K2CO3-mediated annulation of 1,3-acetonedicarboxylates with 2-fluoro-1-nitroarenes: synthesis of indoles.

The K2CO3-mediated one-pot reaction of 1,3-acetonedicarboxylates with 2 equiv. of substituted 2-fluoro-1-nitrobenzenes has been developed to synthesize various 2,3-dicarboxylate indoles via a tandem annulation pathway. In the effective reaction, one carbon-carbon double bond, one carbon-carbon single bond and one carbon-nitrogen single bond are formed under open-vessel conditions. DFT calculations are used to rationalize the plausible mechanisms.

One-pot synthesis of benzofused 8-oxabicyclo[3.3.1]nonanes via GaCl3-mediated cyclocondensation of o-allylbenzaldehydes and 1,3-dicarbonyl synthons.

GaCl3-mediated one-pot cyclocondensation of o-allylbenzaldehydes and 1,3-dicarbonyls generates benzofused 8-oxabicyclo[3.3.1]nonanes in moderate to good yields in refluxing MeNO2 under easy-operational conditions. A plausible mechanism is proposed and discussed here. In the overall reaction process, various metal chloride-promoted conditions were investigated for one-pot cyclocondensation.

6-n-Butoxy-10-nitro-12,13-dioxa-11-azatricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene Improves the X-ray Sensitivity on Inhibiting Proliferation and Promoting Oxidative Stress and Apoptosis of Oral Cancer Cells.

This in vitro study examines the anti-oral cancer effects and mechanisms of a combined X-ray/SK2 treatment, i.e., X-ray and 6-n-butoxy-10-nitro-12,13-dioxa-11-azatricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene (SK2). ATP cell viability and flow cytometry-based cell cycle, apoptosis, oxidative stress, and DNA damage assessments were conducted. The X-ray/SK2 treatment exhibited lower viability in oral cancer (Ca9-22 and CAL 27) cells than in normal (Smulow-Glickman, S-G) cells, i.e., 32.0%, 46.1% vs. 59.0%, which showed more antiproliferative changes than with X-ray or SK2 treatment. Oral cancer cells under X-ray/SK2 treatment showed slight subG1 and G2/M increments and induced high annexin V-monitored apoptosis compared to X-ray or SK2 treatment. The X-ray/SK2 treatment showed higher caspase 3 and 8 levels for oral cancer cells than other treatments. X-ray/SK2 showed a higher caspase 9 level in CAL 27 cells than other treatments, while Ca9-22 cells showed similar levels under X-ray and/or SK2. The X-ray/SK2 treatment showed higher reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) depletion than other treatments. Meanwhile, the mitochondrial superoxide (MitoSOX) and glutathione levels in X-ray/SK2 treatment did not exhibit the highest rank compared to others. Moreover, oral cancer cells had higher γH2AX and/or 8-hydroxy-2-deoxyguanosine levels from X-ray/SK2 treatment than others. All these measurements for X-ray/SK2 in oral cancer cells were higher than in normal cells and attenuated by N-acetylcysteine. In conclusion, X-ray/SK2 treatment showed ROS-dependent enhanced antiproliferative, apoptotic, and DNA damage effects in oral cancer cells with a lower cytotoxic influence on normal cells.

Synthesis of 4-sulfonyl-1,7-diesters via K2CO3-mediated alkylative debenzoylation of α-sulfonyl o-hydroxyacetophenones with acrylates.

The synthesis of 4-sulfonyl-1,7-diesters was well developed, under open-vessel conditions, by K2CO3-mediated double alkylation of α-sulfonyl o-hydroxyacetophenones with acrylates and tandem debenzoylation of the resulting α,α-disubstituted o-hydroxyacetophenones. A plausible mechanism is proposed and discussed here. This high-yielding protocol provides a highly effective intermolecular alkylation and intramolecular debenzoylation via the formation of two carbon-carbon (C-C) single bonds and the cleavage of a carbon-carbon (C-C) single bond.

Synthesis of sulfonyl 2-aryl-5-methylenyltetrahydropyrans.

