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Zanthoxylum simulans Hance, commonly known as Sichuan pepper, is a well-known medicinal plant recognized for its potential as a source of bioactive specialized metabolites. As part of our interest in natural antifungal compounds, the present study describes the discovery of an unreported N-alcoxycarbonylbenzo[c]phenanthridinium salt, N-methoxycarbonyl-9,12-dimethoxy-norchelerythrine 1 (a type-III benzo[c]phenanthridine), isolated from Z. simulans seedlings, which were propagated under controlled greenhouse conditions. Six-month seedlings were harvested and subjected to cold acid–base extraction. Chromatographic techniques achieved the isolation of 1 from raw alkaloid extract. The structural elucidation of 1 was accomplished through comprehensive spectroscopic analysis, including nuclear magnetic resonance and high-resolution mass spectrometry. Fusarium oxysporum, a fungal pathogen responsible for substantial agricultural losses, was exposed to different concentrations of the novel compound, exhibiting potent antifungal efficacy (IC50 < 3 µM) and fungicide effects. These findings highlight the potential of benzophenanthridines as antifungal leads and underscore the importance of exploring natural products for agricultural applications. [ABSTRACT FROM AUTHOR]

Three new phenanthridine peptide derivatives (19, 22, and 23) were synthesized to explore their potential as spectrophotometric probes for DNA and RNA. UV/Vis and circular dichroism (CD) spectra, mass spectroscopy, and computational analysis confirmed the presence of intramolecular interactions in all three compounds. Computational analysis revealed that compounds alternate between bent and open conformations, highlighting the latter's crucial influence on successful polynucleotide recognition. Substituting one glycine with lysine in two regioisomers (22, 23) resulted in stronger binding interactions with DNA and RNA than for a compound containing two glycines (19), thus emphasizing the importance of lysine. The regioisomer with lysine closer to the phenanthridine ring (23) exhibited a dual and selective fluorimetric response with non-alternating AT and ATT polynucleotides and induction of triplex formation from the AT duplex. The best binding constant (K) with a value of 2.5 × 107 M−1 was obtained for the interaction with AT and ATT polynucleotides. Furthermore, apart from distinguishing between different types of ds-DNA and ds-RNA, the same compound could recognize GC-rich DNA through distinct induced CD signals. [ABSTRACT FROM AUTHOR]

The C═N bond is a critical structural piece of many N-donor ligand scaffolds and is central to the properties and reactivity of important coordination complexes. For example, C═N units play a key role in the "redox non-innocence" of α-diimine complexes and in making charge-transfer excited-state character available to complexes of N-heterocyclic ligands such as bipyridine. In N-heterocycles like pyridine, benzannulation can be used to extend the conjugated C═N-containing π-system to quinoline (2,3-benzopyridine) to acridine (2,3-benzoquinoline). This stabilizes the lowest unoccupied molecular orbital of the molecule and boosts its electron-accepting properties, but the position of the benzannulation matters. For example, phenanthridine (3,4-benzoquinoline), an asymmetric isomer of acridine, bears a similarly electronically accessible extended π-system but with a more chemically isolated "imine-like" C═N moiety. This award paper presents an overview of our work investigating the impact of such site-selective benzannulation on the chemistry and properties of phenanthridine as a molecule and ligand. [ABSTRACT FROM AUTHOR]

Targeting thioredoxin reductase (TXNRD) with low-weight molecules is emerging as a high-efficacy anti-cancer strategy in chemotherapy. Sanguinarine has been reported to inhibit the activity of TXNRD1, indicating that benzophenanthridine alkaloid is a fascinating chemical entity in the field of TXNRD1 inhibitors. In this study, the inhibition of three benzophenanthridine alkaloids, including chelerythrine, sanguinarine, and nitidine, on recombinant TXNRD1 was investigated, and their anti-cancer mechanisms were revealed using three gastric cancer cell lines. Chelerythrine and sanguinarine are more potent inhibitors of TXNRD1 than nitidine, and the inhibitory effects take place in a dose- and time-dependent manner. Site-directed mutagenesis of TXNRD1 and in vitro inhibition analysis proved that chelerythrine or sanguinarine is primarily bound to the Sec498 residue of the enzyme, but the neighboring Cys497 and remaining N-terminal redox-active cysteines could also be modified after the conjugation of Sec498. With high similarity to sanguinarine, chelerythrine exhibited cytotoxic effects on multiple gastric cancer cell lines and suppressed the proliferation of tumor spheroids derived from NCI-N87 cells. Chelerythrine elevated cellular levels of reactive oxygen species (ROS) and induced endoplasmic reticulum (ER) stress. Moreover, the ROS induced by chelerythrine could be completely suppressed by the addition of N-acetyl-L-cysteine (NAC), and the same is true for sanguinarine. Notably, Nec-1, an RIPK1 inhibitor, rescued the chelerythrine-induced rapid cell death, indicating that chelerythrine triggers necroptosis in gastric cancer cells. Taken together, this study demonstrates that chelerythrine is a novel inhibitor of TXNRD1 by targeting Sec498 and possessing high anti-tumor properties on multiple gastric cancer cell lines by eliciting necroptosis. [ABSTRACT FROM AUTHOR]

Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs. [ABSTRACT FROM AUTHOR]

Two novel conjugate molecules were designed: pyrene and phenanthridine-amino acid units with a different linker length between the aromatic fragments. Molecular modelling combined with spectrophotometric experiments revealed that in neutral and acidic buffered water solutions conjugates predominantly exist in intramolecularly stacked conformations because of the π–π stacking interaction between pyrene and phenanthridine moieties. The investigated systems exhibited a pH-dependent excimer formation that is significantly red-shifted relative to the pyrene and phenanthridine fluorescence. While the conjugate with a short linker showed negligible spectrophotometric changes due to the polynucleotide addition, the conjugate with a longer and more flexible linker exhibited a micromolar and submicromolar binding affinity for ds-polynucleotides and inactivated a mutant of dipeptidyl peptidase enzyme E451A. Confocal microscopy revealed that the conjugate with the longer linker entered the HeLa cell membranes and blue fluorescence was visualized as the dye accumulated in the cell membrane.

