Phenanthridine Derivatives Research Articles

Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 ~2 to 10 µM) against multiple Mycobacterium strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of Mycobacterium bovis BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to Mycobacterium spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.IMPORTANCEThe emergence of drug-resistant tuberculosis (TB) is a serious global health threat. There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug-resistant Mycobacterium tuberculosis (Mtb). This study shows that novel semi-synthetic compounds can be derived from natural compounds to produce potent activity against Mtb. Importantly, the identified compounds have narrow spectrum activity against Mycobacterium species, including clinical multidrug-resistant (MDR) strains, are effective in infected macrophages and against non-replicating Mtb (NR-Mtb), and show anti-mycobacterial activity in mice. These new compounds provide promising chemical scaffolds to develop potent anti-Mtb drugs of the future.

TEMPO as Hydrogen Atom Transfer Catalyst in Enhancing Iminyl Radical Cyclization of O-Acetyl Oxime toward Phenanthridines and Isoquinolines.

Herein, we present a strategy for promoting the cyclization of ortho-aryl or ortho alkenyl arylketone oxime ethers C-N bonds using TEMPO as a direct hydrogen atom transfer (HAT) catalyst. The reaction employs a green solvent and requires no introduction of metal additives. It only needs catalytic amount of TEMPO to drive the reaction. Gram-scale reaction yields the corresponding products with satisfactory yields, providing a novel and efficient method for the synthesis of phenanthridine and isoquinoline derivatives.

Divergent Reactivity of Iminyl Radicals in Four Interrupted Pathways for the Synthesis of Cyclic/Acyclic Ketones and N-Heterocycles from Vinyl Azides and Phenylacetic Acids.

Herein, we report the Ag-catalyzed substrate-controlled interrupted radical pathways of the iminyl radical. The benzylic groups played a crucial role in pathway selection involving a series of dimerization and hydrolysis, a 1,5-H shift followed by cascade radical cyclization, and direct N-(sp2)/aromatization reactions that provide access to diverse cyclic/acyclic ketones, quinolines, and phenanthridine derivatives. Contrary to previous reports, mechanistic investigations with high-resolution mass spectrometry analysis uncovered the involvement of rare azine, oxime, and β-functionalized vinyl azide intermediates.

Photochemical Decarboxylative Radical Alkylation/Cyclization Reaction to Fused Nitrogen Heterocycles by LiI/PPh3 Catalysis

Comprehensive SummaryA visible‐light‐induced decarboxylative radical cascade cyclization reaction between N‐(2‐cyanoaryl)‐acrylamides and alkyl N‐(acyloxy)phthalimide (NHPI esters) for the construction of phenanthridine derivatives has been developed. This approach utilizes lithium iodide (LiI) and triphenylphosphine (PPh3) as the redox catalysts and the alkyl radical is produced through the photoactivation of the electron donor‐acceptor (EDA) complex. A series of primary, secondary, and tertiary alkyl‐substituted phenanthridines are prepared in up to 82% yield without transition‐metal catalysts, chemical oxidants, or metal‐/organic dye‐based photocatalysts.

O2-promoted photocyclization of arylimines: A mild strategy of generating phenanthridines

A visible light-induced cyclization of arylimines using trifluoromethanesulfonic acid (TfOH) as the catalyst is reported. The transformation, conducted under air and mild conditions utilizes O2 as the oxidant, eliminating the need for leaving groups or excess acid. Optimization studies reveal the pivotal role of TfOH and visible light in the reaction. The methodology allows a broad substrate scope, accommodating various electron-donating and electron-withdrawing groups. The reaction conditions enable gram-scale synthesis and show inhibitory effects on cancer cell lines and low toxicity towards normal cells. Mechanistic insights indicate a visible light-induced 6π-electrocyclization. This method provides a practical and efficient approach for the synthesis of phenanthridine derivatives.

Palladium-catalyzed C-H bond activation and decarboxylation for the assembly of indolo[1,2-f]phenanthridine.

A direct and convenient strategy for the assembly of indolo[1,2-f]phenanthridine via a Pd-catalyzed tandem cyclization reaction is presented. The current strategy delivers a range of indolo[1,2-f]phenanthridine derivatives by utilizing readily available 1-(2-iodophenyl)-1H-indole and commercially available o-bromobenzoic acids as the starting materials. The reaction features the formation of two C-C bonds through Pd-catalyzed C-H bond activation and decarboxylation.

Integration of nonlinear two-photon excited fluorescence and photocatalysis boosts overall water splitting performance.