In this study, the present research describes a high-yield method for the synthesis of sulfonyl 2-aryl-5-methylenetetrahydropyrans by one-pot straightforward DABCO-promoted intramolecular Michael addition of ß-sulfonyl styrene with 2-chloromethyl-1-propenol followed by intramolecular alkylation. This Baylis-Hillman-type pathway provides a highly effective stereoselective annulation by forming one carbon-oxygen bond and one carbon-carbon bond.

A fluorene derivative inhibits human hepatocellular carcinoma cells by ROS-mediated apoptosis, anoikis and autophagy.

Fluorene was previously reported to have anticancer activity against human cancer cells. In this study, we examined the in vitro function of 9-methanesulfonylmethylene-2, 3-dimethoxy-9 H -fluorene (MSDF), a novel fluorene derivative, its anticancer potential in human hepatocellular carcinoma (HCC) cells and its underlying molecular mechanism. The disruption of cellular homeostasis caused by MSDF was found to promote reactive oxygen species (ROS) generation, leading to the activation of cellular apoptosis. As a survival strategy, cells undergo autophagy during oxidative stress. MSDF-induced apoptosis occurred through both receptor-mediated extrinsic and mitochondrial-mediated intrinsic routes. The development of acidic vesicular organelles and the accumulation of LC3-II protein suggest an increase in the autophagic process. Apoptosis was detected by double staining. The MAPK/ERK and PI3K/Akt signaling pathways were indeed suppressed during treatment. Along with elevated ROS generation and apoptosis, MSDF also caused anoikis and cell death by causing cells to lose contact with their extracellular matrix. ROS production was induced by MSDF and sustained by an NAC scavenger. MSDF-induced apoptosis led to increased autophagy, as shown by the suppression of apoptosis by Z-VAD-FMK. However, inhibition of autophagy by inhibitor 3-MA increased MSDF-induced apoptosis. More evidence shows that MSDF downregulated the expression of immune checkpoint proteins, suggesting that MSDF could be used in the future as an adjuvant to improve the effectiveness of HCC immunotherapy. Altogether, our results highlight the potential of MSDF as a multitarget drug for the treatment of HCC.

One-pot synthesis of sulfonyl dibenzosuberdiones via In(OTf)3-promoted double Friedel-Crafts reactions of oxygenated arylacetic acids with ß-arylvinyl sulfones.

Under open-vessel atmosphere conditions, a one-pot easy-to-operate method for the construction of diverse sulfonyl dibenzosuberdiones is developed via In(OTf)3-promoted tandem double Friedel-Crafts reactions of oxygenated arylacetic acids with ß-arylvinyl sulfones. A plausible mechanism is proposed and discussed in detail. This protocol allows for highly effective sequential intermolecular Michael addition, intramolecular ring-closure and α-benzylic oxidation via the formation of two carbon-carbon single (C-C) bonds and one carbon-oxygen double (CO) bond.

Sequential condensation and double desulfonylative cyclopropanation of 1,2-bis(sulfonylmethyl)arenes with 3-arylacroleins: access to biscyclopropane-fused tetralins.

Efficient tBuOK-mediated sequential condensation and double desulfonylative cyclopropanation of readily accessible 1,2-bis(sulfonylmethyl)arenes with 3-arylacroleins is described. This high-yielding, single-step strategy provides a variety of polysubstituted biscyclopropane-fused tetralins with six contiguous stereogenic centers via the construction of five carbon-carbon single bonds. A plausible mechanism is proposed and discussed. In the overall reaction process, water and sulfinic acid salts were generated as the byproducts.

Tandem C- and O-alkylative annulation of ß-ketosulfones with 1,2-bisbromomethyl arenes: one-pot construction of sulfonyl indanes and dioxadibenzofused macrocycles.

Herein, a tandem synthetic route for constructing sulfonyl indanes and dioxadibenzofused macrocycles is described. This strategy involves a transition-metal-free, base-mediated tandem C- and O-alkylative annulation of ß-ketosulfones with 1,2-bisbromomethyl arenes with moderate to excellent yields under open-vessel reaction conditions. In the overall reaction process, two carbon-carbon (C-C) and two carbon-oxygen (C-O) bonds are formed. Various base-promoted reaction conditions are screened for this one-pot easy-to-operate conversion.

