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Abstract: The phenanthridine family is widely found in medicinal chemistry and material science because of the biological activity and its presence in a variety of significant natural products and synthetic dye stuffs. The phenanthridine has many clinical applications, for e.g., being used as an anticancer agent, possessing antibacterial, antiprotozoal, pharmaceutical, and optoelectronic properties. Many methods have been reported for the synthesis of phenanthridine and phenanthridine alkaloids, such as Pd catalyzed C-C bond formation, a reaction involving C-H activation, radical, microwave-assisted, transition metal-catalyzed, one-pot cascade, benzyne mediated, photochemical, hypervalent iodine promoted methods, etc. Here, we have summarized the literature data from 2014 to the present concerning novel or improved synthetic approaches.

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Calorimetric chemosensors are found to be advantageous sensing systems due to their simplicity and favorable responsive properties. Although some colorimetric probes have been reported to detect hydrogen sulfide (H2 S), the creation of rapid, highly selective and sensitive probes for the detection of H2 S remains a challenging target. In this work, we established dinitrosulphonamide decorated phenanthridine and 2,4-dinitro-N-(4-(7,8,13,14-tetrahydrodibenzo[a, i]phenanthridin-5-yl)phenyl)benzenesulfonamide (PHSH), for the calorimetric detection of H2 S. H2 S-triggered thiolysis of PHSH resulted in a marked absorption enhancement alongside a visual color change from colorless to dark yellow. The result indicated that the chemosensor showed high sensitivity and selectivity with a fast response of less than 10 s with a detection limit as low as 6.5 nM. The chemosensor reaction mechanism with H2 S was studied by UV-vis, 1 H NMR, mass and HPLC analysis. In addition, the chemosensor has been used for the determination of H2 S in many real-time samples.

Alkaloids isolated from members of the Amaryllidaceae plant family are promising anticancer agents. The purpose of the current study was to determine if the isocarbostyrils narciclasine, pancratistatin, lycorane, lycorine, crinane, and haemanthamine inhibit phenomena related to cancer progression in vitro. To achieve this, we examined the proliferation, adhesion, and invasion of cultured human colon cancer cells via MTT assay and Matrigel-coated Boyden chambers. In addition, Luminex assays were used to quantify the secretion of matrix metalloproteinases (MMP) and cytokines associated with poor clinical outcomes. We found that all alkaloids decreased cell proliferation regardless of TP53 status, with narciclasine exhibiting the greatest potency. The effects on cell proliferation also appear to be specific to cancer cells. Narciclasine, lycorine, and haemanthamine decrease both adhesion and invasion but with various potencies depending on the cell line. In addition, narciclasine, lycorine, and haemanthamine decreased the secretion of MMP-1, -2, and -7, as well as the secretion of the cytokines pentraxin 3 and vascular endothelial growth factor. In conclusion, the present study shows that Amaryllidaceae alkaloids decrease phenomena and cytokines associated with colorectal cancer progression, supporting future investigations regarding their potential as multifaceted drug candidates.

The reaction of o-benzofulvene with TfOH leads to intramolecular cyclization through novel C-C and C-N bond formation, resulting in the formation of 5H,10'H-spiro[benzo[k]phenanthridine-5,6'-dibenzopentalene]. This protocol provides a new molecular framework with reasonable to excellent yields and tolerates various electron-withdrawing/donating substituents. This method yields diastereoselectivity of up to >20:1. Furthermore, it is free of bases, oxidants, and metals and proceeds under mild reaction conditions, which are favorable for synthetic organic chemistry.

A Rh(III)-catalyzed cascade C–H activation/intramolecular cyclization of 3-aryl-5-isoxazolones with cyclic 2-diazo-1,3-diketones was described, leading to the formation of isoxazolo[2,3-f]phenanthridine skeletons. The protocol features the simultaneous one-pot formation of two new C–C/C–N bonds and one heterocycle in moderate-to-good yields with good functional group compatibility. It is amenable to large-scale synthesis and further transformation.

