Natural Benzo Research Articles

Azaphilone pigments from the marine-derived Penicillium sclerotium UJNMF 0503 and their neuroprotective potential against H2O2-induced cell apoptosis through modulating PI3K/Akt pathway

Azaphilones represent a particular group of fascinating pigments from fungal source, with easier industrialization and lower cost than the traditional plant-derived pigments, and they also display a wide range of pharmacological activities. Herein, 28 azaphilone analogs, including 12 new ones, were obtained from the fermentation culture of a marine fungus Penicillium sclerotium UJNMF 0503. Their structures were elucidated by MS, NMR and ECD analyses, together with NMR and ECD calculations and biogenetic considerations. Among them, compounds 1 and 2 feature an unusual natural benzo[d][1,3]dioxepine ring embedded with an orthoformate unit, while 3 and 4 represent the first azaphilone examples incorporating a novel rearranged 5/6 bicyclic core and a tetrahydropyran ring on the side chain, respectively. Our bioassays revealed that half of the isolates exhibited neuroprotective potential against H2O2-induced injury on RSC96 cells, while compound 13 displayed the best rescuing capacity toward the cell viability by blocking cellular apoptosis, which was likely achieved by upregulating the PI3K/Akt signaling pathway.

Total Synthesis and Revision of Stereochemistry of a Natural Benzo[g]isochromene Stereodiad Isolated from Rubia philippinensis.

This study presents a total synthesis and revision of the stereochemical configuration of the conformationally flexible natural product benzo[g]isochromene stereodiad alongside its diastereomeric counterparts. The highlights of the synthesis are the TiCl4-mediated diastereoselective aldol reaction, Pd-catalyzed lactonization, and Schmidt glycosidation. Our efforts using total synthesis disclosed herein proved that a previously assigned structure required revision.

Chelerythrine suppresses proliferation and metastasis of human prostate cancer cells via modulating MMP/TIMP/NF-κB system.

Chelerythrine is a natural benzo[c]phenanthridine alkaloid found in many herbs and displays a wide range of antitumor activities. Here, the present study tested their effects on prostate cancer cells. The addition of chelerythrine can significantly inhibit the proliferation of androgen-independent prostate cancer DU145 and PC-3 cells at the concentration of 5 and 10μM, but not on androgen-dependent prostate cancer LNCaP cells as well as normal prostate epithelial cell line PrEC cells. Wound migration and transwell invasion assay showed the similar inhibitory effect of chelerythrine on the migration and invasion of DU145 and PC-3 cells in the same condition. Western blot analysis further confirmed that chelerythrine not only dramatically decreased MMP-2, MMP-9, and uPA protein expression, but also augmented the expression of their endogenous inhibitors (TIMP-1 and TIMP-2) and plasminogen activator inhibitors (PAI-1 and PAI-2) in both cancer cells. Meanwhile, NF-κB and AP-1 transcription factors were all suppressed as evidenced by the decline of p-p65, c-Fos, and c-Jun protein expression in both cells. Taken together, these findings suggested that chelerythrine could reduce the metastasis of androgen-independent prostate cancer cells via modulation of MMP/TIMP system and inactivation of NF-κB pathway.

Chelerythrine induces apoptosis via ROS-mediated endoplasmic reticulum stress and STAT3 pathways in human renal cell carcinoma.

Renal cell carcinoma (RCC) is a heterogeneous histological disease and it is one of the most common kidney cancer. The treatment of RCC has been improved for the past few years, but its mortality still remains high. Chelerythrine (CHE) is a natural benzo[c]phenanthridine alkaloid and a widely used broad‐range protein kinase C inhibitor which has anti‐cancer effect on various types of human cancer cells. However, its effect on RCC has not been fully elucidated. In this study, we evaluated the effect and mechanism of CHE on RCC cells. Our study showed that CHE induced colony formation inhibition and G2/M cell cycle arrest in a dose‐dependent manner in RCC cells. In addition, CHE increased cellular ROS level, leading to endoplasmic reticulum (ER) stress, inactivating STAT3 activities and inducing apoptosis in RCC cells which were suppressed by NAC, a special ROS inhibitor. We further found that both knockdown of ATF4 protein and overexpression of STAT3 protein could reduce CHE‐induced apoptosis in Caki cells. These results demonstrated that the apoptosis induced by CHE was mediated by ROS‐caused ER stress and STAT3 inactivation. Collectively, our studies provided support for CHE as a potential new therapeutic agent for the management of RCC.

