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A highly efficient and environmentally benign 1,3-dipolar cycloaddition of C, N - cyclic azomethine imines with 5-alkenyl thiazolones and 2-arylidenindane-1,3-diones is developed for the construction of congested quaternary spiro-carbon centers. All these transformations can be smoothly performed in ethanol at room temperature, providing a catalyst-free and atom-economical access to diversely substituted novel isoquinoline-fused spirocycles in almost quantitative yields with high diastereoselectivities. The promising anti-tumor activity of these structurally novel spirocyclic compounds is reported as well.

Piper sarmentosum Roxb. (PS) and Piper cathayanum M. G. Gilbert & N. H. Xia (PC) are both listed as Traditional Chinese Medicine herbs. In this study, ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) was used to analyze secondary metabolites and metabolically profile the leaves, stems and roots in PS and PC. A total of 110 and 92 differential metabolites were shared from various organs of PS and PC, respectively. Compared to the stems and roots of PS or PC, alkaloids and phenols in leaves of PS or PC accounted for 70% and 57% of the total alkaloids and phenols, respectively. An analysis of enriched metabolic pathways demonstrated that L-tyrosine and 4-hydroxycinnamic acid in PS were directly involved in five and three metabolic pathways, which are related to the biosynthesis of isoquinoline alkaloids and phenol backbones, respectively. The L-glutamic acid and oxoglutaric acid in PC were involved in seven and two metabolic pathways, respectively. L-glutamic acid synthesizes heme, tropane, piperidine and pyridine alkaloids, and the type Ⅱ polyketide backbone. Moreover, oxoglutaric acid generated via L-glutamic acid was mainly involved in the citrate cycle and played a fundamental role in determining these important metabolic processes.

Three new isoquinoline alkaloids, northalifoline 7-O-β-glucopyranoside (1), (R)-isococlaurine 4'-O-β-glucopyranoside (3) and (1R,3S)-1-(4-hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (4) were isolated from the tubers of Stephania perriei in addition to 12 known compounds. The structure determinations were considered based on the spectroscopic evidence including 1D and 2D NMR and HR-ESI-MS experiments.

Isoquinoline alkaloids of the Amaryllidaceae have proven to be of significant value in drug discovery and development. Crossyne guttata is frequently used in traditional medicine as an antiseptic and wound cleaner as well as to treat alcoholism. The aim of the study was to identify the variation in alkaloid content of the species in relation to published works on the genus Boophone. We isolated Distichamine 1 from an ethanolic fraction of Crossyne guttata using column chromatography. Spectroscopic analysis yielded three alkaloids, distichamine 1, crinamine 2 and epibuphanisine 3. Distichamine 1 is a rare β-crinane alkaloid previously isolated only from the genus Boophone. The presence of distichamine 1 in the genus Crossyne suggests that it may be more widespread in tribe Amaryllideae than originally thought.

Stimulated by the promising results seen for its phenanthridones in clinical trials, interest in the Amaryllidaceae as a potential source of anticancer drugs has intensified in recent years. As such, over three hundred isoquinoline principles from its various alkaloid groups have to date been screened against a large number of cancer cell lines. Whilst significant effort has been diverted towards studies of lycorine and its congeners, the closely-allied homolycorine alkaloids of this plant family have largely been overlooked. These compounds have often been used as supporting acts to bolster the diversity of structures in cytotoxicity studies of the more recognized phenanthridone, lycorane and crinane alkaloids of the Amaryllidaceae. This notwithstanding, a substantial amount of information has surfaced over the past several years on such effects for the homolycorine alkaloids. This review takes a detailed look at the cytotoxic effects manifested by over forty of these alkaloids against around sixty cell lines, which may be classified into eighteen different types of cancers. In this regard, good activities were detected for some constituents (such as lycorenine and hippeastrine) against various hepatic and prostate cancers. The structural features which support and fortify the efficacy of the homolycorine alkaloid cytotoxic pharmacophore are also considered. These include the ways in which the innate ring systems are appended as well as the size, geometry and electronics of the attendant substituents. In addition, the various mechanisms used to rationalize the cytotoxic responses are described notably, interaction with DNA, apoptosis induction, protection from tumor invasion, efflux pump perturbation and topoisomerase inhibition.

From camptothecin to vinblastine, plant alkaloids continue to capture the imagination of scientists as a valuable source of anticancer drugs. Given that they are also amongst the most common secondary metabolites encountered in plants, the number of alkaloid entities subjected to cytotoxicity evaluations now runs into several thousands. Interest in the plant family Amaryllidaceae has been persistent owing to the potent cytotoxic activities of several of its isoquinoline alkaloid principles. This survey is an indepth account of such properties discernible for tazettine alkaloids belonging to the minor alkaloid groups of the Amaryllidaceae. Eleven of such compounds have up to now been screened against around 50 cancer cell lines which may be classified into nearly 20 different types of cancers. Although the activities in most instances were moderate to mild, notable responses were observed against some leukemia, adenocarcinoma, lymphoma and glioblastoma cell lines. In fact, pretazettine (ED50 0.3 μg/mL) was amongst the most potent of all Amaryllidaceae alkaloids screened against the human Molt4 T-lymphoma cell line. To most accounts, the parent compounds (such as tazettine and pretazettine) with their distinct ring systems and substitution patterns exhibit the best activities, offering little space for structural adjustments via semi-synthetic operations. Several avenues have been probed in attempts to elucidate the mechanisms by which tazettine alkaloids manifest their cytotoxic effects including, inhibition of protein synthesis, apoptosis and efflux pump interactions, the first of which to date offers the most profound insights.