Introduction Macleaya cordata (Willd) R. Br. (Papaveraceae family) is a well-known traditional Chinese medicine used to treat muscle pain, inflamed wounds, and bee bites. Benzo[c]phenanthridine alkaloids are the main active ingredients in M. cordata. In this work, sanguinarine and chelerythrine were efficiently extracted and purified by ultrahigh-pressure extraction (UHPE) technique and pH-zone-refining counter-current chromatography (PZRCCC) from M. cordata. Objective To develop an efficient UHPE method followed by an efficient separation technique using PZRCCC for benzo[c]phenanthridine alkaloids from the study plant species, and to evaluate the study samples for anti-breast cancer activity. Methodology The optimal extraction conditions were optimised as extraction pressure 200 MPa, extraction solvent 95% ethanol, solid-liquid ratio 1:30 (g/mL) and extraction time 2 min. A two-phase n-hexane/ethyl acetate/i-propanol/water (1:3:1.5:4.5, v/v) solvent system was optimised with 10 mmol triethylamine in the upper phase and 10 mmol trifluoroacetic acid in lower phase in PZRCCC. The sample loading was optimised as 2.50 g. Moreover, the samples were evaluated for anti-breast cancer activity later on. Results The 2.50 g sample loading yielded 0.45 g of sanguinarine and 0.59 g chelerythrine in one-step separation using PZRCCC. The anti-breast cancer activities of sanguinarine and chelerythrine were found stronger than positive control (vincristine 5.04 μg/mL) with half-maximal inhibitory concentration values of 0.96 and 3.00 μg/mL, respectively. Conclusion This study showed that the established methods were efficient in extraction (UHPE) and separation (PZRCCC) of the sanguinarine and chelerythrine from M. cordata.

A photocatalytic xanthate-based radical addition/cyclization reaction cascade toward 2-biphenylisocyanides is described as a practical and modular approach to 6-alkylated phenanthridines. The use of xanthates as radical precursors allowed the synthesis of diversely 6-substituted phenanthridines. Electrophilic radicals derived from nitriles, aromatic and aliphatic ketones, malonates, and amide derivatives, as well as radicals derived from phthalimidomethyl and benzylic derivatives were successfully introduced. The reaction proceeds under mild conditions without a stoichiometric amount of oxidant. Thirty novel phenanthridine scaffolds were synthesized with yields ranging from 24 to 76%.

Specific amplification of nucleic acids is a convenient and quick alternative to the culture-based method of detecting bacterial cells. However, conventional PCR and other amplification reactions can not differentiate between live bacteria and dead or dormant ones, and are also capable of amplifying DNA that persists for a long time and in a cell-free state. Several methods have been developed in order to establish the viability of microorganisms by amplification of specific sequences of nucleic acids, both those controlled by changing temperatures and isothermal ones. For some of them, DNA modified by phenanthridine dyes serves as a target, and simultaneous use of monoazides of ethidium and propidium was shown to be preferable for the purpose. For other methods, the targets are directly RNA molecules or their cDNA copies. Pre-rRNA detection seems to be the most preferable approach, due to the presence of these types of RNA exclusively in living cells.

An I2-mediated synthesis of phenanthridines via intramolecular sp3 C–H amination of readily accessible aniline precursors is reported. The present synthetic process is straightforward and applicable to a broad variety of unprotected aniline substrates, and provides facile and efficient access to phenanthridine derivatives. This C–H amination protocol does not use transition metals, is operationally simple, and can be achieved on a gram scale.

A complementary site selective ortho- vs ipso-amination of aryl halides using non-electrophilic amine sources for construction of indole scaffolds is reported. A palladium-catalyzed alkyne insertion/C-H activation/palladacycle amination via merger of three easily diversified components including iodoarenes, alkynes, and amines delivers indoles with different substitution patterns even in gram scales. By employing ortho-bromoanilines, a consecutive annulative π-extension of indoles proceeds to construct indolo[1,2-f]phenanthridine scaffolds via four C-C and C-N bond formations in one pot.

