Antiproliferative activities through accelerating autophagic flux by basidalin and its analogs in human cancer cells.

Basidalin, isolated from the basidiomycete Leucoagaricus naucina, has previously demonstrated antibacterial and antitumor properties against murine cancer cells in vivo, but its effects on human cancer cells remain unknown. In this study, we found that basidalin possesses antiproliferative activity against human cancer cell lines. To elucidate the antiproliferative mechanism of basidalin, we focused on autophagy. Treatment with basidalin led to an increase in LC3-II expression level, and accelerated autophagic flux through an mTOR-independent pathway. Moreover, according to the structure-activity relationship analysis-including newly synthesized basidalin analogs-the formyl group, not the amino group, contributes to the antiproliferative activities of basidalin against human cancer cells. Additionally, the antiproliferative activity of basidalin analogs was strongly correlated with autophagy-inducing activity, indicating that basidalin exhibits antiproliferative activity through autophagy induction. These data suggest that basidalin, characterized by its ability to upregulate autophagic flux, emerges as a novel anticancer drug.

Red-light-mediated Barton decarboxylation reaction and one-pot wavelength-selective transformations.

In organic chemistry, selecting mild conditions for transformations and saving energy are increasingly important for achieving sustainable development goals. Herein, we describe a red-light-mediated Barton decarboxylation using readily available red-light-emitting diodes as the energy source and zinc tetraphenylporphyrin as the catalyst, avoiding explosive or hazardous reagents or external heating. Mechanistic studies suggest that the reaction probably proceeds via Dexter energy transfer between the activated catalyst and the Barton ester. Furthermore, a one-pot wavelength-selective reaction within the visible light range is developed in combination with a blue-light-mediated photoredox reaction, demonstrating the compatibility of two photochemical transformations based on mechanistic differences. This one-pot process expands the limits of the decarboxylative Giese reaction beyond polarity matching.

Development of TfOH-Catalyzed Spirocyclization by Intramolecular Friedel-Crafts-type 1,4-Addition: Application to the Total Synthesis of the Unusual Proaporphine Alkaloid (±)-Misrametine.

An effective method was developed for TfOH-catalyzed construction of spiroindanes and spirotetralines containing an all-carbon quaternary stereocenter. Intramolecular Friedel-Crafts-type 1,4-addition of the substrates which were di- or trimethoxybenzene and 2-cyclohexenone linked by an alkyl chain proceeded smoothly in the presence of 30 mol % of TfOH. A variety of spiroindanes and spirotetralines were obtained with moderate to excellent yield by this method. The reaction was successfully applied in the first total synthesis of the unusual proaporphine alkaloid (±)-misrametine, which included the gram-scale spirocyclization and selective O-demethylation used KCN in DMSO condition as key steps.

Asymmetric Synthesis of Cyclopentene Compounds Containing All-Carbon Quaternary Stereocenters by (3 + 2) Cycloaddition and Its Application in the Formal Synthesis of (R)-(-)-Puraquinonic Acid.

A highly stereoselective (3 + 2) cycloaddition for the asymmetric synthesis of versatile cyclopentene compounds containing all-carbon quaternary stereocenters was developed. The phosphine-catalyzed reactions of alkynoates with α-alkylated electron-deficient alkenes bearing Oppolzer's camphorsultam showed high to excellent diastereoselectivities and perfect regioselectivities. The usefulness of this reaction was demonstrated in the concise formal synthesis of (R)-(-)-puraquinonic acid.

Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor.

Humulanolides are natural products isolated from Asteriscus, and the isolation and total synthesis of many types of humulanolides have been reported. In this study, we evaluated anti-proliferative activity of twelve humulanolides against various human cancer cell lines and found that humulanolide analog E, which was newly designed and synthesized, exhibited the highest anti-proliferative activity. Structure-activity relationship analysis revealed that α,ß-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. To identify molecular targets of humulanolide analog E, we investigated various cell-based and in vitro assays. Treatment with humulanolide analog E against human fibrosarcoma HT1080 cells increased the expression level of HSP70 protein and decreased the levels of AKT and CDK4, which are HSP90 client proteins. Moreover, humulanolide analog E inhibited refolding of denatured luciferase protein via suppression of HSP90 activity in vitro. These results suggest that humulanolide analog E possesses the anti-proliferative activity against human cancer cells by inhibiting HSP90 functions.