The precise activation of C–H bonds will eventually provide chemists with transformative methods to access complex molecular architectures. Current approaches to selective C–H activation relying on directing groups are effective for the generation of five-membered, six-membered and even larger ring metallacycles but show narrow applicability to generate three- and four-membered rings bearing high ring strain. Furthermore, the identification of distinct small intermediates remains unsolved. Here, we developed a strategy to control the size of strained metallacycles in the rhodium-catalysed C−H activation of aza-arenes and applied this discovery to tunably incorporate the alkynes into their azine and benzene skeletons. By merging the rhodium catalyst with a bipyridine-type ligand, a three-membered metallacycle was obtained in the catalytic cycle, while utilizing an NHC ligand favours the generation of the four-membered metallacycle. The generality of this method was demonstrated with a range of aza-arenes, such as quinoline, benzo[f]quinolone, phenanthridine, 4,7-phenanthroline, 1,7-phenanthroline and acridine. Mechanistic studies revealed the origin of the ligand-controlled regiodivergence in the strained metallacycles. The ability to selectively functionalize different sites on simple starting materials is a constant pursuit in organic chemistry. Here, the authors report a catalytic system to regioselectively differentiate and alkynylate different positions on azaarenes via rhodium catalysis. [ABSTRACT FROM AUTHOR]

A mild, efficient, photocatalytic synthesis of 6-phosphorylated phenanthridines via tandem radical addition/cyclization/aromatization of 2-isocyanobiphenyls with diarylphosphine oxides is reported. The method features operational simplicity in metal-free conditions, using low-cost Rose Bengal as a catalyst and sustainable air as a terminal oxidant at room temperature and providing the desired products in moderate to good yields. [ABSTRACT FROM AUTHOR]

Carbon‐carbon bond formation in the phenanthridine 7‐position was achieved by microwave‐assisted Claisen rearrangement of 8‐allyloxyphenanthridines. The reactions took place with excellent regioselectivity and high chemical yields. If the 7‐position was substituted, rearrangement to C‐9 took place, but the reaction occurred less readily. Rearrangements of 8‐allyloxy‐5,6‐dihydrophenanthridines (phenanthridines with a saturated B‐ring) gave a mixture of 7‐ and 9‐substituted products. The experimental results were supported by DFT (density functional theory) calculations. [ABSTRACT FROM AUTHOR]

In both of the title compounds, C26H19NO2S2, (I), and C25H19NO2S2, (II), the benzothiophene rings are essentially planar with maximum deviations of 0.026 (1) and -0.016 (1) A ° for the carbon and sulfur atoms in compounds (I) and (II), respectively. In (I), the thiophene ring system is almost orthogonal to the phenyl ring attached to the sulfonyl group, subtending a dihedral angle of 88.1 (1)°, and the dihydropyridine ring adopts a screw-boat conformation. In both compounds, the molecular structure is consolidated by weak C--H· · ·O intramolecular interactions formed by the sulfone oxygen atoms, which generate S(5) ring motifs. In the crystal of II, molecules are linked via C--H· · ·O hydrogen bonds, generating C(7) chains running along the [100] direction. No significant intermolecular interactions are observed in I. [ABSTRACT FROM AUTHOR]

The title compounds, C28H21FN2O7S (I) and C25H16N2O2S (II), are carbazoles derivatives with a benzenesulfonyl group attached to the carbazole moiety at the N atom on both molecules. A fluoro-substituted nitrophenyl ring system in I and a fused isoquinoline ring in II are attached to the respective carbazole moieties. In both compounds, the carbazole ring systems are essentially planar, with maximum deviations of 0.028 (2) and 0.026 (2)Å for carbon atoms in compounds I and II, respectively. The carbazole ring system is almost orthogonal to the benzene ring attached to sulfonyl group, with dihedral angles of 79.7 (2) in I and 88.2 (2)° in II, respectively. The mean planes of the carbazole ring systems make dihedral angles of 66.1 (2) and 1.3 (2)°, respectively, with the nitrophenyl ring in I and the planar isoquinoline moiety [maximum deviation of 0.009 (3)Å for a carbon atom in II, indicating that the ring system in II is essentially planar]. The benzenesulfonyl ring is almost normal to the isoquinoline ring, with a dihedral angle of 87.9 (2)° in II and the nitrophenyl ring forms a dihedral angle of 17.8 (2)° in I. In both compounds, intramolecular C--H· · ·O hydrogen bonds generate S(6) ring motifs with the sulfone group O atoms. In crystals of compound I, the molecules are linked by C--H· · ·O intermolecular weak hydrogen bonds, which generate C(7) and C(10) chains running parallel to [010] and [100], respectively. [ABSTRACT FROM AUTHOR]