Tandem cyclocondensation of 1,3-bis-sulfonylpropan-2-ones with arylaldehydes. One-pot synthesis of tris-sulfonyl 3-arylphenols.

One-pot tandem piperidinium acetate-mediated cyclocondensation of 1,3-bis-sulfonylpropan-2-ones with arylaldehydes generates tris-sulfonyl 3-arylphenols in moderate to good yields in refluxing toluene under easy-operational reaction conditions. A plausible mechanism is proposed and discussed. In the overall reaction process, water and sulfinic acid were generated as the byproducts. Various ammonium carboxylate-promoted conditions are investigated for one-pot [3 + 2 + 1]-benzannulation.

Antioral Cancer Effects by the Nitrated [6,6,6]Tricycles Compound (SK1) In Vitro.

A novel nitrated [6,6,6]tricycles-derived compound containing nitro, methoxy, and ispropyloxy groups, namely SK1, was developed in our previous report. However, the anticancer effects of SK1 were not assessed. Moreover, SK1 contains two nitro groups (NO2) and one nitrogen-oxygen (N-O) bond exhibiting the potential for oxidative stress generation, but this was not examined. The present study aimed to evaluate the antiproliferation effects and oxidative stress and its associated responses between oral cancer and normal cells. Based on the MTS assay, SK1 demonstrated more antiproliferation ability in oral cancer cells than normal cells, reversed by N-acetylcysteine. This suggests that SK1 causes antiproliferation effects preferentially in an oxidative stress-dependent manner. The oxidative stress-associated responses were further validated, showing higher ROS/MitoSOX burst, MMP, and GSH depletion in oral cancer cells than in normal cells. Meanwhile, SK1 caused oxidative stress-causing apoptosis, such as caspases 3/8/9, and DNA damages, such as γH2AX and 8-OHdG, to a greater extent in oral cancer cells than in normal cells. Siilar to cell viability, these oxidative stress responses were partially diminished by NAC, indicating that SK1 promoted oxidative stress-dependent responses. In conclusion, SK1 exerts oxidative stress, apoptosis, and DNA damage to a greater extent to oral cancer cells than in normal cells.

BF3·OEt2-mediated nucleophilic fluorocyclization of sulfonyl 3-methylene-oxabenzocyclooctan-6-ones. Diastereocontrolled synthesis of benzofused fluorooxabicyclo[4.2.1]nonanes.

We describe a facile-operational, high-yield method for the diastereocontrolled preparation of novel sulfonyl benzofused fluorooxabicyclo[4.2.1]nonanes by a straightforward synthetic route, including (i) NaBH4-mediated reduction of sulfonyl 3-methylene-oxabenzocyclooctan-6-ones and (ii) BF3·OEt2-mediated intramolecular nucleophilic fluorocyclization. The plausible mechanism for the preparation is proposed and discussed. This protocol can easily install a fluoro-atom on the bridged head position in a short time and under mild conditions, resulting in one carbon-carbon and one carbon-fluorine bond formation.

Synergistic Antiproliferation of Cisplatin and Nitrated [6,6,6]Tricycle Derivative (SK2) for a Combined Treatment of Oral Cancer Cells.

SK2, a nitrated [6,6,6]tricycle derivative with an n-butyloxy group, showed selective antiproliferation effects on oral cancer but not on normal oral cells. This investigation assessed for the first time the synergistic antiproliferation potential of cisplatin/SK2 in oral cancer cells. Cell viability assay at 24 h showed that a low dose of combined cisplatin/SK2 (10 µM/10 µg/mL) provided more antiproliferation than cisplatin or SK2 alone. Cisplatin/SK2 triggered also more apoptosis inductions in terms of subG1 accumulation, annexin V, pancaspase, and caspase 3/8/9 measurements. Moreover, cisplatin/SK2 provided more oxidative stress and DNA damage in oral cancer cells than independent treatments. Oxidative stress inhibitors rescued the cisplatin/SK2-induced antiproliferation and oxidative stress generation. Moreover, cisplatin/SK2 induced more antiproliferation, apoptosis, oxidative stress, and DNA damage in oral cancer cells than in normal oral cells (S-G). In conclusion, low-dose cisplatin/SK2 combined treatment promoted selective and synergistic antiproliferation in oral cancer cells depending on oxidative-stress-associated responses.