A nonlinear two-photon excited fluorescence photocatalytic system was constructed for the first time by integrating (ZnO)1-x(GaN)x photocatalyst and a fluorescence solution of phenanthridine derivatives. This work offers a strategy for increasing the photocatalytic solar spectral utilization rate and boosting the expectation for photocatalytic solar-to-hydrogen efficiencies.

Trifunctionalization of CC bonds in vinyl azides to access densely functionalized phenanthridines enabled by the NCS/AgNO2 system.

An unprecedented trifunctionalization of CC bonds in 2-(1-azidovinyl)-1,1'-biphenyls has been successfully achieved using the NCS/AgNO2 system, leading to the preparation of 6-(dichloro(nitro)methyl)phenanthridines in moderate to good yields. In this process, the NCS/AgNO2 system serves as a NO2 radical initiator as well as a chloro group source. The present protocol is a rare example of the selective construction of densely functionalized phenanthridine derivatives in a one-pot manner.

Redox-Neutral Cyclization of 2-Isocyanobiaryls through Photoredox/PPh3 Dual Catalysis.

The photoredox/PPh3-mediated cyclization of 2-isocyanobiaryls has been developed. A substantial range of functional-group-rich phenanthridine derivatives were synthesized at room temperature in a highly selective and atom-economic manner. Mechanistic studies suggested that the cyclization process is probably mediated both by Ph3P radical cation with key 1,2-hydride transfer and hydrogen atom generated through O-H bond homolytic cleavage of Ph3P-OH radical intermediate.

Recent Advancements in Synthesis of Phenanthridines via 2‐Isocyanobiphenyls

AbstractPhenanthridines are a privileged heterocyclic compound that exists in many natural products and has been known to exhibit a variety of pharmacological properties. In the last few decades, an incredible development has taken place to synthesise this scaffold. In this regard, 2‐isocyanobiphenyl has become one of the most exploited substrates that allow the direct formation of phenanthridine derivatives under various novel and conventional methods. The present review provides an overview of synthetic approaches for the preparation of phenanthridine, and their derivatives form 2‐isocyanobiphenyls′′.

One-Pot Synthesis of Benzo[c]phenanthridine Alkaloids from 7-Azabenzonorbornadienes and Aryl Nitrones.

An efficient synthesis of benzo[c]phenanthridine alkaloids via a synergistic combination of C-C bond formation and a cycloaromatization reaction is described. Aryl nitrones react with 7-azabenzonorbornadienes in the presence of a Rh(III) catalyst, providing pharmaceutically useful benzo[c]phenanthridine derivatives in good to moderate yields. Using this methodology, highly useful alkaloids such as norfagaronine, norchelerythrine, decarine, norsanguinarine, and nornitidine were prepared in a single step.

Visible-Light-Promoted Cyanoalkylation/Cyclization Cascade Reaction to Assemble Polyheterocycles in Continuous Flow.

This study describes a visible-light-induced cascade reaction for preparing cyanoalkyl-containing polyheterocycles initiated by the photoinduced radical cascade addition of N-arylacrylamide derivatives using cyclic oxime esters as radical sources followed by cyanoalkyl-mediated cyclization. This protocol features outstanding functional group compatibility, providing a variety of desired phenanthridine derivatives in moderate to good yields. Moreover, the application of a microflow technique enhanced these reactions compared with the equivalent batch reaction, significantly reducing reaction times to 10 min.

Configuration-Induced Multichromism of Phenanthridine Derivatives: A Type of Versatile Fluorescent Probe for Microenvironmental Monitoring.

Fluorescent probes are attractive in diagnosis and sensing. However, most reported fluorophores can only detect one or few analytes/parameters, notably limiting their applications. Here we have designed three phenanthridine-based fluorophores (i.e., B1, F1, and T1 with 1D, 2D, and 3D molecular configuration, respectively) capable of monitoring various microenvironments. In rigidifying media, all fluorophores show bathochromic emissions but with different wavelength and intensity changes. Under compression, F1 shows a bathochromic emission of over 163 nm, which results in organic fluorophore-based full-color piezochromism. Moreover, both B1 and F1 exhibit an aggregation-caused quenching (ACQ) behavior, while T1 is an aggregation-induced emission (AIE) fluorophore. Further, F1 and T1 selectively concentrate in cell nucleus, whereas B1 mainly stains the cytoplasm in live cell imaging. This work provides a general design strategy of versatile fluorophores for microenvironmental monitoring.