All cholinesterase (ChE) inhibitory drugs in clinical use are nitrogenous compounds and among them, galanthamine as the latest anticholinesterase drug, contains a tetrahydroisoquinoline structure. For this reason, isoquinoline alkaloids seem to be attractive in search for novel drug candidates towards Alzheimer's disease (AD). Therefore, in the current work, we investigated inhibitory capacity of several alkaloids representing expanding group of biogenetically-related isoquinoline alkaloids from the Amaryllidaceae including lycorine, (+)-9-O-demethylhomolycorine, 6-hydroxybuphanisine, 9-O-demethoxymontanine, 3-epi-hydroxy-bulbispermine, tazettine, haemanthamine, (+)-haemanthidine, (-)-crinine, 8-hydroxy-9-methoxycrinine, and N-norgalanthamine against ChEs by microtiter enzyme inhibition assays. Our findings indicated that N-norgalanthamine is the most active one inhibiting both acetylcholinesterase (AChE, IC50 = 2.42 ± 0.16 µg/mL) and butyrylcholinesterase (BChE, IC50 = 20.87 ± 1.01 µg/mL) at 100 μg/mL, whereas IC50 values of galanthamine used as the reference were 1.33 ± 0.11 µg/mL and 37.69 ± 2.93 µg/mL for AChE and BChE, respectively. Beside this, 8-hydroxy-9-methoxycrinine was a strong inhibitor of AChE (IC50 = 6.92 ± 0.51 µg/mL), while (+)-9-O-demethylhomolycorine displayed a moderate BChE inhibition (IC50 = 83.57 ± 1.36 µg/mL). Relevantly, 8-hydroxy-9-methoxycrinine and N-norgalanthamine were docked into active gorges of hAChE (PDB: 4EY6 ) and hBChE (PDB: 4TPK ), which pointed out the detail that N-norgalanthamine displayed a very similar binding mode of to that of galanthamine. Moreover, both AChE-inhibiting alkaloids were found to stably bind to hAChE active site occupying the middle of the gorge between the catalytic site and the peripheral anionic site. 8-Hydroxy-9-methoxycrinine was also docked into the active site of BChE. We can conclude that among the tested alkaloids, N-norgalanthamine with dual ChE inhibitory effect seems to be the most promising anti-Alzheimer candidate molecule for future experiments.

The compound 1-Isoquinolinyl phenyl ketone (1IPK) was studied theoretically as a corrosion inhibitor by quantum mechanics calculations and docking models. Density functional theory (DFT) of B3LYP/6-311G (d,p) and parameterization model 3 (PM3) using the Gaussian-09 and CASTEP programs was also employed to discuss the inhibition ability. Molecular graphic laboratory (MGL) tools program and discovery studio visualizer (DSV) used to estimate the ability for inhibition Acidithiobacillus Ferrooxidans (AF) bacteria, which is responsible for the corrosion. The calculations of physical properties and quantum chemical parameters correlated to the inhibition efficiency and discussed at the equilibrium geometry. The results indicated that the 1-Isoquinolinyl Phenyl Ketone could be adsorbed on the mild steel surface firmly through the nitrogen atom on the isoquinoline rings and the carbonyl group. Besides, the moderate values of parameters describe the low-efficiency of inhibition in acidic and saline medium. Total electron density (TED) and electrostatic surface potential (ESP) Figures showed the active site that is involved in the inhibition processes. In addition, the adsorption types were studied by different parameters.

Reactions between 3-phenyl-2-propynenitrile, secondary phosphine oxides and pyridinoids have been implemented and studied. Pyridine and isoquinoline react with propynenitrile and phosphine oxides at room temperature according to the N-vinylation/C-phosphorylation scheme to afford (Z)-N-(2-cyano-1-phenyl)ethenyl phosphoryl-1,4-dihydropyridines or -1,2-dihydroiso quinolines. In the case of pyridine on heating (80–85 °°°C), the reaction gives 4-phosphorylpyridines ( S N H Ar reaction) and 3-phenyl-acrylonitrile oligomers.

Quantitative structure activity relationship (QSAR) studies were performed to explore the biological efficacy of few tetrahydroisoquinoline derivatives. Using eight descriptors, training set was developed through QSAR modeling and activities were predicted through the developed QSAR model. To validate the model, the predicted activities were compared with experimental activities. Significant correlation was observed between the hydrophobicity (cLogP), Rotatable bond count (RBC), Molecular shape index and activity. The models developed can be used for drug designing of isoquinoline based scaffold molecules as antibacterial and antifungal agents.

The spirocyclic oxindoles have shown their potential in designing new drugs, given their richness in sp3 centers and distinct three‐dimensionality. The biological relevance of nitrogen containing spiro cyclic natural product scaffolds is the key highlight to select and design these systems. But the Spirocycles contained only limited numbers of combinations of differently sized rings. These observations indicate that there should be significant potential to further expand spirocyclic chemical space for drug discovery. In conclusion, we have devised a simple and efficient method for a one-pot three component reaction involving nitrogen nucleophile towards activated isatilidenes leading to the synthesis of various spirocyclic compounds, via 1,4-dipolar cycloaddition reaction under mild conditions.

Indole and isoquinoline nuclei bearing homoallylic amine cores are abundant in several prominent alkaloids, including strychnine. A recent study by Snaddon et al. reports a modular, cooperative catalysis platform to access linear and branched homoallylic amines, thereby streamlining enantioselective access to stereochemically complex Strychnos and Chelidonium alkaloids.

