact of the silyl substituents on the electronic structure of the imidazol‐2‐thione ring.

Synthesis and Antimalarial Evaluation of Halogenated Analogues of Thiaplakortone A.

The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (1), a potent antimalarial marine natural product, is reported. Although yields were low, it was possible to synthesise a small nine-membered library using the previously synthesised Boc-protected thiaplakortone A (2) as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (3-11) were generated using N-bromosuccinimide, N-iodosuccinimide or a Diversinate™ reagent. The chemical structures of all new analogues were fully characterised by 1D/2D NMR, UV, IR and MS data analyses. All compounds were evaluated for their antimalarial activity against Plasmodium falciparum 3D7 (drug-sensitive) and Dd2 (drug-resistant) strains. Incorporation of halogens at positions 2 and 7 of the thiaplakortone A scaffold was shown to reduce antimalarial activity compared to the natural product. Of the new compounds, the mono-brominated analogue (compound 5) displayed the best antimalarial activity with IC50 values of 0.559 and 0.058 μM against P. falciparum 3D7 and Dd2, respectively, with minimal toxicity against a human cell line (HEK293) observed at 80 μM. Of note, the majority of the halogenated compounds showed greater efficacy against the P. falciparum drug-resistant strain.

Thiopurines Analogues with Additional Ring: Synthesis, Spectroscopic Properties, and Anticancer Potency.

Purine scaffolds constitute a starting point for the synthesis of numerous chemotherapeutics used in treating cancer, viruses, parasites, as well as bacterial and fungal infections. In this work, we synthesized a group of guanosine analogues containing an additional five-membered ring and a sulfur atom at the C-9 position. The spectral, photophysical, and biological properties of the synthesized compounds were investigated. The spectroscopic studies revealed that a combination of the thiocarbonyl chromophore and the tricyclic structure of guanine analogues shifts the absorption region above 350 nm, allowing for selective excitation when present in biological systems. Unfortunately, due to the low fluorescence quantum yield, this process cannot be used to monitor the presence of these compounds in cells. The synthesized compounds were evaluated for their effect on the viability of human cervical carcinoma (HeLa) and mouse fibroblast (NIH/3T3) cells. It was found that all of them display anticancer activity. In vitro studies were preceded by in silico ADME and PASS analyses, which confirmed that the designed compounds are promising candidates for anticancer agents.

Transcriptome and metabolome analysis of sesquiterpene diversity in Indian vetiver (Chrysopogon zizanioides L. Roberty)

Vetiver is one of the valued plants in the aromatic world which has been extensively used in fragrances, aromatherapy, and medicines. The essential oils derived from vetiver root portions are mainly responsible for the organoleptic character of the plant. Vetiver essential oil is composed of diverse structural framework biosynthesized by using three isoprene units or sesquitepene leading to a number of bicyclic, tricyclic and tetracylic structures. Sequiterpenoids contribute major proportion to vetiver (Chrysopogon zizanioides) roots. However, the terpene synthases and their role in sesquiterpene biosynthesis in plant have not yet been studied. On the basis of volatile composition, two distinct stable vetiver genotypes viz., ‘CIM-Vridhi’ and ‘CIMAP-Khusinolika’ have been identified in ‘CSIR-CIMAP’ in recent years. Such a unique chemical difference is attributed to the array of structural diversity in sesquiterpenes and their derivatives. The root transcriptome of the two contrasting genotypes ‘CIM-Vridhi’ and ‘CIMAP-Khusinolika’ was carried out and three full length terpene synthase (TPS) genes were analyzed. These synthase genes, CZTPS1, CZTPS2, and CZTPS3 produce multiple sesquiterpenoids and were functionally characterized. In addition, the gene expression studies leading to metabolite biosynthesis in these genotypes were further confirmed by compound isolation and NMR based structural characterization of compounds from each genotypes. A bicyclic cadinane called khusinol identified as unique identifier in ‘CIMAP-Khusinolika’ while khusimol, a tricyclic zizaene dominates the ‘CIM-Vridhi’ oil composition. In conclusion, characterization of unique markers in each genotypes has been well supported by their transcriptomic data. Thus, present study can be utilized to investigate the vetiver terpenoid metabolism and its structure–odor correlations for the production of more potent odor threshold oriented chemicals from this plant.