A “turn-on” Donor-π-Acceptor (D-π-A) containing phenanthridine-functionalized extended π-conjugate terpyridine, 5-(4′-([2,2′:6′,2''-terpyridin]−4′-yl)-[1,1′-biphenyl]4-yl)7,8,13,14-tetrahydrodibenzo [a, i] phenanthridine (TBTP) was synthesised. It shows strong selectivity for the detection of toxic Cd2+ without interference from other metal ions. In the presence of Cd2+, the absorption of the TBTP changes dramatically along with the fluorescent emission with the large Stokes shift of 6300 cm−1. When the compound TBTP is exposed to UV light, its colour changes from blue to orange over the addition of Cd2+. Adding other transition metal ions has no effect. This is based on the mechanism of intramolecular charge transfer. The detection limit for Cd2+ was found to be around 1.181 × 10−8 M. An investigation of the sensing mechanism includes job plot, NMR titration, DFT calculation, and HRMS analyses. Excitingly, the recognition of Cd2+ in CH3CN: H2O (8:2, v/v) medium is quantitative without interference from Zn2+, which is a common interferent for Cd2+. Furthermore, the probe was used for detecting Cd2+ in real water samples and cell imaging in living cells was also performed.

The phytochemical investigations of the methanol extract of Zanthoxylum gilletii bark led to the isolation of thirteen compounds identified as two alkaloids including one acridone 5-hydroxynoracronycine (1) and one benzo [c] phenanthridine decarine (2), three lignans trans- and cis-fagaramide (3 and 4) and sesamin (5), two coumarins scoparone (6) and scopoletin (7), three pentacyclic triterpenoids fridelin (8), lupeol (9) and erythrodiol-3-O-palmitate (10), one phenolic compound vanillic acid (11) as well as two common steroids stigmasterol (12), and its derivative stigmasterol-3-O-β-D-glucopyranoside (13). The structures of all the isolated compounds were elucidated by means of their spectroscopic and spectrometric data (1D, 2D-NMR, MS) as well as the comparison of these data with those reported in the literature. Except for compounds 9 and 11–13, all the other isolated compounds are reported for the first time from Z. gilletii but have been already obtained from other Zanthoxylum species and in the Rutaceae family. Compounds 1, 3–5, and 9 were tested in vitro for their antiplasmodial potencies against Plasmodium falciparum 3D7, and the results revealed that all the tested compounds displayed an inhibition between 51.89% and 54.69% while only the mixture of 3 + 4 gave an IC50 lower than 10 000 nM (IC50 = 1333 nM). Furthermore, all the compounds have been evaluated in silico for their ability to inhibit the Plasmodium falciparum dihydroorotate dehydrogenase 5TBO. Sesamin (5) showed the greatest affinity to the antiplasmodium receptor than artemether® and chloroquine®. Further recorded data from their ADMET study, as well as their chemotaxonomy, are also discussed herein. The present study provides further information to enrich the chemistry of Z. gilletii and its qualification as an important source for good candidates in new antiplasmodial drug development. [ABSTRACT FROM AUTHOR]

The article presents a study on catalytic transfer hydrogenation of Dinitrogen to Ammonia via a photoredox catalysis strategy. It discusses the thermodynamics and strategies for hydrogenation of Dinitrogen. It mentions the application of this study is to in situ recycling of the spent Hantzsch ester pyridine (HE) back to HEH2.

Chelerythrine (CH) and ethoxychelerythrine (ECH) are chemical reference substances for quality control of Chinese herbal medicines, and ECH is the dihydrogen derivative of CH. In this study, their fluorescence and absorption spectra, as well as their structural changes in different protic solvents were compared. It was observed that their emission fluorescence spectra in methanol were almost the same (both emitted at 400 nm), which may be attributed to the nucleophilic and exchange reactions of CH and ECH with methanol molecules with the common product of 6-methoxy-5,6-dihydrochelerythrine (MCH). When diluted with water, MCH was converted into CH, which mainly existed in the form of positively charged CH+ under acidic and near-neutral conditions with the fluorescence emission at 550 nm. With the increase of pH value of the aqueous solution, CH+ converted to 6-hydroxy-5,6-dihydrochelerythrine (CHOH) with the fluorescence emission at 410 nm. The fluorescence quantum yields of MCH and CHOH were 0.13 and 0.15, respectively, and both the fluorescence intensities were much stronger than that of CH+. It is concluded that CH and ECH can substitute each other in the same protic solvent, which was further verified by high-performance liquid chromatography. This study will help in the investigation of structural changes of benzophenanthridine alkaloids and will provide the possibility for the mutual substitution of standard substances in relevant drug testing. [ABSTRACT FROM AUTHOR]

Thirty-three benzophenanthridine alkaloid derivatives (1a–1u and 2a–2l) were synthesized, and their cytotoxic activities against two leukemia cell lines (Jurkat Clone E6-1 and THP-1) were evaluated in vitro using a Cell Counting Kit-8 (CCK-8) assay. Nine of these derivatives (1i–l, 2a, and 2i–l) with IC50 values in the range of 0.18–7.94 μM showed significant inhibitory effects on the proliferation of both cancer cell lines. Analysis of the primary structure–activity relationships revealed that different substituent groups at the C-6 position might have an effect on the antileukemia activity of the corresponding compounds. In addition, the groups at the C-7 and C-8 positions could influence the antileukemia activity. Among these compounds, 2j showed the strongest in vitro antiproliferative activity against Jurkat Clone E6-1 and THP-1 cells with good IC50 values (0.52 ± 0.03 μM and 0.48 ± 0.03 μM, respectively), slightly induced apoptosis, and arrested the cell-cycle, all of which suggests that compound 2j may represent a potentially useful start point to undergo further optimization toward a lead compound. [ABSTRACT FROM AUTHOR]