Benzylisoquinoline alkaloids (BIAs) are a structurally diverse class of plant-specialized metabolites that have been particularly well-studied in the order Ranunculales. The N-methyltransferases (NMTs) in BIA biosynthesis can be divided into three groups according to substrate specificity and amino acid sequence. Here, we report the first crystal structures of enzyme complexes from the tetrahydroprotoberberine NMT (TNMT) subclass, specifically for GfTNMT from the yellow horned poppy (Glaucium flavum). GfTNMT was co-crystallized with the cofactor S-adenosyl-l-methionine (dmin = 1.6 A), the product S-adenosyl-l-homocysteine (dmin = 1.8 A), or in complex with S-adenosyl-l-homocysteine and (S)-cis-N-methylstylopine (dmin = 1.8 A). These structures reveal for the first time how a mostly hydrophobic L-shaped substrate recognition pocket selects for the (S)-cis configuration of the two central six-membered rings in protoberberine BIA compounds. Mutagenesis studies confirm and functionally define the roles of several highly-conserved residues within and near the GfTNMT-active site. The substrate specificity of TNMT enzymes appears to arise from the arrangement of subgroup-specific stereospecific recognition elements relative to catalytic elements that are more widely-conserved among all BIA NMTs. The binding mode of protoberberine compounds to GfTNMT appears to be similar to coclaurine NMT, with the isoquinoline rings buried deepest in the binding pocket. This binding mode differs from that of pavine NMT, in which the benzyl ring is bound more deeply than the isoquinoline rings. The insights into substrate recognition and catalysis provided here form a sound basis for the rational engineering of NMT enzymes for chemoenzymatic synthesis and metabolic engineering.

One S atom contained ligand triethylamine salt of diphenylphosphinodithioic acid (dpss) was firstly developed for two four-membered red-emitting iridium(III) complexes with Ir–S–P–S structures, (tfmpiq) 2 Ir(dpss) and (tfmpqz) 2 Ir(dpss), in which 1-(4-(trifluoromethyl)phenyl)isoquinoline (tfmpiq) and 4-(4-(trifluoromethyl)phenyl)quinazoline (tfmpqz) were employed as the cyclometalated ligands, respectively. Owing to strong bonding ability of sulfur and iridium atom, two Ir(III) complexes were obtained rapidly and efficiently at room temperature in 5 min. The computational Gibbs free energy changes of the complexes formation reactions further indicate that they are exothermic and thermodynamically beneficial processes. They show similar PL emissions at 620 and 621 nm, respectively. Using the two complexes as dopants, both organic light-emitting devices (OLEDs) exhibit good properties with the maximum luminance of 16 400 cd/m 2 and the maximum external quantum efficiency of 19.38%.

An experimentally simple, efficient, and inexpensive catalyst system was developed for the N-arylation of imidazole, indole, pyrrole, alkyl alcohol amines, and alkyl amines with aryl iodides and bromides. The reaction proceeds in water-ethanol media at 120 °C for 12 h with Cu2O as the catalyst, 1-(2-methylhydrazine-1-carbonyl)-isoquinoline 2-oxide (L2) as the ligand, NaOH as the base to generate a wide range of N-arylated products in moderate to excellent yields. Aqueous medium, ease of operation, and broad substrate scope give the process a benign environmental profile.

A highly efficient approach to synthesize isoquinoline derivatives through Iridium(III)-catalyzed cyclization of aryl ketoximes and internal alkynes without oxidant is reported. A broad range isoquinolines are obtained in good to excellent yields and various functional groups are well tolerated.

Several mononuclear complexes with structure of [TpyRu2+(Py)2Cl]+ and [TpyRu2+(Isoq)2Cl]+ have been designed and synthesized. The structures of these complexes were confirmed by NMR and ESI-MS, the properties of all catalysts were also characterized optically and electrochemically. Water oxidation experiments were examined by turnover numbers (TONs), which showed the catalytic properties of all catalysts. In comparison, pyridine functionalized 1a-1d have more catalytic activities than isoquinoline coordinated complexes 2a-2d. It was also observed that attached polycyclic aromatic groups on the terpyridines had limited impact on catalytic activities. Among these ruthenium complexes, Ph-TpyRu2+(Py)2Cl exhibited the highest TON of 897.

A series of novel 1, 2, 4-triazolo isoquinoline derivatives (8a-8p) were synthesized starting from 2-phenylethan-1-ol derivative (1) in a 7 step synthetic sequence. The key step in the scheme involves 1, 3-dipolar [3 + 2] cycloaddition of azomethine imine and ethyl cyanoformate as unknown reaction protocol. We have demonstrated the hydrolysis of both ester and benzoyl group in a single step and the corresponding carboxylic acid derivatives were coupled with various amines to generate unknown 1, 2, 4-triazolo isoquinoline derivatives The structures of the compounds (8a-8p) were characterized by 1H NMR, 13C NMR and HRMS analysis.

Noscapine is an alkaloid based on the isoquinoline ring with many promising biological potential. Noscapine and its derivatives have shown potential as cough suppressant, anti-cancerous activity, ability to inhibit the main protease of SARS-CoV-2 and non-structural protease of chikungunya etc. Literature has reported the problem of solubility of noscapine due to high hydrophobic character, therefore, poorly soluble in water. In view of this, there is a need to find way to increase the solubility of noscapines. Ionic liquids (ILs) are organic salts and considered to have no or permissible toxicity. In the present work, authors report the designing of the ionic liquids (ILs) composed of noscapinium as cation with the different anions. Further, the designed noscapine based ionic liquids were studied using density functional theory (DFT) approach and time dependant density functional theory (TD-DFT). The thermo-chemical data of the designed ionic liquids revealed the stability and reactivity of ILs. Further, the IR and UV–visible spectra of the designed ILs were determined and analyzed. Then, the ADME behavior of designed ILs was calculated and studied using online servers. Based on the DFT calculations performed, (R)-5-((S)-4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6,6-dimethyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium trifluoromethanesulfonate (IL4) is found to be most soluble in the water and most stable amongst the designed ILs.

