Regiodivergent Synthesis of Methylene and Methyl Ring-Fused Isoquinolinones: Base-Promoted Isomerization of N-Allyl Amides.

Methylene and methyl tricyclic isoquinolinones were selectively prepared using a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a base- and temperature-controlled Heck reaction catalyzed by palladium(0). Exo- to endo-double-bond migration in isoquinolinones was achieved with 93-99% yields by treatment of the Heck products with Cs2CO3 in dimethyl sulfoxide (DMSO) at 150 °C. A probable mechanism for Cs2CO3-promoted olefin isomerization was proposed and examined using D-isotope labeling experiments. Finally, yuanamide, a 13-methyl-8-oxoprotoberberine alkaloid, was synthesized using the palladium-catalyzed aza-Wacker/Heck/migration sequence.

ERK-mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer.

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

One-Pot Oxidative Coupling/Decyanation of 6,7-Diphenylindolizine-5-carbonitriles and 2,3-Diphenylquinolizine-4-carbonitriles.

The one-pot oxidative coupling/decyanation reactions of 6,7-diphenylindolizine-5-carbonitriles and 2,3-diphenylquinolizine-4-carbonitriles were investigated using aryl-aryl oxidative coupling reagents. The phenanthroindolizidinones and phenanthroquinolizidinones were produced in 52-89% yields under VOF3/trifluoroacetic acid or [bis(trifluoroacetoxy)iodo]benzene/BF3-mediated conditions. This represents a mild and efficient approach to construct these types of pentacyclic skeletons from the corresponding cyano group-activated aza-Diels-Alder cycloadducts. A plausible mechanism of the one-pot oxidative coupling/decyanation reaction was proposed.

Synthesis, Experimental and Density Functional Theory (DFT) Studies on Solubility of Camptothecin Derivatives.

Two camptothecin derivatives, 10-cyclohexyl-7-methyl-20(S)-camptothecin and 7-methyl-10-morpholino-20(S)-camptothecin, were synthesized and their differences in solubility were investigated using four chosen solvent systems. Based on our results, 10-cyclohexyl-7-methyl-20(S)-camptothecin exhibited higher solubilities than 7-methyl-10-morpholino-20(S)-camptothecin in polar aprotic solvents. However, these two camptothecin derivatives did not exhibit apparent differences in solubility between 5% dimethyl sulfoxide (DMSO)/95% normal saline co-solvent system and 5% dimethylacetamide (DMAC)/95% normal saline co-solvent system. To rationalize their differences in solubility, we also tried to perform a DFT-B3LYP study to investigate their interaction with one water molecule.

Protecting-Group-Free Synthesis of 1-Phenylisoquinolin-4-ols: Thermal Cyclization of Methyl 2-[(Diphenylmethylidene)amino]acetates.

A protecting-group-free synthetic approach to 1-phenylisoquinolin-4-ols was developed by the intramolecular thermal cyclization of methyl 2-[(diphenylmethylidene)amino]acetates. R1 and R2 substituents were found to affect the required reaction temperatures, time, and yields of the cyclized products. The reactivity of the Schiff bases increased upon introduction of α-benzoyl and α-ester groups (R2). The cyclization yield also depended on the position of the R1 substituents on the phenyl groups.

Chemical Constituents of Phaius mishmensis.

The partitioned n-hexane, CHCl3, and EtOAc extracts from the crude MeOH extract of Phaius mishmensis showed considerable cytotoxicities against the human breast carcinoma (MCF-7), lung carcinoma (NCI-H460), and central nervous system carcinoma (SF-268) cell lines. Four new compounds, phaindole (1), (7'R,8'R)-phaithrene (2), methyl 3-hydroxy-4,5-dimethoxypropiophenone (3), and methyl hematinate (4), as well as 44 known compounds were isolated from the MeOH extract of Phaius mishmensis. The structures of the compounds were determined using spectroscopic methods.

Isolation and cytotoxicity evaluation of the chemical constituents from Cephalantheropsis gracilis.

Cephalantheropsis gracilis afforded five new compounds: cephalanthrin-A (1), cephalanthrin-B (2), cephathrene-A (3), cephathrene-B (4), methyl 2-(aminocarbonyl) phenylcarbamate (5), and 52 known compounds. The structures of the new compounds were determined by spectroscopic analysis. Among the compounds isolated, tryptanthrin (6), phaitanthrin A (7), cephalinone D (19), and flavanthrin (30) showed significant cytotoxicity against MCF-7, NCI-H460, and SF-268 cell lines.

Synthesis, anticonvulsant, sedative and anxiolytic activities of novel annulated pyrrolo[1,4]benzodiazepines.

Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

Direct conversion of 1-(2-bromobenzoyl)isoquinolines to dibenzo[de,g]quinolin-7-ones via reductive photocyclization.