[Display omitted] • The phenanthridine sensor (TPTA) has been developed for the ratiometric detection of SOCl 2 and (COCl) 2. • The sensor TPTA exhibited remarkable anti-interference character over other competing analytes. • The detection process is facilitated by a dual (ESIPT & ICT) process. • TPTA is also applied for the detection of SOCl 2 and (COCl) 2 in liquid and vapor phases. As fatal and potentially accessible reagents, oxalyl and thionyl chloride have become severe concerns for public safety. Therefore, it is essential to develop effective methods to discriminate them. Herein, a new fluorescent sensor, 2-(7,8,13,14-tetrahydrodibenzo[a, i]phenanthridin-5-yl)-4,6-di(thiophen-2-yl)aniline (TPTA) has been designed with the incorporation of classical phenanthridine fluorophore and o -aniline functionality to explore the versatile sensing capabilities. Due to the electrophilic character of chlorocarbonyls, the detection process occurs between TPTA and SOCl 2, (COCl) 2 via nucleophilic addition and subsequent cyclization, which produces new, green emissive cyclic adducts. An inhibited excited-state intramolecular proton transfer (ESIPT) followed by the ICT process endows sensitive ratiometric detection of oxalyl and thionyl chloride with a low limit of detection (4.15 and 2.93 nM). The limit of quantification (LOQ) was calculated to be (9.81 and 13.8 nM for SOCl 2 and (COCl) 2 , which is far lower than the LD 50 values. Because of its reaction-based sensing mechanism, robust selectivity with rapid response time has been achieved towards SOCl 2 and (COCl) 2 (<5 sec) with good stability. The anti-interference properties reveal that the sensor TPTA can efficiently detect SOCl 2 and (COCl) 2 even in the presence of other analytes. Further, the detection mechanism of the TPTA induced by oxychlorides was studied and well supported by NMR, HRMS, and DFT theoretical calculations. Remarkably, smartphone-assisted concentration-dependent test kit experiments enhance the practical utility of TPTA and facilitate the real-time detection of oxychlorides. Hence, TPTA has proven to be an inevitable and promising tool for the sensitive recognition oxychloride species. [ABSTRACT FROM AUTHOR]

In discovery of novel HDAC inhibitory with anticancer potency, pharmacophores of phenanthridine were introduced to the structure of HDAC inhibitors. Fatty and aromatic linkers were evaluated for their solubility and activity. Both enzyme inhibitory and in vitro antiproliferative (against U937 cells) screening results revealed better activities of compounds with aromatic linker than molecules with fatty linker. Compared with SAHA (IC50 values of 1.34, 0.14, 2.58, 0.67 and 18.17 µM), molecule Fb-4 exhibited 0.87, 0.09, 0.32, 0.34 and 17.37 µM of IC50 values against K562, U266, MCF-7, U937 and HEPG2 cells, respectively. As revealed by cell cycle and apoptotic analysis, induction of G2/M phase arrest and apoptosis plays an important role in the inhibition of MCF-7 cells by Fb-4. Generally, a potent HDAC inhibitor was developed in the present study which could be utilised as a lead compound for further anticancer drug design.

Limited pharmacological studies have been conducted on plant species used against poultry helminths. The objective of this study was to provide a basis for plant based anthelmintics as possible alternatives against poultry anthelmintic resistance. The study justified the need for alternative anthelmintics. The study places emphasis on the increasing anthelmintic resistance, mechanism of resistance, and preparational protocols for plant anthelmintics and their associated mechanism of action. Pharmaceutical studies on plants as alternative therapies for the control of helminth parasites have not been fully explored especially in several developing countries. Plants from a broad range of species produce a wide variety of compounds that are potential anthelmintics candidates. Important phenolic acids have been found in Brassica rapa L. and Terminalia avicenniodes Guill. and Perri that affect the cell signaling pathways and gene expression. Benzo (c) phenanthridine and isoquinoline alkaloids are neurotoxic to helminths. Steroidal saponins (polyphyllin D and dioscin) interact with helminthic mitochondrial activity, alter cell membrane permeability, vacuolation and membrane damage. Benzyl isothiocyanate glucosinolates interfere with DNA replication and protein expression, while isoflavones from Acacia oxyphylla cause helminth flaccid paralysis, inhibit energy generation, and affect calcium utilization. Condensed tannins have been shown to cause the death of nematodes and paralysis leading to expulsion from the gastro-intestinal tract. Flavonoids from Chenopodium album L and Mangifera indica L act through the action of phosphodiesterase and Ca2+-ATPase, and flavonoids and tannins have been shown to act synergistically and are complementary to praziquantel. Artemisinins from Artemisia cina O. Berg are known to disrupt mitochondrial ATP production. Terpenoids from Cucurbita moschata L disrupt neurotransmission leading to paralysis as well as disruption of egg hatching. Yeast particle encapsulated terpenes are effective for the control of albendazole-resistant helminths. [ABSTRACT FROM AUTHOR]