Diaryliodonium Salt-Based Synthesis of N-Alkoxyindolines and Further Insights into the Ishikawa Indole Synthesis.

A diaryliodonium salt-based strategy enabled the first systematic synthesis of rarely accessible N-alkoxyindolines. Mechanistic analyses suggested that the reaction likely involves reductive elimination of iodobenzene from iodaoxazepine via a four-membered transition state, followed by Meisenheimer rearrangement. Substrates with N-carbamate protection afforded indole in a manner similar to that of the Ishikawa indole synthesis. Preinstallation of a stannyl group as an iodonium salt precursor greatly expanded the substrate scope, and further mechanistic insights are discussed.

Glycothermally Synthesized Carbon Dots with Narrow-Bandwidth and Color-Tunable Solvatochromic Fluorescence for Wide-Color-Gamut Displays.

Fluorescent carbon dots (CDs) represent a promising eco-friendly next-generation phosphor. However, most CDs exhibit broad photoluminescence (PL) spectra [full width at half-maximum (fwhm) over 60 nm]; few works on CDs with sharp PL spectra (fwhm less than 40 nm) have been reported. In addition, their syntheses and color tuning require harsh conditions of high temperatures, long reaction times, and high pressures with catalysts. Here, we successfully prepared narrow-bandwidth emissive CDs (fwhm of 27-40 nm) from phloroglucinol in a glycol solvent of 1,2-pentanediol at temperatures as low as 180 °C for a reaction duration of as short as 6 h under ambient conditions without any catalysts via an open reaction system in which dehydration and condensation reactions among phloroglucinol molecules were enhanced. We shifted the emission peak from 463 to 511 nm by selecting seven kinds of solvents with different polarities, that is, emission colors could be tuned from blue to green by taking advantage of fluorescence solvatochromism. The CD-dispersed polymer films showed a similar solvatochromic behavior and sharp PL spectra, verifying the feasibility of applying the CDs to displays with a wide color gamut.

Enantioselective Organocatalytic Construction of Spirochroman Derivatives.

Highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. Intramolecular oxy-Michael addition was catalyzed with a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivities of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

Stereoselective Synthesis of the Tricyclic Core of (-)-Callophycoic Acid A.

Two stereocontrolled routes to the tricyclic core of (-)-callophycoic acid A are described. Our synthetic strategy relied on stereoselective allylboration using a new allylboronate reagent to construct the all-carbon quaternary stereocenter in the core, followed by efficient radical cyclization or palladium-catalyzed reductive cyclization to form its multisubstituted cyclohexane ring. The tetrahydrooxepin ring was constructed by intramolecular etheration. This study provides the first method for the stereoselective synthesis of the characteristic tricyclic skeleton of callophycoic acids.

Identification of vibsanin A analog as a novel HSP90 inhibitor.

Vibsanin A is the first natural product isolated from Viburnum awabuki and has several biological activities. We have reported that a vibsanin A analog, obtained from process of total synthesis of vibsanin A, has anti-proliferative activity against human cancer cell lines. In this study, we evaluated anti-proliferative effect of the vibsanin A analogs against various human cancer cell lines and examined molecular target of the analog in human cells. Among the vibsanin A analogs, vibsanin A analog C (VAC) showed anti-proliferative effect against various cancer cell lines, and the anti-proliferative activity was strongest among the vibsanin A analogs. Additionally, VAC fluctuated amounts of HSP90-related proteins in cells and inhibited HSP90-mediated protein refolding of luciferase in vitro. These results suggest that the anti-proliferative activity of VAC is due to HSP90 inhibition, and VAC has a potential as novel anti-cancer drug as HSP90 inhibitor.

Identification of topoisomerases as molecular targets of cytosporolide C and its analog.