The formation of intramolecular C-N bond represents a powerful strategy in organic transformation as the great importance of N-heterocycles in the fields of natural products and bioactive molecules. This personal account describes the synthesis of cyclic phosphinamidation, benzosultam, benzosulfoximine, phenanthridine and their halogenated compounds through transition-metal-free intramolecular oxidative C-N bond formation. Mechanism study reveals that N-X bond is initially formed under the effect of hypervalent halogen, which is very unstable and easily undergoes thermal or light homolytic cleavage to generate nitrogen radical. Then the nitrogen radical is trapped by the arene to give aryl radical. Rearomatization of aryl radical under the oxidant to provide corresponding N-heterocycle. Under suitable conditions, the N-heterocycles can be further transformed to halogenated N-heterocycles.

Herein we report a protocol for visible-light-induced copper-catalyzed decarboxylative coupling reactions between N-heteroarenes and redox-active esters. Various N-hydroxyphthalimide esters reacted with isoquinoline, quinoline, pyridine, pyrimidine, quinazoline, phthalazine, phenanthridine, and pyridazine to give the corresponding products in modest to excellent yields. The reactions proceed under mild conditions and have a broad scope and high functional group tolerance. Mechanistic studies revealed that the catalytic behavior of CuI photocatalyst generated in situ was consistent with that of preformed [Cu(dmp)(xantphos)]BF4.

Garratt-Braverman cyclization has been employed to synthesize a series of dihydroisofuran fused phenanthridine derivatives. The established protocol proposes a simpler synthetic alternative to have access to these therapeutically relevant cytotoxic scaffolds. Single crystal X-ray data unambiguously confirmed the structures of the synthesized phenanthridine derivatives. UV–Vis absorption titration with calf-thymus DNA followed by fluorescence-based competitive ethidium bromide displacement assay established the synthesized target compounds as potent DNA-intercalating agents with intrinsic binding constant of the range 103-105. Results obtained from the molecular docking further justified the spectroscopically obtained results.

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.

1,3-Dipolar cycloaddition reactions between a new azomethine ylide and three BPhMes2-functionalized internal alkynes produced three pairs of fluorescent push–pull regioisomers, which show distinct electronic and photophysical properties. All the six compounds are found to exhibit charge-transfer (CT) fluorescence, and some of which show rare and interesting temperature “turn-on” fluorescence.

An efficient and general visible-light-mediated trifluoromethylthiolation of N-(o-cyanobiaryl)acrylamides has been successfully accomplished using N-trifluoromethylthiosaccharin as an effective source of SCF3 radicals. The reaction was proposed to proceed via a domino radical trifluoromethylthiolation/cyano insertion/cyclization to afford the corresponding SCF3-containing ring-fused phenanthridine derivatives in moderate to good yields.

The monofunctional Pt(II) drug phenanthriplatin is a leading preclinical anticancer drug, whose main characteristic is the presence of the extended aromatic system of the phenanthridine ligand, which allows intercalation. Intercalation, in turn, induces DNA unwinding and facilitates DNA binding. Aiming at verifying to what extent the peculiar cytotoxic activity of phenanthriplatin depends on the specific size of the aromatic system, two phenanthriplatin derivatives have been designed increasing the number of the rings in the N-heterocyclic ligand, and their reactivity has been computationally investigated. Both quantum mechanical DFT computations and molecular dynamics (MD) simulations have been employed to investigate some of the aspects that are considered important for the activity of Pt(II) monofunctional complexes. In particular, the substitution of the chlorido ligand with water, subsequent interaction of the aquated complexes with guanine as a model, eventual deactivation by the model N-acetyl methionine as well as intercalation into, binding to and distortion of DNA have been examined. The outcomes of such analysis have been compared with the analogous ones for the phenanthriplatin complex in order to highlight how the addition of one more ring to the phenanthridine ligand and, eventually, its identity influence the reactivity and, consequently, the cytotoxic profile of the complexes.

Photodegradation of azilsartan produces a phenanthridine derivative, with its molecular structure determined by 1H and 13C NMR spectroscopy. This structure is confirmed by single-crystal X-ray diffraction and alternative synthesis. The phenanthridine ring formation is explained through the ring closure of an imidoylnitrene intermediate produced by decarboxylation of the 5-oxo-1,2,4-oxadiazole ring (oxadiazolone).