In discovery of novel HDAC inhibitory with anticancer potency, pharmacophores of phenanthridine were introduced to the structure of HDAC inhibitors. Fatty and aromatic linkers were evaluated for their solubility and activity. Both enzyme inhibitory and in vitro antiproliferative (against U937 cells) screening results revealed better activities of compounds with aromatic linker than molecules with fatty linker. Compared with SAHA (IC50 values of 1.34, 0.14, 2.58, 0.67 and 18.17 µM), molecule Fb-4 exhibited 0.87, 0.09, 0.32, 0.34 and 17.37 µM of IC50 values against K562, U266, MCF-7, U937 and HEPG2 cells, respectively. As revealed by cell cycle and apoptotic analysis, induction of G2/M phase arrest and apoptosis plays an important role in the inhibition of MCF-7 cells by Fb-4. Generally, a potent HDAC inhibitor was developed in the present study which could be utilised as a lead compound for further anticancer drug design. [ABSTRACT FROM AUTHOR]

Background: Ethidium bromide is a common reagent that is used in nucleic acid staining. However, ethidium bromide has toxic and carcinogenic properties that are harmful to the environment. Phenanthrene dioxygenase (encoded by phdA, phdB, phdC, and phdD genes) in Nocardioides sp. KP7 can oxidize the phenanthridine structure aim to eliminate carcinogenic properties. Objective: This study aims to visualize and predict the structure, active site, and characteristics of the phenanthrene dioxygenase using bioinformatics tools. Methods: Plasmid design were prepared by inserting genes of interest phdA, phdB, phdC, and phdD from the NCBI database. Furthermore, several protein analysis tools were used for structure visualization, active site enzyme improvement, and protein characteristic of phenanthrene dioxygenase. Results: The prediction results found that phenanthrene dioxygenase reacts with the ethidium bromide substrate through the interaction of Fe3+ ions with water. The solubility level of phenanthrene dioxygenase protein is 0.404, suggesting that the protein has low solubility. The protein isoelectric point (pI) is between 5.17 to 5.36, and the protein molecular weight is 121.143 kDa. Conclusion: In silico analysis has supported that recombinant plasmid met characteristics for the construct which consists of gene interest and protein library.

An N-heterocyclic carbene ligand precursor bearing a π-extended phenanthridine (3,4-benzoquinoline) unit is presented. The proligand was isolated as the imidazolium salt of chloride (1•HCl), bromide (1•HBr), or hexafluorophosphate (1•HPF6) counterions. These salts can be deprotonated and the carbene installed on silver centres using Ag2O as both a base and a source of metal ion. The resulting Ag(I) complex (1)AgCl can be used in a transmetalation reaction to generate a Pd(II) coordination complex (1)Pd(CH3CN)Cl2. The characterization and photophysical properties of these complexes is presented, along with a demonstration of the utility of (1)Pd(CH3CN)Cl2 in mediating a catalytic C-N cross-coupling reaction for the preparation of the pharmaceutical Piribedil. [ABSTRACT FROM AUTHOR]

In the present study, the antiviral activity of phenanthridine derivatives was assessed. In total, the inhibitory effect of eight structurally similar low-molecular-weight hydrophobic compounds on HIV-1 protease (HIVp) was investigated. HIVp is a key enzyme in the HIV-1 life cycle. Surface plasmon resonance technology was used for affinity assessment of compounds binding with either monomeric or dimeric forms of HIVp. HIVp enzyme inhibition assays with chromogenic substrate VII were also used to determine the IC50 values. The most potent compound was 3,3,9,9-tetrameth yl-3,4,9,10-tetrahydro-2H,8H-phenanthridine-1,7-dione which binds to monomeric and dimeric forms of HIVp (apparent dissociation constant, 2-7 µM; IC50, 36 µ), while possessing the most favorable Absorption, Distribution, Metabolism and Excretion parameters. Molecular docking simulations highlighted certain differences in the binding patterns of the phenanthridine derivatives with HIVp amino acid residues forming the flaps domain, monomer/monomer interfaces and the active site cavity of HIVp. Thus, it was hypothesized that the inhibitory effect of phenanthridine compounds on the enzymatic activity of HIVp may be due to restriction of substrate access to the HIVp active site. [ABSTRACT FROM AUTHOR]

Background: Sanguinarine (SAG), a benzophenanthridine alkaloid, occurs in Papaveraceas, Berberidaceae and Ranunculaceae families. Studies have found that SAG has antioxidant, anti-inflammatory, and antiproliferative activities in several malignancies and that it exhibits robust antibacterial activities. However, information reported on the action of SAG against Providencia rettgeri is limited in the literature. Therefore, the present study aimed to evaluate the antimicrobial and antibiofilm activities of SAG against P. rettgeri in vitro. Methods: The agar dilution method was used to determine the minimum inhibitory concentration (MIC) of SAG against P. rettgeri. The intracellular ATP concentration, intracellular pH (pHin), and cell membrane integrity and potential were measured. Confocal laser scanning microscopy (CLSM), field emission scanning electron microscopy (FESEM), and crystal violet staining were used to measure the antibiofilm formation of SAG. Results: The MIC of SAG against P. rettgeri was 7.8 mµ/mL. SAG inhibited the growth of P. rettgeri and destroyed the integrity of P. rettgeri cell membrane, as reflected mainly through the decreases in the intracellular ATP concentration, pHin and cell membrane potential and significant changes in cellular morphology. The findings of CLSM, FESEM and crystal violet staining indicated that SAG exhibited strong inhibitory effects on the biofilm formation of P. rettgeri and led to the inactivity of biofilm-related P. rettgeri cells. [ABSTRACT FROM AUTHOR]