In the present study, we applied the molecular hybridization approach to combine isoquinolinedione and urea pharmacophores in the same molecules. The hybrid compounds (IU1-IU14) were obtained by the reaction of 2-aminohomophthalimide and an equivalent amount of various isocyanate derivatives. After confirming the chemical structures and evaluating drug-likeness properties, the synthesized compounds were examined for their antibacterial activities against a wide range of bacteria. The compounds possessing lipophilic halogen substituents showed better activities against Gram-positive bacteria, particularly on Staphylococcus aureus strains. This activity trend was further supported by molecular docking studies in the ATP pocket of S. aureus DNA gyrase. Several important parameters such as, ionization potential (IP), electron affinity (EA), global chemical hardness (eta), global softness (sigma), and electronegativity (chi) were carried out to gain insights into the structural properties and stabilities of selected active compounds by means of density functional theory (DFT) at the B3LYP functional using basis set B3LYP/6-311G(d,p). Electrostatic potential maps (ESPs) and frontier orbital visualizations were further used to comment on molecular polarity and stability. (C) 2021 Elsevier B.V. All rights reserved.

It is challenging for the recovery of methane from coal mine methane due to the involvement of air. Also, similar physical properties between methane and nitrogen increase the difficulty of methane separation. In this regard, a thermally stable microporous metal-organic framework was synthesized based on quinoline-5-carboxylic acid to enhance the separation of CH4 against N2. Its adsorption isotherms for CH4 and N2 were collected at 1 bar and 298 K. The highest adsorption CH4 uptake (1.3 mmol/g) was achieved as compared to N2 (0.28 mmol/g). Compared with other MOFs materials, Ni-Qc-5 possessed very low adsorption energy and high selectivity at low pressure 0.1 bar. Additionally, a density functional (DFT) simulation has been used to achieve a deep understanding of the adsorption binding sites. DFT results showed that CH4 have superior adsorption energy compared to N2. Moreover, dynamic breakthrough experiments were performed at different pressure over synthesized sample. The results showed that Ni-Qc-5 is the promising candidate for trapping of coal mine methane due to its outstanding regeneration and separation performance.

A convenient and one-pot synthetic method for the construction of indolo[2,1-a]isoquinolines is developed by the dehydrative cyclocondensation reactions of the easily available 2-hydroxymethyl anilines with 2-ethynylbenzaldehydes in DMSO in the presence of KOH and TBAI under air.

An efficient and simple protocol for the Heck reaction of accessible natural eudesmane-type methylene lactone isoalantolactone or its derivatives - 4,15-epoxyisoalantolactone, and 3-hydroxyisoalantolactone, with halosubstituted quinolines and isoquinolines using Pd(OAc)2 as the catalyst is presented. The reactions proceed well in dimethylformamide and TBAB in the absence of phosphine ligands. The structures of isoalantolactone-quinoline and isoalantolactone-isoquinoline hybrids were analyzed by mass spectrum, elemental analysis and NMR spectral studies. The crystal structure of new compounds was determined from single crystal X-ray diffraction data.

The synthesis of 1,2-dihydroisoquinoline, [2,1-a] isoquinoline and [5,1-a] isoquinoline is very important because of their biological and medicinal activities as well as their conversion to corresponding isoquinoline. Various nucleophiles and pronucleophiles could be added to Ortho-alkynylbenzaldehydes, ortho-alkynylaryl aldimines and ortho-alkynylbenzaldoximes in the presence of different Lewis acids and generate derivatives of 1,2-dihydroisoquinoline in tandem route. Also, 1,4-dipolar intermediate which synthesized from the reaction of isoquinoline and electron-deficient compounds reacted with various dipolarophiles for the formation of five- and six-membered heterocycles including [2,1-a] isoquinoline and [5,1-a] isoquinoline. In recent years, these interesting zwitterions have been used in multicomponent reactions to produce a considerable number of heterocyclic compounds. In this review, we have classified a variety of methods since 2006 until now, for the generation of 1,2-dihydroisoquinoline, [2,1-a] isoquinoline and [5,1-a] isoquinoline via the above routes.

In this study, we synthesised and characterised two benzimidazole-quinoline-based copper complexes, namely, [Cu(btmbq)Br]2 (1) and [Cu(btmbq)Cl]2 (2), (btmbq = 3-(1-(1H-benzotriazol-1-y-l)methyl)-6-bromo-1H-benzoimidazol-2-yl)isoquinoline). Both complexes showed strong antitumor abilities against the colon cancer cell line (HCT116) and low cytotoxicity against the normal liver cell line (L-02). The DNA binding affinity was evaluated using CD and fluorescence spectroscopy, and the Ksv and Kapp values were further quantified, revealing that the complexes bound to DNA in the intercalation mode, and caused oxidative damage to pBR322 DNA. Furthermore, complex 1 interfered with the steady-state balance of redox and Ca2+ in HCT116 cells, as well as induced cell mitochondrial membrane potential (Δψm) collapse, ATP dissipation, ultimately arrested the cell cycle in G2 phase and induced cell apoptosis. Further exploration demonstrated that the production of reactive oxygen species (ROS) might be the major contributors to the apoptotic death of HCT116 cells.