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes.

In this work, the interaction of six natural benzo[c]phenanthridine alkaloids (macarpine, sanguilutine, sanguirubine, chelerythrine, sanguinarine and chelirubine) with parallel and antiparallel G-quadruplex DNA structures was studied. HT22 corresponding to the end of human telomeres and the modified promoter oncogene c-kit21 and Pu22 sequences have been used. Spectroscopically-monitored melting experiments and fluorescence titrations, competitive dialysis and nuclear magnetic resonance spectroscopy were used for this purpose. The results showed that these alkaloids stabilized G-quadruplex structures in terms of increments of Tm values (from 15 to 25 °C) with high selectivity over duplexes and unfolded DNA. The mode of binding was mainly by stacking on the terminal G-tetrads with stoichiometries of 1 : 2 (DNA : ligand). The presence of non-specific electrostatic interactions was also observed. Overall, the results pointed to a strong stabilization of G-quadruplex structures by these alkaloids.

Induction of reactive oxygen species-stimulated distinctive autophagy by chelerythrine in non-small cell lung cancer cells

Chelerythrine (CHE), a natural benzo[c]phenanthridine alkaloid, shows anti-cancer effect through a number of mechanisms. Herein, the effect and mechanism of the CHE-induced autophagy, a type II programmed cell death, in non-small cell lung cancer (NSCLC) cells were studied for the first time. CHE induced cell viability decrease, colony formation inhibition, and apoptosis in a concentration-dependent manner in NSCLC A549 and NCI-H1299 cells. In addition, CHE triggered the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II). The CHE-induced expression of LC3-II was further increased in the combination treatment with chloroquine (CQ), an autophagy inhibitor, and large amounts of red-puncta were observed in the CHE-treated A549 cells with stable expression of mRFP-EGFP-LC3, indicating that CHE induces autophagy flux. Silence of beclin 1 reversed the CHE-induced expression of LC3-II. Inhibition of autophagy remarkably reversed the CHE-induced cell viability decrease and apoptosis in NCI-H1299 cells but not in A549 cells. Furthermore, CHE triggered reactive oxygen species (ROS) generation in both cell lines. A decreased level of ROS through pretreatment with N-acetyl-L-cysteine reversed the CHE-induced cell viability decrease, apoptosis, and autophagy. Taken together, CHE induced distinctive autophagy in A549 (accompanied autophagy) and NCI-H1299 (pro-death autophagy) cells and a decreased level of ROS reversed the effect of CHE in NSCLC cells in terms of cell viability, apoptosis, and autophagy.

ВИКОРИСТАННЯ 3-АРИЛІЗОКУМАРИНІВ У СИНТЕЗІ 3-АРИЛІЗОХІНОЛОНІВ

The review systematizes and analyzes the literature data (100 sources) regarding the recyclization of 3-arylisocoumarins (3-aryl-1H-isochromen-1-ones) under the action of primary N-nucleophiles that leads to the formation of 3-arylisoquinolones (3-arylisoquinolin-1(2H)-ones). This reaction may be carried out with a wide range of primary aminogroup-containing compounds: ammonia, primary aliphatic, aromatic, and heteroaromatic amines, hydrazine, and hydroxylamine. This transformation is not hindered by the presence of active functional groups (hydroxyl, acetal, carboxyl, ester, nitrile groups, or additional aminogroup) neither in 3-arylcoumarin nor in the primary amine. A special attention has been paid to reaction conditions (temperature regime, duration, solvent, catalysts), which may vary greatly. In particular, it is pointed out that in most cases to carry out high-temperature recyclization of 3-arylisocoumarins with ammonia and volatile amines with low molecular weight the use of closed reactors and high-pressure flasks was required. The cases of successful recyclization of 11,12-dihydrodibenzo[c,h]chromen-6-ones, indeno[1,2-c]isochromen-5(11H)-ones, isochromeno[4,3-c]chromen-6,11-dione and 5H-benzofuro[3,2-c]isochromen-5-one are reviewed separately. The polycondensated heterocyclic system of these compounds contains a 3-arylisocoumarin fragment. The biological activity data is presented for the compounds obtained via this transformation – 3-arylisoquinolin-1(2H)-ones, and also polycondensated systems that contain this fragment, e.g. 11,12-dihydrobenzo[c]phenanthridin-6(5H)-ones and 6H-indeno[1,2-c]isoquinoline-5,11-diones. The opportunities to use 3-arylisoquinolin-1(2H)-ones in the synthesis of other compounds of isoquinoline family, e.g. natural benzo[c]phenanthridinealocoloids, are demonstrated.