Sanguinarine is a bioactive compound as a quaternary benzophenanthridine alkaloid from plant of the Macleaya cordata, Papaveraceae family. The present study was conducted to investigate the effects of dietary sanguinarine supplementation on growth performance, serum biochemistry parameters, intestinal mucosal morphology and gut microbiome in yellow feathered broilers. Two hundred and seventy 1-d-old female broilers were randomly assigned to 3 treatments ① Basal diet (NG); ② Basal diet containing bacitracin methylene disalicylate (50mg/Kg diet) (ANT); ③ Basal diet containing sanguinarine (0.7 mg/ kg of feed) (SAG). The statistical results showed that dietary sanguinarine supplementation enhanced growth performance and decreased glucose, uric acid as well as urea nitrogen levels of broilers at 28d of age (P<0.05). The 16S rRNA gene sequence analysis revealed that sanguinarine significantly decreased the species from the phyla Bacteroidetes, and increased the species from phyla Firmicutes. Moreover, dietary sanguinarine supplementation improved mucosal morphology to achieve higher ratio of intestinal villus height to crypt depth (P < 0.05), and decreased the concentrations of TNF-α and IL-4 in jejunum mucosal. This study demonstrated that sanguinarine supplementation in the diet of yellow feathered broilers improved intestinal morphology and microbiota community structure to promote growth performance on 1-28d. [ABSTRACT FROM AUTHOR]

Two new co-crystals, tetraiodoethylene-phenanthridine (1/2), 0.5C2I4·C13H9N (1) and tetraiodoethylene-benzo[f]quinoline (1/2), 0.5C2I4·C13H9N (2), were obtained from tetraiodoethylene and azaphenanthrenes, and characterized by IR and fluorescence spectroscopy, elemental analysis and X-ray crystallography. In the crystal structures, C-I···π and C-I···N halogen bonds link the independent molecules into one-dimensional chains and two-dimensional networks with subloops. In addition, the planar azaphenanthrenes lend themselves to π-π stacking and C-H···π interactions, leading to a diversity of supramolecular three-dimensional structural motifs being formed by these interactions. Luminescence studies show that co-crystals 1 and 2 exhibit distinctly different luminescence properties in the solid state at room temperature. [ABSTRACT FROM AUTHOR]

Based on the structure of sanguinarine, fourteen phenanthridine derivatives were designed and synthesized in the current study. The cytotoxic activities of synthesized compounds were evaluated against five human cancer cell lines (MCF-7, PC3, Hela, A549, and HepG2 cell lines) via MTT assay. Among all the compounds tested, molecule 8a exhibited significant cytotoxic activity against MCF-7 cells with a IC50 value of 0.28 μM. A following up enzymatic assay indicated that compound 8a could inhibit the activity of DNA topoisomerase I/II. Further mechanistic studies performed in the MCF-7 cell line revealed that compound 8a could arrest cell cycle in S phase and induce cell apoptosis via downregulation of Bcl-2 and upregulation of Bax. Collectively, a potent DNA topoisomerase inhibitor (8a) was discovered, which exhibited potential as a candidate chemotherapeutic agent for the management of tumors in the present study.

Malaria is responsible for majority of the morbidity and mortality statistics reflected by tropical diseases. Whilst effectively managed in most parts of the globe, it remains a scourge on the African continent where most cases of the disease are diagnosed annually. Plants have played a leading role as a source of malarial drugs which continue to dominate the clinical landscape today. Most if not all of these discoveries have as their basis evidence which can be traced back to traditional medicine. There is likewise precedence for the use of Amaryllidaceae plants in traditional medicinal approaches towards malaria. The chief phytochemical principles of the Amaryllidaceae are its isoquinoline alkaloids which are responsible for its diverse biological properties. These alkaloids may be divided into major and minor groups based on their distinguishing structural features as well as their natural abundance and distribution in the family. Whilst much has been written about the biological and chemical properties of the major alkaloid groups of the Amaryllidaceae, relatively little is known or understood about its minor alkaloid groups. This review focuses on the antiplasmodial activities described in the literature for the minor alkaloid group members of the Amaryllidaceae against various strains of the malarial pathogen Plasmodium falciparum. Three database platforms (Google Scholar, SciFinder and Scopus) were utilized for the literature search. Articles were accessed from journals licensed to the University of KwaZulu-Natal, or directly via the respective corresponding authors. Also considered are structural elements of these alkaloids which may be used to explain such activities as well as to provide a foundation in attempts to modulate activities. In addition, evidence is provided on the molecular basis to these effects which could guide efforts in drug discovery. • Antiplasmodial effects surveyed for the minor alkaloid groups of the Amaryllidaceae. • Thirty-six compounds screened against six strains of Plasmodium falciparum. • Cripowellin C identified as most active (IC 50 0.014 μg/mL against strain Dd2). • Phenanthridine nucleus is integral to the antiplasmodial pharmacophore. • Targets are enzymes of the plasmodial FAS-II biosynthetic pathway. [ABSTRACT FROM AUTHOR]

Here we study the effect of nitrogen insertion on the electronic spectra of polycyclic aromatic hydrocarbon (PAH) molecules measured under laboratory conditions that are relevant for comparison with astronomical data. We examine the case of the substitution of carbon atoms by nitrogen atoms in the benzenoid skeleton of phenanthrene (C14H10), a prototype non-compact PAH. The vibronic transitions of the 2 1 A 1 ( S 1 ) ⟵ X 1 A 1 ( S 0 ) electronic absorption band system of neutral phenanthrene (C14H10) and phenanthridine (C13H9N) molecules seeded in a supersonic free jet expansion of argon gas are measured in the 315-345 nm region using the cavity ring down spectroscopy (CRDS) technique. Additional measurements of the absorption spectra of the phenanthrene, phenanthridine, and 1,10-phenanthroline (C12H8N2) molecules isolated in 10-K solid argon matrices are also presented. The results obtained confirm that laboratory spectra of cold, isolated molecules obtained under astrophysically relevant conditions are required for a direct, unambiguous comparison with astronomical observations as well as for the understanding of the physical evolution of the interstellar medium. [ABSTRACT FROM AUTHOR]