Phytochemical investigation of the aerial parts of Glaucium arabicum Fresen. (Papaveraceae) led to the isolation of two previously undescribed isoquinoline alkaloids araglaucine A, and araglaucine B, together with seven known ones 1-[(3`,4`-dimethoxy-2`-methylcarboxy)benzoyl]-6,7-methylenedioxy isoquinoline (araglaucine C), (7R,14S)-trans-N-methylcanadinium nitrate, (R,S)-trans-N-methylstylopine, 14-hydroxy-N-methyl canadine, 14-hydroxy-N-methyl stylopine, protopine, norsanguinarine, as well as β-sitosterol, and β-sitosterol 3-O-β– d -glucoside. Their structural elucidation was based on the measurements of 1D, 2D NMR, HRESIMS, UV, IR and X-ray crystallography. The compounds were evaluated for their anti-melanogenesis activity using B16 melanoma cell lines. Compound (7R,14S)-trans-N-methylcanadinium nitrate exhibited a promising melanin synthesis inhibitory activity (∼35%) at concentration 5 μg/ml (12.01 μM) with low cytotoxicity (∼12%).

Using 1-(4-(trifluoromethyl)phenyl)isoquinoline (tfmpiq) and 4-(4-(trifluoromethyl)phenyl) quinazoline (tfmpqz) as the main ligands and pyrazole pyridine derivatives (mepzpy: 2-(3-methyl-1H-pyrazol-5-yl)pyridine, cf3pzpy: 2-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridine) as the ancillary ligands, four iridium(III) complexes (PIQ-Ir1-me, PIQ-Ir2-cf3, PQZ-Ir3-me and PQZ-Ir4-cf3) were synthesized and investigated. Due to the variation of the ligands, these Ir(III) complexes showed different emissions peaking from 602 to 628 nm with the phosphorescence quantum yields of 0.40–0.67. Moreover, applying these Ir(III) complexes as emitters, the organic light-emitting diodes (OLEDs) with the configuration of ITO/HATCN (hexaazatriphenylenehexacabonitrile, 5 nm)/TAPC (bis[4-(N,N-ditolylamino)-phenyl] cyclohexane, 50 nm)/Ir(III) complexes (8 wt%): TCTA (4,4′,4″-tri(9-carbazoyl)triphenylamine, 20 nm)/TmPyPB (1,3,5-tri[(3-pyridyl)-phen-3-yl]benzene, 40 nm)/LiF (1 nm)/Al (100 nm) exhibited good performances. Especially, the device with orange-red PQZ-Ir4-cf3 emitter obtained the best device performances with the maximum current efficiency of 40.04 cd A−1 and the maximum power efficiency of 33.98 lm W−1. For the pure red complex PQZ-Ir4-me with CIE coordinates at (0.64, 0.34) showed the maximum external quantum efficiency of 22.3%.

Two iridium(III) complexes with 1-(3,5-bis(trifluoromethyl)-pyridin-4-yl)isoquinoline (tntpiq) as main ligand, 2-(5-pyridin-4-yl)-1,3,4-oxadiazol-2-yl)phenol (pop) and 2-(5-pyridin-4-yl)-1,3,4-thiadiazol-2-yl)phenol (psp) as ancillary ligands were investigated. Both complexes emit orange red lights with different photoluminescence efficiencies (Ir(tntpiq)2(pop): λem = 585 nm, Φ = 0.41 and Ir(tntpiq)2(psp): λem = 590 nm, Φ = 0.59). Moreover, the electron mobility values of the two complexes are higher than that of the electron transport material Alq3 (tris(8-hydroxyquinoline)aluminium), which are beneficial for their performances in organic light-emitting diodes (OLEDs). The devices with a structure of ITO/MoO3 (3 nm)/TAPC (1,1-bis[4-[N,N-di(p-tolyl)amino]pyridin-4-yl]cyclohexane, 30 nm)/Ir(III) complexes (2 wt%): 26DCzPPy (2,6-bis(3-(carbazol-9-yl)pyridin-4-yl)pyridine, 10 nm)/TmPyPB (1,3,5-tri(m-pyrid-3-yl-pyridin-4-yl)benzene, 40 nm)/LiF (1 nm)/Al (100 nm) displayed similar performances with a maximum current efficiency of 24.3 cd A−1 and a maximum external quantum efficiency of 11.6%, respectively, and the efficiency roll-off is very mild.

The 1,4-dipoles derived from isoquinolines and methyl perfluoroalk-2-ynoates reacted readily with arylidene-substituted N,N-dimethylbarbituric acids resulting in the first diastereoselective synthesis of perfluoroalkylated cis-spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidine derivatives in good to excellent yields under mild conditions. The reaction mechanism was proposed to illustrate the formation of the diastereoisomers and proton-promoted transformation of trans-spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidines to the more thermodynamically stable cis-isomers. The DFT calculation demonstrated the diastereoselectivity of the reaction.