Spectral characteristics and luminescence under the photo- and electro-excitation of substituted dibenzthiophene sulfone and phenanthridine were studied in this paper. Diphenylamines are substituents introduced in the 2nd and 7th positions (linear configuration) or the 3rd and 6th positions (angular configuration) of dibenzthiophene sulfone or phenanthridine. All molecules show delayed fluorescence, both in solutions and films produced by thermal vacuum deposition. The value of the energy gap between the S1 and T1 states has been estimated and is shown to depend not only on the spatial arrangement of the fragments among themselves (linear or angular), but also on the nature of the substituent in diphenylamine. The highest electroluminescence brightness was found for the molecules, in which triplet levels are involved, both through the process of triplet–triplet annihilation and through thermally activated delayed fluorescence.

Cytological profiling (CP) assay against a human olfactory neuroshpere-derived (hONS) cell line using a library of traditional Chinese medicinal plant extracts gave indications that the ethanolic extract of Macleaya cordata (Willd) R. Br. elicited strong perturbations to various cellular components. Further chemical investigation of this extract resulted in the isolation of two new benzo[c]phenanthridine alkaloids, (6R)-10-methoxybocconoline (1) and 6-(1-hydroxyethyl)-10-methoxy-5,6-dihydrochelerythrine (2). Their planar structures were elucidated by extensive 1D and 2D NMR studies, together with MS data. The absolute configuration for position C-6 of 1 and relative configurations for position C-6 and C-1' of 2 were assigned by density functional theory (DFT) calculations of ECD and NMR data, respectively. Also isolated were fourteen known metabolites, including ten alkaloids (3-12) and four coumaroyl-containing compounds (13-16). Cytological profiling of the isolates against Parkinson's Disease (PD) patient-derived olfactory cells revealed bocconoline (3) and 6-(1-hydroxyethyl)-5,6-dihydrochelerythrine (4) significantly perturbated the features of cellular organelles including early endosomes, mitochondria and autophagosomes. Given that hONS cells from PD patients model some functional aspects of the disease, the results suggested that these phenotypic profiles may have a role in the mechanisms underlying PD and signified the efficacy of CP in finding potential chemical tools to study the biological pathways in PD.

The transcription factor ΔFosB accumulates in response to chronic insults such as drugs of abuse, L-3,4-dihydroxyphenylalanine (l-DOPA) or stress in specific regions of the brain, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, dyskinesia, and depression. Thus, small molecule chemical probes are urgently needed to investigate biological functions of ΔFosB. Herein we describe the identification of a novel phenanthridine analogue ZL0220 (27) as an active and promising ΔFosB chemical probe with micromolar inhibitory activities against ΔFosB homodimers and ΔFosB/JunD heterodimers.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 μM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents., Graphical abstract Image 1

An efficient and transition-metal-free method for the synthesis of the structurally diversified trifluoroethylthiol phenanthridines and 3,4-dihydroisoquinolines is described. Various 2-isothiocyanobiaryls and aryl alkyl isothiocyanates reacted with phenyl(2,2,2-trifluoroethyl)iodonium triflate in CH2Cl2 in the presence of trifluoromethanesulfonic acid at 40 °C to form the corresponding trifluoroethylation/cyclization products in good to quantitative yields. This work represents the first construction of trifluoroethylthiol phenanthridine and isoquinoline derivatives from isothiocyanates in the absence of transition-metal catalysts by a one-pot procedure.

The main object of this research is chemical modification of the nanofibrillated cellulose (NFC) surface with a phenanthridinium silane salt to develop durable non-leaching antibacterial surface. Initially, (3-trimethoxysilylpropyl) phenanthridinium iodide (TMSPhI) as an antibacterial agent was synthesized using (3-chloropropyl trimethoxysilane) (CPTMS) and phenanthridine in the presence of potassium iodide. Subsequently, NFC was cationized by reaction of its hydroxyl groups with the trimethoxysilane group of TMSPhI to prepare the modified sample (NFC-TMSPhI). The synthesized TMSPhI was characterized by FT-IR, 1H and 13C NMR spectroscopies. The modified NFC samples were also characterized by FE-SEM/EDX, XRD, TGA, elemental analysis, contact angle measurement, FT-IR, UV–Visible and fluorescence spectroscopies. The obtained NFC–TMSPhI samples presented fluorescence property at the maximum emission wavelength in the range of 539-549 nm. Additionally, the antibacterial activity of the modified samples were evaluated quantitatively against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria. All the modified samples displayed promising results with at least bacteriostatic effect or bactericidal properties. Finally, the cytotoxic effect of the modified sample on human dermal fibroblasts (HDFs) and two cancer cell lines (MCF-7 and Hela) was investigated that showed dose- and surface charge-dependent toxicity.