Combined Treatment of Nitrated [6,6,6]Tricycles Derivative (SK2)/Ultraviolet C Highly Inhibits Proliferation in Oral Cancer Cells In Vitro.

Combined treatment is an effective strategy to improve anticancer therapy, but severe side effects frequently limit this application. Drugs inhibiting the proliferation of cancer cells, but not normal cells, display preferential antiproliferation to cancer cells. It shows the benefits of avoiding side effects and enhancing antiproliferation for combined treatment. Nitrated [6,6,6]tricycles derivative (SK2), a novel chemical exhibiting benzo-fused dioxabicyclo[3.3.1]nonane core with an n-butyloxy substituent, exhibiting preferential antiproliferation, was chosen to evaluate its potential antioral cancer effect in vitro by combining it with ultraviolet C (UVC) irradiation. Combination treatment (UVC/SK2) caused lower viability in oral cancer cells (Ca9-22 and OC-2) than single treatment (20 J/m2 UVC or 10 µg/mL SK2), i.e., 42.3%/41.1% vs. 81.6%/69.2%, and 89.5%/79.6%, respectively. In contrast, it showed a minor effect on cell viability of normal oral cells (HGF-1), ranging from 82.2 to 90.6%. Moreover, UVC/SK2 caused higher oxidative stress in oral cancer cells than normal cells through the examination of reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane potential. UVC/SK2 also caused subG1 increment associated with apoptosis detections by assessing annexin V; panaspase; and caspases 3, 8, and 9. The antiproliferation and oxidative stress were reverted by N-acetylcysteine, validating the involvement of oxidative stress in antioral cancer cells. UVC/SK2 also caused DNA damage by detecting γH2AX and 8-hydroxy-2'-deoxyguanosine in oral cancer cells. In conclusion, SK2 is an effective enhancer for improving the UVC-caused antiproliferation against oral cancer cells in vitro. UVC/SK2 demonstrated a preferential and synergistic antiproliferation ability towards oral cancer cells with little adverse effects on normal cells.

Antiproliferation- and Apoptosis-Inducible Effects of a Novel Nitrated [6,6,6]Tricycle Derivative (SK2) on Oral Cancer Cells.

The benzo-fused dioxabicyclo[3.3.1]nonane core is the central framework in several natural products. Using this core, we had developed a novel nitrated [6,6,6]tricycle-derived compound containing an n-butyloxy group, namely, SK2. The anticancer potential of SK2 was not assessed. This study aimed to determine the antiproliferative function and investigated possible mechanisms of SK2 acting on oral cancer cells. SK2 preferentially killed oral cancer cells but caused no harmful effect on non-malignant oral cells. After the SK2 exposure of oral cancer cells, cells in the sub-G1 phase accumulated. This apoptosis-like outcome of SK2 treatment was validated to be apoptosis via observing an increasing annexin V population. Mechanistically, apoptosis signalers such as pancaspase, caspases 8, caspase 9, and caspase 3 were activated by SK2 in oral cancer cells. SK2 induced oxidative-stress-associated changes. Furthermore, SK2 caused DNA damage (γH2AX and 8-hydroxy-2'-deoxyguanosine). In conclusion, a novel nitrated [6,6,6]tricycle-derived compound, SK2, exhibits a preferential antiproliferative effect on oral cancer cells, accompanied by apoptosis, oxidative stress, and DNA damage.

Bsi(OTf)3-mediated tandem annulation of 1-aryl isochroman-3-ones with oxygenated arenes: one-pot synthesis of polyoxygenated homotriptycenes.

Bi(OTf)3 (bismuth triflate)-mediated one-pot tandem annulation of oxygenated 1-aryl isochroman-3-ones with oxygenated arenes provides polyoxygenated homotriptycenes in moderate to good yields in MeNO2 at reflux (101 °C) for 10 h under an air atmosphere and easy-operational conditions via intermolecular and intramolecular Friedel-Crafts type procedures. A plausible mechanism is proposed and discussed. This protocol provides a highly effective ring-closure via three carbon-carbon (C-C) bond formations.