A series of A/D-ring substituted dibenzo[de,g]quinolin-7-ones was produced from the corresponding isoquinolinones and (2-bromophenyl)acetonitriles in four steps. This represents a convenient approach toward the synthesis of tetracyclic alkaloids. A direct conversion of 1-(2-bromobenzoyl)isoquinolines to dibenzo[de,g]quinolin-7-ones is the key step in the total synthesis. The yield of the reductive photocyclization depends on the position of the substituents at the isoquinolyl ring and the phenyl group. The mechanism of the reductive photocyclization is also discussed.

Synthesis and cytotoxicity testing of new amido-substituted triazolopyrrolo[2,1-c][1,4]benzodiazepine (PBDT) derivatives.

A series of amido-substituted triazolopyrrolo[2,1-c][1,4]benzodiazepine (PBDT) derivatives was synthesized from isatoic anhydride, and their cytotoxicity against the MRC-5 and Mahlavu cell lines was evaluated. The results suggest that compound PBDT-7i with the meta-trifluoromethylbenzoyl substituent can selectively inhibit the growth of Mahlavu cells and has low toxicity towards MRC-5 cells.

Substituent effects on the iodine-catalyzed thermal cyclization of 3,4-diphenylbuta-1,3-dienyl isocyanates: mechanistic studies.

The thermal cyclization of 3,4-diphenylbuta-1,3-dienyl isocyanates 1, generated in situ from the corresponding azides, was investigated using iodine as a catalyst. Diphenylpyridinones 2, phenylnaphthalenes 3, and indenes 4 were produced via intramolecular ring closure. The nature of the substituents on the phenyl rings was found to be crucial to the distribution of cyclized products 2-4. The mechanism of the reaction is also discussed.

Chemical constituents and biological studies of the leaves of Grevillea robusta.

Three new compounds: Graviquinone (1), cis-3-hydroxy-5-pentadecylcyclohexanone (2), and methyl 5-ethoxy-2-hydroxycinnamate (3), and thirty-eight known compounds were isolated and identified from the leaves of Grevillea robusta. The structures of these compounds were determined by spectroscopic and chemical transformation methods. Graviquinone (1) showed the strongest cytotoxicity against MCF-7, NCI-H460, and SF-268 cell lines. Methyl 2,5-dihydroxycinnamate (4), graviphane (13), and dehydrograviphane (14) exhibited very potent DPPH scavenging activity compared with α-tocopherol. Methyl 2,5-dihydroxycinnamate (4) and bis-norstriatol (17) demonstrated strong inhibition of L-DOPA oxidation by mushroom tyrosinase compared with kojic acid.

Use of the curtius rearrangement of acryloyl azides in the synthesis of 3,5-disubstituted pyridines: mechanistic studies.

A series of disubstituted pyridine derivatives was synthesized from the corresponding acryloyl azides by acetic acid-promoted cycloaddition. This represents a novel and convenient synthetic approach to the symmetric 3,5-disubstituted pyridines. The nature of the substituent on the double bond and the utilized solvent were found to be crucial to the yield of pyridines. The reactivity of the acid-promoted cycloaddition increases with the presence of aryl groups, such as phenyl and pyridinyl. We also explored the comprehensive mechanism by the acid-promoted cycloaddition of (13)C-labeled cinnamoyl azide. The symmetric 3,5-disubstituted pyridines were synthesized from acryloyl azides by acetic acid-promoted trimolecular condensation.

Palladium-Catalyzed Stereoselective Aza-Wacker-Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles.

Palladium-catalyzed intramolecular tandem cyclization reactions were conducted for the synthesis of densely cis/cis-fused aza-tetracyclic structures. The process involved a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a palladium(0)-catalyzed Heck reaction. The effects of the solvent and benzene substitution pattern on the one-pot, two-step cascade reaction were studied systematically, and a probable mechanism was proposed. Strained pentahydrobenzo[f]cyclopenta[hi]indolizin-6-one and racemic γ-lycorane can also be synthesized rapidly using this palladium-catalyzed aza-Wacker-Heck cyclization reaction.

Tylophorine arrests carcinoma cells at G1 phase by downregulating cyclin A2 expression.

Tylophorine, a representative phenanthroindolizidine alkaloid from Tylophoraindica plants, exhibits anti-inflammatory and anti-cancerous growth activities. However, the underlying mechanisms of its anti-cancer activity have not been elucidated and its effects on cell cycle remain ambiguous. Here, we reveal by asynchronizing and synchronizing approaches that tylophorine not only retards the S-phase progression but also dominantly arrests the cells at G1 phase in HepG2, HONE-1, and NUGC-3 carcinoma cells. Moreover, tylophorine treatment results in down regulated cyclin A2 expression and overexpressed cyclin A2 rescues the G1 arrest by tylophorine. Thus, we are the first to report that the downregulated cyclin A2 plays a vital role in G1 arrest by tylophorine in carcinoma cells.