A convenient and straightforward synthesis of 6-sulfonylated phenanthridines via silver-catalyzed sequential radical insertion, cyclization and aromatization of 2-isocyanobiphenyls is reported. The protocol does not require a phenanthridine scaffold as a substrate and presents a highly regioselective synthesis of 6-alkyl/arylsulfonyl phenanthridines. The protocol utilizes readily available and easy to handle sodium sulfinates as sulfonating agents and potassium persulfate as an oxidant to afford good to excellent yields of the desired products in a one-pot operation at room temperature.

A palladium-catalyzed double isocyanide insertion using 2-iodo-2'-isocyano-1,1'-biphenyls followed by copper-catalyzed intramolecular C-N coupling, delivering a unique heterocyclic structure containing both phenanthridine and carbazole scaffolds, has been developed. In this cascade process, four chemical bonds, including two C-C, one C-O, and one C-N bonds are formed consecutively without isolating an intermediate. The strategy of using a functionalized isocyanide in double insertion provides a quick approach for constructing heterocyclic systems with high bond-forming efficiency.

In the presence of Ru(phen)3Cl2 or fac-Ir(ppy)3 under visible-light irradiation, the addition of fluorinated radicals to N-arylacrylamides followed by an intramolecular cyano group insertion cascade cyclization process produced trifluoroalkyl or difluoroalkyl phenanthridine derivatives in moderate to good yields. Three easily available fluoroalkylated reagents CF3SO2Cl, BrCF2CO2Et and BrCF2PO(OEt)2 were used as the sources of fluorinated radicals.

Sanguinarine is a benzo[c]phenanthridine alkaloid with interesting cytotoxic properties, such as induction of oxidative DNA damage and very rapid apoptosis, which is not mediated by p53-dependent signaling. It has been previously documented that sanguinarine is reduced with NADH even in absence of any enzymes while being converted to its dihydro form. We found that the dark blue fluorescent species, observed during sanguinarine reduction with NADH and misinterpreted by Matkar et al. (Arch. Biochem. Biophys. 2008, 477, 43–52) as an anionic form of the alkaloid, is a covalent adduct formed by the interaction of NADH and sanguinarine. The covalent adduct is then converted slowly to the products, dihydrosanguinarine and NAD+, in the second step of reduction. The product of the reduction, dihydrosanguinarine, was continually re-oxidized by the atmospheric oxygen back to sanguinarine, resulting in further reacting with NADH and eventually depleting all NADH molecules. The ability of sanguinarine to diminish the pool of NADH and NADPH is further considered when explaining the sanguinarine-induced apoptosis in living cells.

In the current work, sixteen novel amide derivatives of phenanthridine were designed and synthesized using 9-fluorenone, 4-Methoxy benzyl amine, and alkyl/aryl acids. The characterization of the title compounds was performed using LCMS, elemental analysis, 1HNMR, 13CNMR and single crystal XRD pattern was also developed for compounds A8. All the final analogs were screened in vitro for anti-leishmanial activity against promastigote form of L. infantum strain. Among the tested analogs, four compounds (A-06, A-11, A-12, and A-15) exhibited significant anti-leishmanial activity with EC50 value ranges from 8.9 to 21.96 μM against amastigote forms of tested L. infantum strain with SI ranges of 1.0 to 4.3. From the activity results it was found that A-11 was the most active compound in both promastigote and amastigotes forms with EC50 values 8.53 and 8.90 µM respectively. In-silico ADME prediction studies depicted that the titled compounds obeyed Lipinski's rule of five as that of the approved marketed drugs. The predicted in-silico toxicity profile also confirmed that the tested compounds were non-toxic. Finally, molecular docking and molecular dynamics study was also performed for significantly active compound (A-11) in order to study it’s putative binding pattern at the active site of the selected leishmanial trypanothione reductase target as well as to understand the stability pattern of target-ligand complex for 100 ns. Single crystal XRD of compound A-08 revealed that the compound crystallizes in monoclinic C2/c space group and showed interesting packing arrangements.