From the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae), ten new naphthylisoquinoline alkaloids (7a, 7b, 8a, 8b, and 9-14), displaying three different coupling types (5,1', 5,8', and 7,8'), were isolated, among them a series of five 5,1'-linked representatives and four metabolites belonging to the rare group of 7,8'-coupled alkaloids. Two of the alkaloids, the ancistrobrevines I (13) and J (14), are only the fourth and fifth examples of 7,8'-linked naphthyldihydroisoquinolines ever found in nature. The stereostructures of the new plant metabolites were determined by spectroscopic, chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods. For the assignment of the axial configuration of 13 and 14 relative to the stereocenter at C-3, which is too far away for significant NOE long-range interactions, these 7,8'-coupled naphthyldihydroisoquinolines were stereoselectively converted into the respective cis-configured tetrahydroisoquinoline analogs. The newly generated 'auxiliary' stereocenter at C-1 permitted decisive NOE interactions between the isoquinoline and the naphthalene parts, and thus a reliable attribution of the axial configuration of 13 and 14. In addition, five known compounds (3, 5, 16, 17, and 20), previously discovered in related African and Asian Ancistrocladus species, have now for the first time been identified in A. abbreviatus. All of these alkaloids are S-configured at C-3 and bear an oxygen function at C-6, and are, thus, typical Ancistrocladaceae-type compounds. Some of the alkaloids of A. abbreviatus exhibited promising activities against the malaria parasite Plasmodium falciparum and PANC-1 human pancreatic cancer cells.

Flavin-dependent enzymes catalyze many oxidations, including formation of ring structures in natural products. The gene cluster for biosynthesis of fumisoquins, secondary metabolites structurally related to isoquinolines, in the filamentous fungus Aspergillus fumigatus harbors a gene that encodes a flavoprotein of the amine oxidase family, termed fsqB (fumisoquin biosynthesis gene B). This enzyme catalyzes an oxidative ring closure reaction that leads to the formation of isoquinoline products. This reaction is reminiscent of the oxidative cyclization reported for berberine bridge enzyme and tetrahydrocannabinol synthase. Despite these similarities, amine oxidases and berberine bridge enzyme–like enzymes possess distinct structural properties, prompting us to investigate the structure–function relationships of FsqB. Here, we report the recombinant production and purification of FsqB, elucidation of its crystal structure, and kinetic analysis employing five putative substrates. The crystal structure at 2.6 Å resolution revealed that FsqB is a member of the amine oxidase family with a covalently bound FAD cofactor. N-methyl-dopa was the best substrate for FsqB and was completely converted to the cyclic isoquinoline product. The absence of the meta-hydroxyl group, as e.g. in l-N-methyl-tyrosine, resulted in a 25-fold lower rate of reduction and the formation of the demethylated product l-tyrosine, instead of a cyclic product. Surprisingly, FsqB did not accept the d-stereoisomer of N-methyltyrosine, in contrast to N-methyl-dopa, for which both stereoisomers were oxidized with similar rates. On the basis of the crystal structure and docking calculations, we postulate a substrate-dependent population of distinct binding modes that rationalizes stereospecific oxidation in the FsqB active site.

A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-tetrahydrobenzazepines derivatives with electron-withdrawing substituents at C-2 position by the diastereoselective Stevens rearrangement. The structure-activity relationship of these compounds was explored to evaluate the effect of the functional group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-6,7-dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor, with Ki value of 31 nM. This significant affinity can be attributed to the presence of a thiomethyl group, and it is the most active 1-aryl-6,7-dihydroxy tetrahydroisoquinoline derivative reported to date.

Propylphosphonic anhydride (T3P®) was successfully applied to the synthesis of an isoindolinone library by the utilization of an Ugi four-center, three-component reaction (Ugi-4C-3CR). The use of T3P® significantly shortened the required reaction time and the corresponding products were obtained in good to high yields. Moreover, a side-reaction was observed when phenylethylamine derivatives and tryptamine were used as the amine component. The latter reaction was applied to the microwave-assisted, one-pot synthesis of the isoquinoline alkaloid (±)-nuevamine. Surprisingly, the traditional Ugi four-component reaction (Ugi-4CR) was unsuccessful in the presence of T3P®. In this case an α-amino amide was produced excluding the carboxylic acid from the multicomponent reaction.

Vinyl acetate is used as an acetylene equivalent in rhodium(III)-catalysed C-H activation/annulation with aryl ketoxime esters. Extension to an aldoxime ester allows for a concise formal synthesis of decumbenine B.

Aminolithiation–arylation tandem cyclization of N-(2-fluorophenyl)methylaminoalkylstyryls proceeded smoothly to give hexahydro-2H-pyrido[1,2-b]isoquinoline using a stoichiometric amount of n-BuLi with high trans selectivity. The arylation reaction was highly accelerated by the addition of HMPA. Both pyrido- and pyrrolo-[1,2-b]isoquinoline were successfully constructed by this tandem reaction.

The synthesis and resolution of new tridentate isoquinoline-derived ligands has been developed. The key steps in the synthetic sequence include successive, chemo-selective Suzuki-Miyaura cross-couplings of 1,3-dichloroisoquinoline with suitable arylboronic acids. The new ligands prepared in this manner were resolved either via molecular complexation with N-benzylcinchonidinium chloride as with 1-[3-(2-hydroxyphenyl)isoquinolin-1-yl]naphthalen-2-ol or via chromatographic separation of its epimeric camphorsulfonates as for 1,3-bis-(2-hydroxynaphthalen-1-yl)isoquinoline. 4-tert-Butyl-2-chloro-6-[1-(2-hydroxymethylnaphthalen-1-yl)isoquinolin-3-yl]phenol was resolved by chiral semi-preparative HPLC. The application of these ligands in the diethylzinc addition to aldehydes was investigated. In certain cases, the desired secondary alcohols were obtained in high yield with excellent enantiomeric excess (ee > 99%) at low catalyst loading (1 mol%).