New nitro-benzo[c]phenanthridine and indolopyridoquinazoline alkaloids from Zanthoxylum atchoum

• Isolation and characterization of four new compounds: two benzophenanthridine and two indoloquinazoline alkaloids from Zanthoxylum atchoum . • First report of a nitro group on the biosynthesis of the natural benzo[ c ]phenantridine alkaloids. • Interesting analysis of deuterium exchange during the 1 H-NMR experiments. • Potent antibacterial activity for the new nitro-benzophenanthridine alkaloid. The first phytochemical investigation of the roots of Zanthoxylum atchoum has led to the isolation of two new nitro-benzo[ c ]phenanthridine alkaloids 6-nitronitidine ( 1 ) and 6-nitro-8-methoxy-7,8-dihydronitidine ( 2 ), two new salts of indolopyridoquinazoline alkaloids 3-hydroxy-8,13-dihydro-14-methyl-5-oxo-7 H -indolo[2’,3’:3,4]pyrido[2,1- b ]quinazolin-14-ium ( 3 ) and its zwitterionic form 3-phenolate-8,13-dihydro-14-methyl-5-oxo-7 H -indolo[2’,3’:3,4]pyrido[2,1- b ]quinazolin-14-ium ( 4 ) along with 18 ( 5 – 22 ) known compounds. Their chemical structures were elucidated by spectroscopic analysis including 1D and 2D NMR and MS techniques. This is the first report of the nitro group on the biosynthesis of the natural benzo[ c ]phenantridine alkaloids. Compound 2 exhibited potent antibacterial activity against Staphylococcus aureus of MIC 50 = 4 μg·mL −1 . La première étude phytochimique des racines de Zanthoxylum atchoum a conduit à l’isolement de deux nouveaux alcaloïdes nitro-benzo[ c ]phénanthridine, le 6-nitronitidine ( 1 ) et 6-nitro-8-méthoxy-7,8-dihydronitidine ( 2 ), de deux nouveaux sels d’indolopyridoquinazoline, le 3-hydroxy-8,13-dihydro-14-méthyl-5-oxo-7 H -indolo[2’,3’:3,4]pyrido[2,1- b ]quinazolin-14-ium ( 3 ), et sa forme zwittérionique, le 3-phénolate de 8,13-dihydro-14-méthyl-5-oxo-7 H -indolo [2’,3’:3,4]pyrido[2,1- b ]quinazolin-14-ium ( 4 ), et de 18 composés connus ( 5 – 22 ). Leurs structures chimiques ont été élucidées par analyse des techniques spectroscopiques 1D et 2D-RMN et SM. C’est le premier rapport d’un groupement nitro dans la biosynthèse de benzo[ c ] phénantridines naturelles. Le composé ( 2 ) montre une puissante activité antibactérienne contre Staphylococcus aureus , avec une CMI50 = 4 μg·mL −1 .