Calothrixin A (CLA), as a carbazole-1,4-quinone alkaloid with unique indolo [3,2-j] phenanthridine framework, is a natural metabolite from the Calothrix cyanobacteria. Since the interaction to the functional serum albumins may play an important role in estimating its potential physiological or toxicological effects in vivo, we here explored the binding information of CLA with human serum albumin (HSA) by multi-spectroscopic experiments and computational approaches. The molecular docking results showed that there was one binding site of CLA to the site I (subdomain IIA) of HSA, causing the spontaneous formation of the ground state complex of CLA-HSA through the integration of hydrogen bond, hydrophobic interaction, and electrostatic interaction. Moreover, CLA could effectively trigger the change of HSA's secondary structure because of an obvious decrease of α-helical content in HSA. Taking into consideration of the crucial role of HSA to transport extraneous functional small molecules in vivo, this study may provide a worthy theoretical basis to evaluate the in vivo toxicity of CLA, aiming to reduce/avoid the potential toxic side effects of CLA in the next hit-to-lead campaign.

A palladium-catalyzed C-H bond activation reaction, via a redox-neutral pathway, for the preparation of dihydrophenanthridine, phenanthridine, and carbazole derivatives from biaryl 2-iminoquinones is developed. The preinstalled iminoquinone was designed to act as a directing group for ortho C-H activation and an internal oxidant or a co-oxidant. This catalysis proceeded through the following sequence: C-H bond activation, coordination and insertion of activated olefins, β-hydride elimination, H-shift, insertion, and protonation or β-hydride elimination. In addition, carbazoles can be prepared efficiently by using this method without the addition of external oxidants.

G-quadruplex (G4) DNA structures are involved in many important biological processes and can be linked to several human diseases. Drug-like low molecular weight compounds that target G4 structures are therefore interesting not only for their potential therapeutic properties but also for their potential use as chemical research tools. We report here on the development of methods to synthesize spiropyrans using a condensation-cyclisation reaction of quaternary salts of α-methyl quinoline or phenanthridine with salicylaldehydes. Evaluation of the synthesized phenanthridine spiropyrans' interactions with G4 DNA was performed with a Thioflavin T displacement assay, circular dichroism, Taq DNA polymerase stop assay, and NMR. This revealed that the substitution pattern on the phenanthridine spiropyrans was very important for their ability to bind and stabilize G4 structures. Some of the synthesized low molecular weight spirocyclic compounds efficiently stabilized G4 structures without inducing structural changes by binding the first G-tetrad in the G4 structure.

Introduction: Multidrug resistance remains a major obstacle hindering successful antimalarial chemotherapy. In the current study, 50% methanol in dichloromethane extract and six compounds from the stem bark of Zanthoxylum gilletii were explored for their antiplasmodial potential against three strains of Plasmodium falciparum. Materials and Methods: The extract was obtained by cold percolation using 50 % MeOH in CH2Cl2 and the antiplasmodial activities were assayed using a non–radioactive Malaria SYBR Green I assay to determine a concentration that inhibits growth of 50% of parasites in culture (IC 50 ). Results and Discussion: Chromatographic separation of the crude extract yielded six known compounds including: one lignan, sesamin (1), an alkamide, fagaramide (2), three benzo [c] phenanthridine alkaloids, 8–acetonyldihydrochelerythrine (3), dihydrochelerythine (4), norchelerythrine (5) and one pentacyclic triterpenoid, lupeol (6). The extract and sesamin (1) showed promising antiplasmodial activities against the chloroquine resistant (W2), chloroquine sensitive (D6) and 3D7 strains of P. falciparum, with IC50 values of 2.52, 1.48 and 1.43 µg/mL and 5.4, 9.1 and 8.3 µM, respectively. To the best of our knowledge, this is the first report on antiplasmodial activities of the stem bark extract (50% MeOH in CH2Cl2) and compound 1–3 and 6. Furthermore, three of the isolated compounds; 1, 3, 6 are reported from this species for the first time. Conclusion: The good antiplasmodial activities exhibited by the stem bark of Z. gilletii against three different strains of P. falciparum may be attributed to the presence of 1-3 exhibiting good activities against all strains of P. falciparum.