Insight into structural topology and supramolecular assembly of tetrahydrocarbazole-carbonitrile: On the importance of noncovalent interactions and urease inhibitory profile

Organic crystals hold a significant importance in pharmaceuticals, biological systems and functional materials. In the present study, a tricyclic aromatic structure, tetrahydrocarbazole (THC), incorporating a nitrile functionality was synthesized via the Fischer indolization of 4-hydroxycyclohexanone with 4-hydrazinobenzonitrile hydrochloride in 70% yield. The detailed description of noncovalent interactions of various types and strengths in the crystal structure of tetrahydrocarbazole-carbonitrile was investigated using a combination of experimental and theoretical methods. The supramolecular assembly of THC involved the extensive network of NH…O and OH…N hydrogen bonds, and weaker π…π and CH…π contacts. The nature of noncovalent interactions was visualized using molecular electrostatic potential whereas QTAIM and NCIPlot methods revealed the energetic features of π-stacking and H-bonding in the supramolecular assemblies of tetrahydrocarbazole-carbonitrile. In vitro evaluation of urease inhibitory potential of target compound revealed a 4-fold strong inhibition (IC50 = 5.26 ± 0.10 µM) compared to standard drug (thiourea; IC50 = 22.3 ± 1.06 µM). Finally, molecular docking analysis showed significant interactions of target compound with various active site amino acids of Jack bean urease.

Effects of fullerene C60 with antihypoxants

BACKGROUND: Drug improvement is often carried out with the help of chemical modifications that improve the receptor action or transport of drugs to their target tissues.
 AIM: The aim of this study was to investigate the effect of combinations of C60 fullerene with amtizol, 2-amino-4-acetylthiazolo[5,4-b]indole, metaprot, metaprot base, and rutin on antihypoxic activities in a model of acute hypoxia with hypercapnia.
 MATERIALS AND METHODS: Several compounds with mono-, bi-, and tricyclic structures were examined separately or combined with C60 fullerene. All compounds, except for rutin, were synthesized at the Department of Pharmacology of the S.M. Kirov Military Medical Academy and contain active amino groups, nitrogen, and sulfur atoms in the cycles: amtizol (3,5-diamino-1,2,4-thiadiazole), VM-606 (2-amino-4-acetylthiazolo[5,4-b]indole), Metaprot (2-ethylthiobenzimidazole hydrobromide monohydrate), and Metaprot base. All compounds demonstrated antihypoxic activity. Hypobaric hypoxia was simulated in a flow pressure chamber by lifting animals to a height of 10,000 m at a speed of 50 m/s and exposure for 60 min. The preparations were administered intraperitoneally 60 min before the experiment. The protective effect was evaluated by the average life expectancy at altitude. Hypoxia with hypercapnia was assessed on male white mice weighing 2022 g, which were placed in 200 mL glass jars with hermetic lids, which were lowered under water to prevent air leakage. The studied preparations and their complexes with fullerene in the form of a thin suspension with Tween-80 were administered intraperitoneally min before hypoxia. The lifespan of the animals was recorded.
 RESULTS: The formation of the complex and its properties depend on the development of a donoracceptor bond between the drug and fullerene. An increase in the bioavailability of amtizol in the form of a complex with C60 fullerene increased the antihypoxic activity of the mixture by 40%. For the first time, dynamic curves of the activities of amtizol and 2-amino-4-acetylthiazolo[5,4-b]indole depending on time were obtained in a model of hypercapnic hypoxia.
 CONCLUSION: Fullerene C60 enhances the antihypoxic activity of the studied compounds due to an increase in the bioavailability of the antihypoxant caused by the microporation of tissue membranes due to the action of fullerene C60.

An Enantiospecific Synthesis of Isoneoamphilectane Confirms Its Strained Tricyclic Structure.