Synthesis of benzofused cyclobutaoxepanones via intramolecular annulation of o-cinnamyl chalcones.

Intramolecular stereoselective annulation of o-cinnamyloxy chalcones provides two kinds of tricyclic benzofused cyclobutaoxepanones via the synthesized routes of DABCO/NBS (1,4-diazabicyclo[2.2.2]octane/N-bromosuccinimide)-mediated Baylis-Hillman type cyclization or low-pressure mercury (LP Hg) lamp-promoted photocontrolled [2 + 2] cycloaddition. Diversified reaction conditions have been investigated for one-pot facile, high-yield transformation.

HCl-mediated cascade cyclocondensation of oxygenated arylacetic acids with arylaldehydes: one-pot synthesis of 1-arylisoquinolines.

In this paper, a concise, open-vessel synthesis of 1-arylisoquinolines is described via HCl-mediated intermolecular cyclocondensation of oxygenated arylacetic acids with arylaldehydes in the presence of NH2OH and alcoholic solvents under mild and one-pot reaction conditions. A plausible mechanism is proposed and discussed herein. In the overall reaction process, only water was generated as the byproduct. Various environmentally friendly reaction conditions are investigated for convenient transformation via the (4C + 1C + 1N) annulation. This protocol provides a highly effective ring closure via the formations of one carbon-carbon (C-C) bond, two carbon-nitrogen (C-N) bonds and one carbon-oxygen (C-O) bond.

A novel one-pot synthesis of flavones.

In this paper, a one-pot facile route for the BiCl3/RuCl3-mediated synthesis of functionalized flavones is described, including: (i) intermolecular ortho-acylation of substituted phenols with cinnamoyl chlorides, and (ii) intramolecular cyclodehydrogenation of the resulting o-hydroxychalcones. The reaction conditions are discussed herein.

Combined Treatment of Sulfonyl Chromen-4-Ones (CHW09) and Ultraviolet-C (UVC) Enhances Proliferation Inhibition, Apoptosis, Oxidative Stress, and DNA Damage against Oral Cancer Cells.

The sensitizing effect of chromone-derived compounds on UVC-induced proliferation inhibition has not been comprehensively investigated so far. The subject of this study was to examine the proliferation change of oral cancer cells while using the combined treatment of UVC (254 nm) with our previously developed sulfonyl chromen-4-ones (CHW09), namely UVC/CHW09. Cell viability, apoptosis, oxidative stress, and DNA damage for the individual and combined treatments for UVC and/or CHW09 were examined in oral cancer Ca9-22 cells. In 24 h MTS assay, UVC (30 J/m2; UVC30), or CHW09 (25 and 50 µg/mL; namely, CHW09-25 and CHW09-50) show 54%, 59%, and 45% viability. The combined treatment (UVC30/CHW09-25 and UVC30/CHW09-50) show lower cell viability (45% and 35%). Mechanistically, UVC/CHW09 induced higher apoptosis than individual treatments and untreated control, which were supported by the evidence of flow cytometry for subG1, annexin V/7-aminoactinomycin D, pancaspase and caspases 3/7 activity, and western blotting for cleaved poly(ADP-ribose) polymerase. Moreover, this cleaved PARP expression was downregulated by pancaspase inhibitor Z-VAD-FMK. UVC/CHW09 showed higher oxidative stress than individual treatments and untreated control in terms of flow cytometry for reactive oxygen species, mitochondrial membrane potential, and mitochondrial mass. Furthermore, UVC/CHW09 showed higher DNA damage than individual treatments and untreated control in terms of flow cytometry for H2A histone family member X and 8-oxo-2'-deoxyguanosine. In conclusion, combined treatment UVC/CHW09 suppresses proliferation, and promotes apoptosis, oxidative stress, and DNA damage against oral cancer cells, providing a novel application of sulfonyl chromen-4-ones in order to sensitize UVC induced proliferation inhibition for oral cancer therapy.