Novel syntheses of both the benzo[b]phenanthridine and the 6H-dibenzo[c,h]chromen-6-one motif are described. Reaction of (2-(3-bromo-1,4-dimethoxynaphthalen-2-yl)phenyl)methanamine with PIFA afforded benzo[b]phenanthridine-7,12-dione, while the related nonbrominated precursor, (2-(1,4,5-trimethoxynaphthalen-2-yl)phenyl)methanamine on treatment with PIFA, furnished the ortho-quinone 1-methoxybenzo[c]phenanthridine-11,12-dione. Unexpectedly, treatment of related oxygen analogs such as (2-(1,4-dimethoxynaphthalen-2-yl)phenyl)methanol with NBS under an O2 atmosphere, afforded a chromenone, 12-methoxy-6H-dibenzo[c,h]chromen-6-one.

A practical method for the synthesis of 6-aroyl phenanthridine derivatives by Fe-catalyzed oxidative radical cyclization of 2-isocyanobiphenyls with benzylic alcohols is described. In addition, this cyclization could be occurred by using toluene as aroyl source. The procedure tolerates various functional groups under simple conditions. A single-electron-transfer pathway is proposed according to mechanistic studies.

A series of imidazo[1,2-f]phenanthridine derivatives were synthesized from phenanthridin-6-amine and aldehydes through sulfur endorsed oxidative cyclization reaction under a metal- and base-free condition with atom economy strategy and evaluated their anticancer activity. Among all the synthesized derivatives, the compound 3d and 3f exhibited IC50 values of 2.18 ± 0.08 and 2.24 μM ± 0.71 μM, respectively. Compound 3d had the strongest inhibitory activity against HT-29 cells with an IC50 value being 1.25 μM ± 0.22 μM, which was even stronger than that of paclitaxel.

A new method for synthesizing phenanthridines by photocyclization has been established. This method does not require inert gas protection, does not require transition metal catalysts and is environmentally friendly, efficient and convenient. It is proposed to use (E)-N,1-diphenylformimines as substrates to synthesize phenanthridine and its derivatives by ultraviolet light, which provides a new synthesis route for further research on the synthesis of phenanthridines by photocyclization. Eight new phenanthridine compounds were synthesized. The confirmation of their structures provides a material basis for further study of their properties and tapping of their potential for applications. The establishment of this method further broadens the synthetic pathways of phenanthridine compounds.

Two new hexahydrobenzo[c] phenanthridine alkaloids, ambiguanine H (1) and ambiguanine I (2) together with six known hexahydrobenzo[c] phenanthridine alkaloids (3⿿8), were isolated and purified from the Corydais ambigua var. amurensis leaves. Their structures were elucidated by extensive spectroscopic methods and all the compounds except comp. 6 showed the remarkable protective effect on myocardium ischemia-hypoxia cells and comp. 4 was the most active compound with cell viability of 49.4, 53.3, 68.2 and 84.5% in the range of at 0.01⿿10 μmol/L which were stronger than that of salvia acid B.

Strategies for the synthesis of Amaryllidaceae alkaloids, including crinasiadine, trisphaeridine, bicolorine, N-methylcrinasiadine, 5,6-dihydrobicolorine, galanthindole, lycosinine A and lycosinine B were reported. Investigation of optionally synthetic routes to approach bicolorine, 5,6-dihydrobicolorine, trisphaeridine and N-methylcrinasiadine were demonstrated as well. In addition, three structurally related alkaloids galanthindole, lycosinine A and lycosinine B were concisely prepared by using Suzuki coupling reaction as the key step.

An unprecedented C(8)-H bond allylation of quinoline with allyl carbonate and allyl alcohol catalyzed by Cp*Co(III) using a traceless directing group via β-oxygen and β-hydroxy elimination is described. This site-selective allylation reaction proceeds smoothly with various functional group tolerance including quinoxaline and phenanthridine. Under the nonoxidative reaction conditions, the difference in selectivity between Rh(III) and Co(III), which proceeds through β-hydride and β-hydroxy elimination using allyl alcohol, is shown for the first time.