We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product─along with a hypothesis about a biosynthetic relationship to related family members─inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis-to-trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama-Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C-N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.

Antibiotic Guanacastane Diterpenoids with Two New Skeletons from Psathyrella candolleana Uncovered by Semisolid and Liquid Media

The culture of Psathyrella candolleana in host Dioscorea opposite medium produced seven new guanacastane diterpenoids, psayamin (1) as an unprecedented 5/7/6/6/6/6/7/5-fused octacyclic spiro scaffold both under liquid and semisolid conditions, psathins A-C (4-6) with a 5/7/6 tricyclic backbone by liquid medium, psathins D-E (7-8) as the same unprecedented skeletons of 5/6/7/6-fused tetracyclic or 6/7/6 tricyclic structures, and psathin F (9) with a 5/7/5/6 tetracyclic backbone by semisolid medium. The structures were elucidated by detailed spectroscopic analyses and those of 1 and 7 were determined by single-crystal X-ray crystallography. The semisolid culture led to four structure types of the guanacastane diterpenoid. Compound 5 showed antifungal activity against phytopathogen Fusarium incarnatum with a minimum inhibitory concentration (MIC) of 8 μg/mL, while compound 4 showed significant antifungal activity against Alternaria sp. with an MIC of 2 μg/mL. Compounds 1 and 8 also showed antifeedant activities against the silkworms with the feeding deterrence indices of 50%, at the concentrations of 50 μg/cm2. Compound 1 showed significant cytotoxicity with IC50 at 10.87 ± 0.24-15.96 ± 0.30 μM and anti-acetylcholinesterase activity with IC50 at 37.3 μM. Also, compound 1 remarkably induced apoptosis of HL-60 at 10, 20 μM in a concentration-dependent manner. The spiral ring of 1 was vital in cytotoxicity and anti-acetylcholinesterase activity. The different media fermented by P. candolleana resulted in the chemical diversity of bioactive guanacastane diterpenoids and potential applications in the agricultural and food functions.

Protecting‐Group‐Free Total Synthesis of (−)‐Boscartin A in 3 Steps from (−)‐Boscartin F via Wharton Reaction

AbstractIn this report, we described the first total synthesis of (−)‐boscartin A, a cembranoid featuring a 5/5/12‐fused tricyclic structure. Via the key reactions, including stereoselective epoxidation and Wharton reaction, (−)‐Boscartin A was obtained in three steps from (−)‐boscartin F, with 46 % overall yield.

Thiol-Michael addition based conjugate for glutathione activation and release

Glutathione (GSH) level has long been recognized as a valuable tumor biomarker. GSH-mediated activation and release systems have been extensively developed for cancer diagnosis and treatment, but mainly focused on disulfide-based conjugate. We reported here a new thiol-Michael addition based GSH response conjugate TC6, which consists of a unique tricyclic structure containing α, β-unsaturated ketone responsive groups. The conjugate was easily synthesized and showed good selectivity to glutathione with certain stability. The camptothecin delivery experiment of TC6 showed improved anti-tumor ability in cells and tumor-bearing mice. TC6 could be used for the development of antibody or small molecule conjugated drugs.

Fusion of Aza- and Oxadiborepins with Furans in a Reversible Ring-Opening Process Furnishes Versatile Building Blocks for Extended π-Conjugated Materials.

A modular synthesis of both difurooxa- and difuroazadiborepins from a common precursor is demonstrated. Starting from 2,2'-bifuran, after protection of the positions 5 and 5' with bulky silyl groups, formation of the novel polycycles proceeds through opening of the furan rings to a dialkyne and subsequent re-cyclization in the borylation step. The resulting bifuran-fused diborepins show pronounced stability, highly planar tricyclic structures, and intense blue light emission. Deprotection and transformation into dibrominated building blocks that can be incorporated into π-extended materials can be performed in one step. Detailed DFT calculations provide information about the aromaticity of the constituent rings of this polycycle.

CRISPR/Cas9 targeted inactivation of the kauniolide synthase in chicory results in accumulation of costunolide and its conjugates in taproots.