Background Nucleic acids are now important targets for therapeutic intervention. Alkaloids are an important class of molecules that have myriad therapeutic utility. Isoquinoline and benzophenanthridine alkaloids exhibit multiple pharmacological activities which are often related to their strong nucleic acid binding abilities. Therefore, a review of their interaction aspects with varying nucleic acid structures is essential for rational design and development as therapeutic agents. Scope of the review This work reviews the interaction of various therapeutically important isoquinoline and benzophenanthridine alkaloids with nucleic acids. The review lends insights into the molecular aspects of the interaction that is critical from the perspective of designing better therapeutics. Major conclusions This review provides a concise report on the recent developments and advancements on the interaction of various alkaloids with natural and synthetic nucleic acids. The review focuses on the mode, mechanism, specificity, conformational aspects and energetics of the interaction that will be helpful in the design and synthesis nucleic acid targeted alkaloid analogs. General significance The molecular aspects of the interaction presented here will benefit the development of effective drugs for many diseases. The fundamental results discussed in this review can serve as a database for the design and development of futuristic nucleic acid based small molecule therapeutics.

The reaction of the complexes trans-[RuCl2(η2-C2H4){(S,S)-iPr-pybox}] (1a) and trans-[RuCl2(η2-C2H4){(R,R)-Ph-pybox}] (1b) with nitrogen heterocyclic ligands, provide the complexes trans-[RuCl2(L)(R-pybox)] (L = py (3a,b), 3-Br-py (4a,b), isoquinoline (5a,b), pyrazine (6a,b), 1-methylimidazole (7a,b), 1-benzylimidazole (8a,b), pyrazole (9a,b), 3-methylpyrazole (10a,b), and 1H-1,2,4-triazole (11a,b)). The complexes trans-[OsCl2(L){(S,S)-iPr-pybox}] (L = py (12), 3-Br-py (13), 3-CN-py (14), 3-MeO-py (15), 3-NO2-py (16), 4-CN-py (17), 4-MeO-py (18), isoquinoline (19), 1-methylimidazole (20), 1-benzylimidazole (21), pyrazole (22)) have been similarly synthesized by the substitution of ethylene from the precursor complex trans-[OsCl2(η2-C2H4){(S,S)-iPr-pybox}] (2) by the corresponding N-donor ligand in refluxing toluene. Moreover, the dinuclear complexes [(RuCl2{(S,S)-iPr-pybox})2(μ-N,N-C4H4N2)] (23a), [(RuCl2{(R,R)-Ph-pybox})2(μ-N,N-C4H4N2)] (23b) and [(OsCl2{(S,S)-iPr-pybox})2(μ-N,N-C4H4N2)] (24) have been prepared by the reaction of the complexes 1 and 2 with pyrazine (1:0.5 M ratio for 23 and 1:1.5 for 24). The structure of the complexes 9a, 12, 23a and 24 has been determined by single-crystal X-ray diffraction analysis. The ruthenium 3a,b, 6a and 10a,b and osmium complexes 12–22 and 24 have been assayed as catalysts for the asymmetric transfer hydrogenation reaction. Among them, the osmium complexes 12, 15, 16, 18 and 24 have proven more efficient in the reduction of a variety of aromatic ketones affording the (R)-benzylalcohols with very high conversion and moderate enantioselectivity up to 73% e.e.

Chelerythrine, an isoquinoline alkaloid isolated from the herbaceous perennial Chelidonium majus, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A) with an IC50 value of 0.55 µM. Chelerythrine was a reversible competitive MAO-A inhibitor (Ki = 0.22 µM) with a potency much greater than toloxatone (IC50 = 1.10 µM), a marketed drug. Other isoquinoline alkaloids tested did not effectively inhibit MAO-A or MAO-B. A structural comparison with corynoline suggested the 1- and/or 2-methoxy groups of chelerythrine increase its inhibitory activity against MAO-A. Molecular docking simulations revealed that the binding affinity of chelerythrine for MAO-A (−9.7 kcal/mol) was greater than that for MAO-B (−4.6 kcal/mol). Docking simulation implied that Cys323 and Tyr444 of MAO-A are key residues for hydrogen-bond interaction with chelerythrine. Our findings suggest chelerythrine is one of the most reversible selective and potent natural inhibitor of MAO-A, and that it be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors.

Five new phenyl-C1 substituent aporphine alkaloids, 6aR-2′-methoxycarbonyl-thaliadin (1), 6aR-2′-carboxyl-thaliadin (2), 6aR-3-methoxy-hernandalinol (3), 6aS-1,3,10-trimethoxy-natalamine (4), and 3-methoxy-2′-methoxycarbonyl-oxohernandalincin (5), together with sixteen known isoquinoline alkaloids (6–21) were isolated from the whole herb of Thalictrum cirrhosum (Levl.). Their structures were elucidated by extensive spectroscopic measurements, and six isoquinoline alkaloids showed significant inhibitory activity on concanavalin A-stimulated splenocytes proliferation with IC50 values 36–44 μM by the immunosuppressive bioassay.

Nine new isoquinoline alkaloids, including two proaporphine (1–2), three aporphine (3–5), two oxoaporphine (6–7), and two seco-bisbenzylisoquinoline (8–9), together with three known alkaloids (10−12) were isolated from the whole plant of Thalictrum wangii. Their structures were established on the basis of spectroscopic data. The antitumor activities of the isolated compounds were evaluated in vitro against glioma stem cells. Compounds 3–8 showed the cytotoxicity with IC50 values 15–20 μg/mL.