Acetophenone derivatives were reacted with ethyl cyanoacetate, sulfur, and alkynes to yield either benzo[c]chromen-6-ones or phenantheridin-6(5H)-ones. The multicomponent reaction takes place under increased pressure utilizing Q-Tubes™ as a safe reactor to enhance the reaction rate.

Bioactive indolo[3,2- j ]phenanthridine alkaloids, calothrixin A, B, and their analogues have been synthesized via formal cycloaddition of arynes and 2-aminophenanthridinedione as the key step, which proceeds through successive C–C/C–N bond formation and subsequent oxidation under transition-metal-free and mild conditions in the final stage of the synthesis.

We have developed a Cu(II) -, Ag(I) -, and NaOTf-mediated intramolecular quaternization by arylation reactions to synthesize a variety of N-heterocyclic carbene (NHC) precursors with a benzene-fused backbone. The methodology also provides a convenient alternative route for the synthesis of 6-H-phenanthridine derivatives. A novel silver-NHC complex was prepared by treatment of Ag2 O with the free carbene, which was in situ prepared from the deprotonation of a representative quinazolinonium salt.

An expeditious route involving a Pd-catalyzed intramolecular biaryl-coupling for the synthesis of the N -methyl-5,6-dihydrobenzo[ c ]phenanthridine scaffold has been developed. For the first time, we herein report the sp 3 C(6)–H functionalization of this heterocyclic scaffold through DDQ-mediated cross-dehydrogenative coupling reactions with nitroalkanes, dialkyl malonates, alkynes, dialkyl phosphites, carbonyl compounds, pyrrole, and indoles.

We report a Pd-catalyzed arylation of 1,4-naphthoquinones with aryl iodides. This reaction shows excellent functional group tolerance and high regioselectivity when using nonsymmetric 1,4-naphthoquinone. Furthermore, the resulting 2-aryl-1,4-naphthoquinone could be successfully converted into benzo[b]phenanthridine-7,12-dione through treatment with aqueous ammonia, followed by oxidative cyclization using MnO2.

In this report, we present a study on the synthesis, structure, and electronics of a series of (8-amino)quinoline and (4-amino)phenanthridine complexes of Re(CO)3X, where X = Cl and Br. In all cases, the (amino)heterocycles bind as bidentate ligands, with surprisingly symmetric modes of binding based on Re-N bond lengths. Between the complexes of (8-amino)quinolines and (4-amino)phenanthridines studied in this report, we do not observe much structural variation, and remarkably similar UV-visible absorption spectra. Expansion of the π-system in the (4-amino)phenanthridine complexes does result in an increase in the intensity of the lowest energy transitions (λmax), which computational modeling suggests are more purely MLCT in character compared with the mixed π-π*/MLCT character of these transitions in the smaller (8-amino)quinoline-supported complexes. DFT and TDDFT modeling further showed that consideration of spin-orbit coupling (SOC) is essential; omitting SOC misses the π-π* contributions to λmax and is unable to accurately model the observed electronic absorption spectra.

In spite of their various pharmacological properties the anti-inflammatory potential of benzo[c]phenanthridines remained underexplored. Thus, for the first time PDE4 inhibitory potential of 11,12-dihydro benzo[c]phenanthridine/benzo[c]phenanthridine was assessed in vitro. Elegant synthesis of these compounds was performed via a multi-step sequence consisting of a Pd-catalyzed unusual construction of 4-allyl isocoumarin ring and FeCl3-mediated intramolecular regio- as well as site-selective arene-allyl cyclization as key steps. The overall strategy involved Sonogashira coupling followed by isocoumarin and isoquinolone synthesis, then chlorination and subsequent cyclization to afford a range of 11,12-dihydro derivatives. One of these dihydro compounds was converted to the corresponding benzo[c]phenanthridine that showed concentration dependent inhibition of PDE4B affording an initial hit molecule. The SAR study suggested that 11,12-dihydro analogs were less potent than the compound having unsaturation at the same part of the ring.