Based on the structure of sanguinarine, fourteen phenanthridine derivatives were designed and synthesized in the current study. The cytotoxic activities of synthesized compounds were evaluated against five human cancer cell lines (MCF-7, PC3, Hela, A549, and HepG2 cell lines) via MTT assay. Among all the compounds tested, molecule 8a exhibited significant cytotoxic activity against MCF-7 cells with a IC50 value of 0.28 μM. A following up enzymatic assay indicated that compound 8a could inhibit the activity of DNA topoisomerase I/II. Further mechanistic studies performed in the MCF-7 cell line revealed that compound 8a could arrest cell cycle in S phase and induce cell apoptosis via downregulation of Bcl-2 and upregulation of Bax. Collectively, a potent DNA topoisomerase inhibitor (8a) was discovered, which exhibited potential as a candidate chemotherapeutic agent for the management of tumors in the present study. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 36 phenanthridine Wnt agonists were designed and synthesized. • 3f and 3g , showed 10 times stronger agonist activity than that of HLY78. • Methyl and smaller nitrogen heterocyclic substituents can improved Wnt activation. • Why 3f and 3g showed different effects were explained by docking analysis. Abstract Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/ β -catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/ β -catenin signalling pathway, HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/ β -catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78. In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation. [ABSTRACT FROM AUTHOR]

Over the past decade, bioorthogonal chemistry that facilitates the efficient conjugation of biomolecules has expanded from the copper-catalyzed alkyne-azide cycloadditions to a multitude of diverse reactions, varying additives and reactional partners, and most often offering better alternatives with faster rates and lower toxicity of employed reactants. Among these, the copper-free strain-promoted cycloaddition reactions have been demonstrated to be more promising, offering a reaction without toxic metal catalysts and with faster inherent kinetic rate constants. The strain-promoted alkyne-nitrone cycloadditions are easily tunable from both the (strained) alkyne and nitrone perspective, both compounds giving the opportunity to modulate the rate of reaction by substituting various positions. Previously, acyclic nitrones have been evaluated in the strain-promoted alkyne-nitrone reactions; however, they were notably prone to hydrolysis. Some five-membered ring endocyclic nitrones developed concomitantly offered the advantage of relatively fast kinetics and better resistance to degradation in aqueous conditions and have been successfully used for labelling of biomolecules in living systems. Herein, we have prepared and studied nitrones inspired by the phenanthridine scaffold that efficiently undergo strain-promoted alkyne-nitrone reactions. Phenanthridine nitrones react fast with strained cyclooctynes with large bimolecular rate constants while maintaining bioorthogonality and resistance to hydrolysis. [ABSTRACT FROM AUTHOR]

Abstract Nitrogen-containing polycyclic core 5-phenylnaphtho[1,2,3,4-lmn] phenanthridine and its nitro-functionalized positional isomers were synthesized using Pictet-Spengler reaction between hexaalkoxytriphenylene-1-amine and various aryl aldehydes. The hexagonal columnar phase was observed in all the synthesized novel compounds. Mesomorphic characterization was carried out using conventional thermal analysis and X-ray diffraction techniques. These compounds showed room temperature liquid crystal phase and there is no crystalline phase observed even at −20 °C upon cooling from the isotropic temperature. Further, the long range of mesophase was confirmed by polarizing optical microscopy. Subsequently, charge transfer complexes were prepared by mixing the synthesized polycyclic hetero-aromatic compounds with 2,3,6,7,10,11-hexakis(octyloxy)-triphenylene. In UV–Vis absorption spectra, a redshift was found for the charge transfer complexes; which confirmed the interaction between donor-acceptor counterparts. The electrical conductivity of the charge transfer complexes and their pure target compounds was measured. Graphical abstract Unlabelled Image Highlights • Novel 5-phenylnaphtho[1,2,3,4-lmn] phenanthridine based DLCs are prepared using Pictet-Spengler reaction. • The liquid crystals properties were evaluated by POM, DSC and XRD techniques. • The charge transfer complexes with equimolar concentration of HAT8 are prepared and characterized. • The electrical conductivity of pure N-heterocyclic compounds as well as charge transfer mixtures is evaluated. [ABSTRACT FROM AUTHOR]

Phenanthridine derivatives are one of the most intensively studied families of biologically active compounds with efficient DNA binding capability. Attracting attention since DNA structure discovery (1960s), they were early recognized as a symbol of DNA intercalative binding, for many decades applied as gold-standard DNA- and RNA-fluorescent markers (ethidium bromide), probes for cell viability (propidium iodide), but also “ill-famed” for various toxic (genotoxic) and mutagenic effects. After two decades of low interest, the discovery of phenanthridine alkaloids and new studies of antiparasitic/antitumor properties of phenanthridine derivatives resulted in the strong increase of the scientific interest about the turn of this century. Here are summarized phenanthridine-related advances in the 21st century (2000-present period) with emphasis on the supramolecular interactions and bioorganic chemistry, as well as novel or improved synthetic approaches.