Chicory taproots accumulate sesquiterpene lactones lactucin, lactucopicrin, and 8-deoxylactucin, predominantly in their oxalated forms. The biosynthetic pathway for chicory sesquiterpene lactones has only partly been elucidated; the enzymes that convert farnesyl pyrophosphate to costunolide have been described. The next biosynthetic step of the conversion of costunolide to the tricyclic structure, guaianolide kauniolide, has so far not been elucidated in chicory. In this work three putative kauniolide synthase genes were identified in chicory named CiKLS1, CiKLS2, and CiKLS3. Their activity to convert costunolide to kauniolide was demonstrated in vitro using yeast microsome assays. Next, introduction of CRISPR/Cas9 reagents into chicory protoplasts was used to inactivate multiple chicory KLS genes and several chicory lines were successfully regenerated. The inactivation of the kauniolide synthase genes in chicory by the CRISPR/Cas9 approach resulted in interruption of the sesquiterpene lactone biosynthesis in chicory leaves and taproots. In chicory taproots, but not in leaves, accumulation of costunolide and its conjugates was observed to high levels, namely 1.5 mg/g FW. These results confirmed that all three genes contribute to STL accumulation, albeit to different extent. These observations demonstrate that three genes oriented in tandem on the chicory genome encode kauniolide synthases that initiate the conversion of costunolide toward the sesquiterpene lactones in chicory.

Combustion kinetics and fuel performance of tackifying resins by TG-FTIR and DFT analysis

Combustion kinetics and fuel performance of tackifying resins such as glycerol ester of colophony (GEC), glycerol ester of hydrogenated colophony (GEHC), C9 petroleum resin (C9PR) and hydrogenated C9 petroleum resin (HC9PR) were studied. Non-isothermal thermal analysis was performed in an air atmosphere, and the combustion characteristic, kinetic and thermodynamic parameters were calculated. Results show that all the resins studied have good combustion performance and environmental characteristics, and their experimental calorific values are 1.15–1.54 times of standard coal-equivalent (29.31 MJ/kg), indicating that tackifying resins and their corresponding wastes are promising fuel for generating energy. Furthermore, based on the isoconversional and master plots methods, it was found that the combustion of different resins was a kinetically complicated reaction, but the R3 model had an acceptable fitting effect in the whole combustion process. TG-FTIR and density functional theory (DFT) results demonstrate that colophony-based resins tend to degrade/burn the branched chains first and then the tricyclic phenanthrene structures, while petroleum resins degrade/burn the CC bonds on the backbone first and then the aromatic compounds, and the volatiles are mainly composed of H2O, CH4, CO2, CO, aromatic compounds and carbonyl derivatives.

Identification of the Early Steps in Herbicidin Biosynthesis Reveals an Atypical Mechanism of C-Glycosylation

Herbicidins are adenosine-derived nucleoside antibiotics with an unusual tricyclic core structure. Deletion of the genes responsible for formation of the tricyclic skeleton in Streptomyces sp. L-9-10 reveals the in vivo importance of Her4, Her5, and Her6 in the early stages of herbicidin biosynthesis. In vitro characterization of Her4 and Her5 demonstrates their involvement in an initial, two-stage C-C coupling reaction that results in net C5'-glycosylation of ADP/ATP by UDP/TDP-glucuronic acid. Biochemical analyses and intermediate trapping experiments imply a noncanonical mechanism of C-glycosylation reminiscent of NAD-dependent S-adenosylhomocysteine (SAH)-hydrolase catalysis. Structural characterization of the isolated metabolites suggests possible reactions catalyzed by Her6 and Her7. An overall herbicidin biosynthetic pathway is proposed based on these observations.

Total Synthesis of (±)-Fasicularin through Double Consecutive Epimerizations.

The total synthesis of tricyclic marine alkaloid fasicularin (1b) has been accomplished from a novel sterically well-defined α-aminonitrile 7, featuring a novel double consecutive epimerization process and Ir-catalyzed reductive functionalization of a tertiary γ-lactam. The required configuration is obtained through the thermodynamically stereoselectively driven isomerization of a readily available 8a-cyanodecahydroquinoline framework. The strategy allows us to achieve the tricyclic core structures efficiently from affordable starting materials through simple operations.