Configuration‐Induced Multichromism of Phenanthridine Derivatives: A Type of Versatile Fluorescent Probe for Microenvironmental Monitoring

AbstractFluorescent probes are attractive in diagnosis and sensing. However, most reported fluorophores can only detect one or few analytes/parameters, notably limiting their applications. Here we have designed three phenanthridine‐based fluorophores (i.e., B1, F1, and T1 with 1D, 2D, and 3D molecular configuration, respectively) capable of monitoring various microenvironments. In rigidifying media, all fluorophores show bathochromic emissions but with different wavelength and intensity changes. Under compression, F1 shows a bathochromic emission of over 163 nm, which results in organic fluorophore‐based full‐color piezochromism. Moreover, both B1 and F1 exhibit an aggregation‐caused quenching (ACQ) behavior, while T1 is an aggregation‐induced emission (AIE) fluorophore. Further, F1 and T1 selectively concentrate in cell nucleus, whereas B1 mainly stains the cytoplasm in live cell imaging. This work provides a general design strategy of versatile fluorophores for microenvironmental monitoring.

Photoredox-catalyzed C-heteroaryl glycosylation of biphenyl isocyanides with glycosyl bromides.

8,9-Dimethoxyphenanthridine derivatives, as potential antitumor drugs, need modification to improve their biocompatibility and water solubility. Reported here is a strategy to access C-heteroaryl glycosides by photoredox catalysis. C6-glycosylated phenanthridine derivatives are synthesized from biphenyl isocyanides and glycosyl bromides. The reaction conditions are mild and widely applicable, with anomeric α selectivity and good functional group tolerance.

Photocatalytic radical cascade cyclization of N‐(o–cyanobiaryl) acrylamides: access to CF2H‐functionalized pyrido[4,3,2‐gh] phenanthridines

AbstractHere we report a simple and efficient method for the preparation of CF2H‐substituted pyrido[4,3,2‐gh]phenanthridines under photoredox conditions. The reactions are triggered by addition of a CF2H radical to a carbon–carbon double bond to form three different types of bonds via a cascade radical difluoromethylation/cyano insertion/cyclization. This difluoromethylated transformation exhibits good functional group compatibility, leading to the construction of the desired ring‐fused phenanthridine derivatives in moderate to excellent yields.

The Photoactive Hydrazone-Linked Covalent Organic Frameworks for Photocyclization Approach to Phenanthridine Derivatives

The Photoactive Hydrazone-Linked Covalent Organic Frameworks for Photocyclization Approach to Phenanthridine Derivatives

Photochemical palladium-catalyzed methylation and alkylation reactions in cascade reactions of isonitriles

Photochemistry of palladium catalysis has been proved as an efficient strategy for cross coupling and multifunctionalization reaction of olefins via alkyl radicals. Herein, we demonstrate that isonitriles can serve as radical acceptors, which engage in a further radical cascade cyclization to furnish phenanthridine derivatives. We have also extended this photocatalytic process to cascade methylation reaction in one-pot with TMSCH2I as the radical precursor. Further experimental and computational studies indicate an intramolecular single electron transfer process to obtain alkyl radicals is involved in this transformation.

Redox-Neutral Generation of Iminyl Radicals by N-Heterocyclic Carbene Catalysis: Rapid Access to Phenanthridines from Vinyl Azides.

An N-heterocyclic carbene-catalyzed oxidant-, metal- and light-free iminyl radical generation pathway stemming from the reaction of vinyl azide and α-bromo ester is uncovered. This newly developed methodology is successfully applied to the redox-neutral construction of a number of diversified phenanthridine derivatives with nice functional group compatibility. Insights from the mechanism study reveal that this NHC-catalyzed transformation potentially proceeds through an alkyl radical addition-initiated HAS process, with the iminyl radical as an active intermediate.

Practical and modular construction of benzo[c]phenanthridine compounds

Here, we describe a general and modular strategy for the rapid assembly of benzo[c]phenanthridine (BCP) derivatives using homogeneous gold catalysis. Notably, in contrast to traditional methods based on the specially preformed substrates that have an inherent preference for the formation of this class of compounds with limited flexibility, this protocol is achieved via a selectively intramolecular cascade of a diazo-tethered alkyne and subsequently an intermolecular cyclization with a nitrile to facilitate the successive C-N and C-C bonds formation. This methodology uses readily available nitriles as the nitrogen source to deliver the products in good yield with excellent functional group compatibility. A preliminary anti-tumor activity study of these generated products exhibits high anticancer potency against five tumor cell lines, including HeLa, Mel624, SW-480, 8505C, LAN-1. Besides, we report a catalyst-controlled intermolecular cycloaddition/intramolecular insertion of the substrate with a fulvene to provide fused polycarbocycles containing a seven-membered ring.