Chelerythrine (CH), is a kind of benzo[c] phenanthridine alkaloid isolated from plants such as Chelidonium, with pharmacological activities as antitumor, antibiosis and anti-inflammation. However, few studies have demonstrated whether CH could protect against lipopolysaccharide (LPS)-induced acute lung injury (ALI), and the underlying mechanism is also uncertain. The purpose of the present study was to investigate the anti-inflammatory effects of CH on LPS-induced ALI in mice and in RAW264.7 cells. In this study, we demonstrated that treatment with CH significantly ameliorated LPS-induced pathological changes in the lung. CH also attenuated LPS-induced W/D ratio, inflammatory cell infiltration. Meanwhile, LPS-induced Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β) production and oxidative stress were markedly suppressed by CH. Furthermore, western blot showed that CH suppressed LPS-stimulated inflammation of RAW264.7 cells through activation of nuclear factor kappa-B (NF-κB) pathway. Knocking down of nuclear factor erythroid 2-related factor 2 (Nrf2) led to the reduction of nuclear translocation of the NF-κB p65, which triggered inflammation. These experimental results provided evidence that CH could be a potential therapeutic candidate for the intervention of ALI caused by LPS. [ABSTRACT FROM AUTHOR]

Background: Trypanosoma evansi is mechanically transmitted by biting flies and affects camels, equines, and other domestic and wild animals in which it causes a disease called surra. At least two types of Trypanosoma evansi circulate in Ethiopia: type A, which is present in Africa, Latin America and Asia, and type B, which is prevalent in Eastern Africa. Currently, no information is available about the drug sensitivity of any Ethiopian T. evansi type. Methodology/principal findings: This study was conducted with the objective of determining the in vivo drug sensitivity of two T. evansi type A and two type B stocks that were isolated from camels from the Tigray and Afar regions of Northern Ethiopia. We investigated the efficacy of four trypanocidal drugs to cure T. evansi infected mice: melarsamine hydrochloride (Cymelarsan), diminazene diaceturate (Veriben and Sequzene), isometamidium chloride (Veridium) and homidium chloride (Bovidium). Per experimental group, 6 mice were inoculated intraperitoneally with trypanosomes, treated at first peak parasitemia by daily drug injections for 4 consecutive days and followed-up for 60 days. Cymelarsan at 2 mg/kg and Veriben at 20 mg/kg cured all mice infected with any T. evansi stock, while Sequzene at 20 mg/kg caused relapses in all T. evansi stocks. In contrast, Veridium and Bovidium at 1 mg/kg failed to cure any T. evansi infection in mice. Conclusions/significance: We conclude that mice infected with Ethiopian T. evansi can be cured with Cymelarsan and Veriben regardless of T. evansi type. In contrast, Veridium and Bovidium are not efficacious to cure any T. evansi type. Although innate resistance to phenanthridines was previously described for T. evansi type A, this report is the first study to show that this phenomenom also occurs in T. evansi type B infections. [ABSTRACT FROM AUTHOR]

In this study, we report the synthesis, antibacterial and anticancer evaluation of 38 novel phenanthridines that were designed as analogs of the benzo[c]phenanthridine alkaloids. The prepared phenanthridines differ from the benzo[c]phenanthridines in the absence of a benzene A-ring. All novel compounds were prepared from 6-bromo-2-hydroxy-3-methoxybenzaldehyde in several synthetic steps through reduction of Schiff bases and accomplished by radical cyclization. Twelve derivatives showed high antibacterial activity against Bacillus subtilis, Micrococcus luteus and/or Mycobacterium vaccae at single digit micromolar concentrations. Some compounds also displayed cytotoxicity against the K-562 and MCF-7 cancer cell lines at as low as single digit micromolar concentrations and were more potent than chelerythrine and sanguinarine. The active compounds caused cell-cycle arrest in cancer cells, increased levels of p53 protein and caused apoptosis-specific fragmentation of PARP-1. Biological activity was connected especially with the presence of the N-methyl quaternary nitrogen and 7-benzyloxy substitution (compounds 7i, 7j, 7k, and 7l) of phenanthridine. [ABSTRACT FROM AUTHOR]

Four new, stabilized phosphonium ylides containing a 2-(benzyl(methyl)amino)phenyl group have been prepared and characterized and are found, upon pyrolysis under gas-phase flow conditions, to lose Ph3PO and benzyl radicals to afford new heterocyclic products resulting from domino cyclization of both C- and N-centered radicals. Most products arise from processes of the former type and have quinoline, phenanthridine, or ring-fused phenanthridine structures, while in one case, a process of the latter type leads to a benzocarbazole product. The X-ray structure of a 2-(methyl(tosyl)amino)phenyl ylide is also reported. [ABSTRACT FROM AUTHOR]

Association of ethidium bromide and caffeine in aqueous solution was studied using spectrophotometry. The results were analyzed using a molecular dimer heteroassociation model. The molecular association equilibrium constants were determined. The experimental absorption spectrum of a mixture of heterocyclic molecules was deconvoluted into individual components using a regularization method. Quantitative information on the structure of the heterocomplex was obtained using data for the individual spectral components. The distance and angle between point transition dipole moments of the heterogeneous molecules were 0.3 nm and 16o. A calculation of the relative contents of different types of associates in a mixed solution showed that heteroassociation of the molecules decreased the effective concentration of ethidium bromide and, accordingly, the mutagenic activity of the dye. [ABSTRACT FROM AUTHOR]