Encouraged by the anti-myocardial ischemic effect of Corydalis hendersonii ethanol extract, a chemical reinvestigation of the whole plant of C. hendersonii was performed, which led to the isolation of four new spirobenzylisoquinoline N-oxide alkaloids, hendersines C-F (1-4), along with seven known isoquinoline alkaloids (5-11). The structures of the new isolates including absolute configurations were elucidated by the analysis of spectroscopic data and comparison of the experimental and calculated electronic circular dichroism (ECD) data. Compound 1 inhibited the NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells with an IC50 value of 70.3 μM, and increased the cell viabilities with 40.0 ± 3.9% against the oxygen glucose deprivation injury in H9c2 cells at 40 μM.

An efficient copper-catalyzed cascade cyclization reaction for selectively synthesizing a variety of benzo[4,5]imidazo[2,1-a]isoquinoline derivatives has been developed. The reaction features the formation of three different C N bonds in sequence. In the presence of Cu(OAc)2 and KOtBu, o-alkynylbenzonitriles and 2-iodoanilines proceeded smoothly to obtain the corresponding benzo[4,5]imidazo[2,1-a]isoquinolines in moderate to good yields.

Thermoregulated phase-transfer Pt nanocatalyst was shown to be highly active, selective and recyclable in the hydrogenation of quinolines and isoquinolines. The catalyst could be easily separated from the product by simple phase separation and directly reused in the next cycle without evident loss in catalytic activity and selectivity, even after ten recycles. Importantly, for quinoline, the TON of 10,474 is the highest value ever reported among Pt catalysts. More remarkably, for isoquinoline, the TON of 5340 is far ahead of the highest record among transition metal catalysts.

Appendix A. Supplementary data CCDC #1588031–1588035 contains the supplementary crystallographic data for compounds 4, 5, 3, 6, and 1, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.

We report our complete mechanistic study on the highly diastereo- and enantioselective reductive coupling of isoquinoline templated by a chiral diboron. An uncommon activation mode, activation of the B-B bond via double N-B coordination followed by [3,3]-sigmatropic migration was computed to be more preferable over the radical pathway involving the B-B bond homolysis. On the basis of this mechanism, origins of the excellent enantio- and chemoselectivity were found to be driven by less steric repulsion and more secondary orbital interactions in the most favorable reductive coupling transition state. The reductive coupling of dihydroisoquinoline was also investigated and found to have a lower barrier and a larger thermodynamic driving force for the rate-determining second N-B coordination concerted with sigmatropic migration step, compared to isoquinoline. Higher chemoselectivity for the reductive coupling was computed to be achieved by using a strong Lewis-acidic diboron (B2F4). These computational results should be helpful for future development of this unusual reductive coupling by diborons.

An efficient one-pot synthetic methodology has been developed for the benzylic amination reactions of methyl-substituted azine N-oxides that operate under mild conditions. The reaction was found to tolerate quinoline and isoquinoline N-oxides with electron donating and withdrawing substituents as the electrophilic reaction partners as well as a broad range of nucleophilic primary, secondary and aromatic amines, affording the benzylic amination products in up to 82% yield. Financial support from the Scientific and Technological Research Council of Turkey (TÜBİTAK; Grant No: 115Z865 ) is gratefully acknowledged. A

To discover more derivatives with better glucose-lowering efficacy compared with berberine, twenty-three novel compounds with 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinoline or 5,8,12,12a-tetrahydro-6H-thieno[2',3':4,5]pyrido[2,1-a]isoquinoline cores were designed, synthesized, and biologically evaluated in vitro in continuation of our previous work on indirect activators of adenosine 5'-monophosphate-activated protein kinase (AMPK). Nine compounds effectively stimulated glucose consumption (>2.3-fold at 10 μM) in L6 myotube cells, and two compounds (4d and 4s) exhibited superior inhibitory activity (

ortho-Amidation of 2-pyridinyl ferrocenes with 1,4,2-dioxazol-5-ones was achieved via Cp*Co(III)-catalyzed direct C-H bond functionalization reaction. In the presence of Cp*Co(CO)I-2, in combination with AgPF6 and AgOPiv, a wide range of ferrocene-based amidated products were obtained in up to 96% yield under mild reaction conditions. A gram-scale reaction proceeded smoothly with high efficiency. Isoquinoline and pyrimidine are also suitable directing groups in this transformation. (C) 2018 Elsevier Inc. All rights reserved.

Macleaya cordata (Willd.) R. Br. (McRB) is utilized in traditional medicine and is mainly distributed in North America, Europe, Japan, and China. McRB honey known as “mad honey” produced by honey bees from the nectar of McRB contains isoquinoline alkaloids that give rise to potential consumer risk. In this study, a QuEChERS (Quick, Easy, Cheap, Effective, Rugged, Safe) extraction procedure followed by ultra-high performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UHPLC–MS/MS) was developed and optimized for the determination of seven isoquinoline alkaloids in McRB bee pollen and honey. The results revealed the presence of seven alkaloids in McRB bee pollen, four of which were also detected in McRB honey. Protopine and allocryptopine were the two predominant alkaloids, with concentrations of 0.17–0.66 mg/kg and 0.068–0.19 mg/kg in McRB honey and 1.25*10^3–3.07*10^3 mg/kg and 1.12*10^3–2.52*10^3 mg/kg in McRB bee pollen, respectively. None of the seven alkaloids were detected in commercial honey (n = 130) or pollen samples (n = 30). This study shows that protopine and allocryptopine could serve as potential markers of honey and pollen specifically from McRB.