Rapid and Convergent Assembly of Natural Benzo[c]phenanthridines by Palladium/Norbornene Catalysis

A straightforward total synthesis of a small panel of natural benzo[c]phenanthridines is described. The selective coupling of an aryl triflate with a bromobenzylamine by means of palladium/norbornene joint catalysis and a sequential transfer hydrogenation deliver these alkaloids in one pot. Dihydrophenanthridines initially formed undergo dehydrogenation smoothly while norbornene acts both as a catalyst for their assembly and as a sacrificial olefin in their dehydrogenation. Palladium catalysis is a powerful tool for organic chemistry and found wide applications in synthesis owing to its versatility. By employing readily available substrates many protocols for the selective formation of C–C and C–Heteroatom bonds were reported in the last two decades. A powerful strategy in the construction of cyclic scaffolds is based on the use of reagents possessing a suitably tethered (masked) nucleophile which could terminate the catalytic cycle by reacting with an electrophilic organopalladium(II) intermediate. In this context, the association of a palladium salt with norbornene delivers a remarkable catalytic system that allows the multiple functionalization of an aryl halide in one pot. After seminal work by Catellani, many synthetic applications were reported which delivers complex polycyclic scaffolds adopting this strategy. In the context of nitrogen heterocycles, methods that deliver carbazoles, phenanthridines or dibenzoazepines have been reported and this variety clearly demonstrates the large scope of this catalytic system. An efficient synthesis of phenanthridines from aryl iodides and bromobenzylamines is accessible by merging a palladium/norbornene co-catalyzed formation 1 In honor of Professor Victor Sniekus on 77th Birthday HETEROCYCLES, Vol. 88, No. 1, 2014 807

Biomimetic Synthesis of Natural and “Unnatural” Lignans by Oxidative Coupling of Caffeic Esters

AbstractThe metal‐mediated oxidative coupling of caffeic acid esters has been employed in the biomimetic synthesis of dimeric lignans and neolignans. Phenethyl and methyl caffeate esters were used as substrates and MnO2, Mn(OAc)3 and Ag2O as oxidative coupling agents. The manganese‐mediated reactions afforded in good yields the unusual benzo[kl]xanthene lignans 6 and 15 as the major products accompanied by minor amounts of the aryldihydronaphthalene lignans (±)‐7 and (±)‐16. When Ag2O was employed, the neolignan (±)‐17 was obtained as the major product. This biomimetic route was also used to obtain the natural benzo[kl]xanthene lignans rufescidride (9) and mongolicumin A (10). A computational study of the coupling reactions was also carried out.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Synthesis and cytotoxic activity of benzo[ c][1,7] and [1,8]phenanthrolines analogues of nitidine and fagaronine

Fagaronine and nitidine are natural benzo[ c] phenanthridinium alkaloids, which display antileukemic activity. Both act as topoisomerase I and topoisomerase II inhibitors. The objective of the present study was to prepare noncharged isosters of these compounds, with replacement of the aromatic A ring by a pyridine ring, present in other topoisomerase I inhibitors. Various 7,8- and 8,9-dimethoxy and metylenedioxy benzo[ c][1,7] and [1,8]phenanthrolines were readily synthesized by benzyne-mediated cyclization of the corresponding substituted N-(2-halobenzyl)-5-quinolinamines or 5-isoquinolinamines. In both series, compounds bearing oxygenated substituents at positions 8 and 9 exhibited cytotoxic properties towards L1210 murine leukemia cells, which may result from their capacities to intercalate into DNA. Topoisomerase I inhibition was observed for all active compounds.

Structural considerations of NK109, an antitumor benzo[c]phenanthridine alkaloid.

The antitumor activities of a synthetic benzo[c]phenanthridine, NK109 (7-hydroxy-2, 3-methylenedioxy-5-methyl-8-methoxybenzo[c]phenanthridinium hydrogensulfate dihydrate), and of natural benzo[c]phenanthridines were tested in vitro and in vivo. NK109 (3) had the highest activity among them. NK109 is similar in structure to fagaronine and fagaridine; however, it has a phenolic-OH at C-7. NK109 exists as a resonance hybrid, the keto-amine and zwitterionic forms in neutral media. The resonance hybrid is cationic and has molecular planarity; these have been considered to be essential for the antitumor activity of the benzo[c]phenanthridinium salts. On the other hand, the structurally similar benzo[c]phenthridine alkaloids, chelerythrine and sanguinarine, exist as pseudobases under the same conditions. The latter do not exhibit antitumor activity in vivo, probably because they lose both the immonium region and molecular planarity. Thus, 3 may be considered to be novel category of benzo[c]phenanthridinium salt from the viewpoint of its structure under biological conditions.