Photogeneration and thermal generation of pentacene from soluble precursors for OTFT applications.

A CO adduct of pentacene with an unsymmetrical structure is synthesized; it is soluble and can be spin-coated into thin films. Pentacene is regenerated in near quantitative yield by either thermal or photoinduced elimination of CO. OTFT devices fabricated by this compound exhibit typical FET characteristics.

Cyano Group Removal from Cyano-Promoted Aza-Diels-Alder Adducts: Synthesis and Structure-Activity Relationship of Phenanthroindolizidines and Phenanthroquinolizidines.

Phenanthroindolizidines and phenanthroquinolizidines were concisely synthesized by the reductive decyanization of cyano-promoted intramolecular aza-Diels-Alder cycloadducts followed by aryl-aryl coupling. Cyano groups were removed from α-aminoacrylonitriles via treatment with sodium borohydride in 2-propanol in almost quantitative yields; a possible mechanism was proposed and examined using D-labeling experiments. A systematic study of the effects of the phenanthrene substitution pattern on the anticancer activity against three human cancer cell lines was discussed.

Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells.

In this study, six 2-phenylnaphthalenes with hydroxyl groups were synthesized in high yields by the demethylation of the corresponding methoxy-2-phenylnaphthalenes, and one 2-phenylnaphthalene with an amino group was obtained by hydrogenation. All of the 2-phenylnaphthalene derivatives were evaluated for cytotoxicity, and the structure-activity relationship (SAR) against human breast cancer (MCF-7) cells was also determined. The SAR results revealed that cytotoxicity was markedly promoted by the hydroxyl group at the C-7 position of the naphthalene ring. The introduction of hydroxyl groups at the C-6 position of the naphthalene ring and the C-4' position of the phenyl ring fairly enhanced cytotoxicity, but the introduction of a hydroxyl group at the C-3' position of the phenyl ring slightly decreased cytotoxicity. Overall, 6,7-dihydroxy-2-(4'-hydroxyphenyl)naphthalene (PNAP-6h) exhibited the best cytotoxicity, with an IC50 value of 4.8 µM against the MCF-7 cell line, and showed low toxicity toward normal human mammary epithelial cells (MCF-10A). PNAP-6h led to cell arrest at the S phase, most likely due to increasing levels of p21 and p27 and decreasing levels of cyclin D1, CDK4, cyclin E, and CDK2. In addition, PNAP-6h decreased CDK1 and cyclin B1 expression, most likely leading to G2/M arrest, and induced morphological changes, such as nuclear shrinkage, nuclear fragmentation, and nuclear hypercondensation, as observed by Hoechst 33342 staining. PNAP-6h induced apoptosis, most likely by the promotion of Fas expression, increased PARP activity, caspase-7, caspase-8, and caspase-9 expression, the Bax/Bcl-2 ratio, and the phosphorylation of p38, and decreased the phosphorylation of ERK. This study provides the first demonstration of the cytotoxicity of PNAPs against MCF-7 cells and elucidates the mechanism underlying PNAP-induced cytotoxicity.

Cytotoxic 5-alkylresorcinol metabolites from the leaves of Grevillea robusta.

Bioassay-guided fractionation of the MeOH extract of the leaves of Grevillea robusta led to the isolation of six new 5-alkylresorcinols, gravicycle (1), dehydrogravicycle (2), bisgravillol (3), dehydrobisgravillol (4), dehydrograviphane (5), and methyldehydrograviphane (6), as well as eight known compounds. The structures of these compounds were determined by spectroscopic and chemical methods. Graviphane (7) and methylgraviphane (8) were isolated in the pure form for the first time from a natural source. The compounds all showed marginal cytotoxicity against MCF-7, NCI-H460, and SF-268 cell lines.

Anti-inflammatory effects of 7-methoxycryptopleurine and structure-activity relations of phenanthroindolizidines and phenanthroquinolizidines.

A cryptopleurine analogue, 7-methoxycryptopleurine, a phenanthroquinolizidine, was first found to exert potent anti-inflammatory activity in vitro and in vivo as well as have remarkable cytotoxic activity against cancer cells. The non-planar structure between the two major moieties, phenanthrene and indolizidine/quinolizidine, played a crucial role in the activity of phenanthroindolizidines or phenanthroquinolizidines in terms of cytotoxic effects on cancer cells and anti-inflammatory activity. We also showed that increase in planarity and rigidity of the indolizidine/quinolizidine moiety and change of the amine group into an amide by introducing a keto group to phenanthroindolizidines or phenanthroquinolizidines at the equivalent position 9 of tylophorine significantly reduced their activities. Moreover, in general, phenanthroquinolizidines are more potent than their respective phenanthroindolizines.