Effect of ambient atmosphere on the formation and evolution of conjugated structure of pre-oxidized polyacrylonitrile

The ambient atmosphere has the remarkable effect on the chemical reaction mechanism and the formation of characteristic chemical structures and conjugated structures for pre-oxidized polyacrylonitrile (PAN). In the present paper, fourier transform infrared spectroscopy (FT-IR) and ultraviolet visible spectroscopy (UV–vis) were used to characterize the variations of chemical reaction characteristic structures and conjugate structures of copolymerized PAN in nitrogen and air atmosphere, respectively. Combined with the multivariate reaction model proposed by the predecessors, it can be found that two main conjugated structures (conjugated polyene and conjugated aromatic heterocycle) formed during the pre-oxidation process of copolymerized PAN. In nitrogen atmosphere, the formed main structure units were the conjugated diene and conjugated double ring with 1–2 double bonds. By contrast, the formed main units in air were the conjugated diene and conjugated tricyclic with a double bond. During the whole pre-oxidation process, the maximum unit numbers of conjugated double bonds and conjugated rings were no more than four and six, respectively. Increasing the heat treatment temperature favored to form more conjugate structures than prolonging the heat treatment time. Furthermore, with the increase of heat treatment temperature or time in air, the main conjugate unit numbers had no obvious change, while the maximum unit numbers increased slightly. For the exposure in nitrogen atmosphere, the main conjugated polycyclic structure was transformed into conjugated tricyclic structure after the heat treatment at 250 °C for more than 3 h. In addition, when the heat treatment temperature and time were 280 °C for more than 4 h, the main conjugated polyene structure was transformed into conjugated triene, and the maximum conjugated unit numbers increased slightly.

Inverse α-Effect as the Ariadne's Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities.

Stable tricyclic aminoperoxides can be selectively assembled via a catalyst-free three-component condensation of β,δ'-triketones, H2O2, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of tricyclic heterocycles, containing peroxide, nitrogen, and oxygen cycles in one molecule. Amazingly, such complex tricyclic molecules are selectively formed despite the multitude of alternative reaction routes, via equilibration of peroxide, hemiaminal, monoperoxyacetal, and peroxyhemiaminal functionalities! The reaction is initiated by the "stereoelectronic frustration" of H2O2 and combines elements of thermodynamic and kinetic control with a variety of mono-, bi-, and tricyclic structures evolving under the conditions of thermodynamic control until they reach a kinetic wall created by the inverse α-effect, that is, the stereoelectronic penalty for the formation of peroxycarbenium ions and related transition states. Under these conditions, the reaction stops before reaching the most thermodynamically stable products at a stage where three different heterocycles are assembled and fused at the acyclic precursor frame.

A C-H Activation Approach to the Tricyclic Core of Glionitrin A and B.

Synthesis of diketopiperazines has been of long-standing interest in both natural product synthesis and medicinal chemistry. Here, we present an operationally convenient and efficient approach to the fused indoline-diketopiperazine tricyclic core of glionitrin A/B and related structures using a Pd-catalyzed C–H activation reaction to form the indoline five-membered ring. Exploratory work aimed at elaborating the tricyclic structures into the corresponding natural products is discussed.

Oxygenated Cyclopentenones via the Pauson-Khand Reaction of Silyl Enol Ether Substrates.

We report here the application of silyl enol ether moieties as efficient alkene coupling partners within cobalt-mediated intramolecular Pauson–Khand reactions. This cyclization strategy delivers synthetically valuable oxygenated cyclopentenone products in yields of ≤93% from both ketone- and aldehyde-derived silyl enol ethers, incorporates both terminal and internal alkyne partners, and delivers a variety of decorated systems, including more complex tricyclic structures. Facile removal of the silyl protecting group reveals oxygenated sites for potential further elaboration.