Cytosporolide (Cytos) A-C, isolated from the fungus Cytospora sp., have anti-microbial activity, but their molecular targets in mammalian cells are unknown. We have previously reported the total synthesis of Cytos A by biomimetic hetero-Diels-Alder reaction. In this study, to examine the novel bioactivity of Cytos, we synthesized Cytos C and measured cell growth-inhibiting activities of 7 compounds, including Cytos A and C, in several human cancer cell lines. Among these compounds, Cytos C and tetradeoxycytosporolide A (TD-Cytos A), a model compound for the synthesis of Cytos A, had anti-proliferative effects on cancer cells, and TD-Cytos A exhibited stronger activity than Cytos C. In vitro topoisomerase-mediated DNA relaxing experiments showed that TD-Cytos A inhibited the activities of topoisomerase I and II, whereas Cytos C targeted only topoisomerase I. These data suggest that the anti-proliferative activities of Cytos correlate with the inhibition of topoisomerases and implicated TD-Cytos A as a novel anti-cancer drug that suppresses the activities of topoisomerase I and II.

Total Syntheses of (+)-Aquatolide and Related Humulanolides.

The short, efficient total synthesis of (+)-aquatolide was achieved by a biomimetic transannular [2+2] photocycloaddition, and provides the first example of constructing a 5/5/4/8-ring system from asteriscunolides. Furthermore, the reaction leading to a 5/4/4/7-ring system, the originally proposed structure of aquatolide, was also developed. This strategy achieved syntheses of five more humulanolides, (-)-asteriscunolides A, C, D, and I, and (+)-tetradehydroasteriscanolide.

Enantioselective Total Synthesis of (-)-Misramine.

The enantioselective total synthesis of an unusual pentacyclic proaporphine alkaloid, (-)-misramine, was achieved. The synthetic strategy relied on an enantioselective intramolecular Friedel-Crafts-type 1,4-addition using an asymmetric organocatalyst to construct a spiroindane skeleton containing an all-carbon quaternary stereocenter and a double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. This work is the first example of asymmetric synthesis of a proaporphine alkaloid.

Total Synthesis of Clavilactones.

Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that were isolated from cultures of the fungus Clitocybe clavipes. Here, we report full details of the total synthesis of these clavilactones. A key feature of our synthetic approach is a ring-opening/ring-closing metathesis strategy that allows the concise transformation of a cyclobutenecarboxylate into a γ-butenolide. Coupled with enantioselective Ti/BINOL-catalyzed alkynylation of a multisubstituted benzaldehyde and ring-closing metathesis of a diene-bearing silylene acetal to construct the 10-membered carbocycle, this strategy enabled the total synthesis of the natural enantiomers (+)-clavilactone A and (-)-clavilactone B. In addition, the correct structure of clavilactone D was determined by the synthesis of two newly proposed structures. This research resulted in the asymmetric synthesis of the revised (+)-clavilactone D.

Synthesis and evaluation of biological activities of vibsanin A analogs.

Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs.

Total Synthesis and Structural Revision of Clavilactone†D.

A structural revision of clavilactone D, a potent inhibitor of protein tyrosine kinases, was achieved by total syntheses of two newly proposed structures. The syntheses relied on ring-opening/ring-closing metathesis, which transformed a cyclobutenecarboxylate into a γ-butenolide. The syntheses confirmed that the correct structure of clavilactone D has an amino group at C-3 instead of a hydroxy group at C-2 in the originally proposed structure.

Enantioselective Organocatalytic Construction of Spiroindane Derivatives by Intramolecular Friedel-Crafts-Type 1,4-Addition.

The highly enantioselective organocatalytic construction of spiroindanes containing an all-carbon quaternary stereocenter by intramolecular Friedel-Crafts-type 1,4-addition is described. The reaction was catalyzed by a cinchonidine-based primary amine and accelerated by water and p-bromophenol. A variety of spiro compounds containing quaternary stereocenters were obtained with excellent enantioselectivity (up to 95 % ee). The reaction was applied to the asymmetric formal synthesis of the spirocyclic natural products (-)-cannabispirenones A and B.

Identification of seco-clavilactone B as a small-molecule actin polymerization inhibitor.

Phenotype-based chemical screening is an attractive strategy for the identification of bioactive compounds. We searched for a compound that induces cellular morphological change and identified a novel compound that we named seco-clavilactone B (Seco-CB). Treatment with Seco-CB decreased the ratio of filament actin (F-actin) to globular actin (G-actin). An in vitro actin polymerization assay revealed that Seco-CB inhibited actin polymerization directly. Further analysis demonstrated that the inhibitory effect of Seco-CB on actin polymerization was associated with Seco-CB binding to either Thr5 or Cys285 of actin. These data indicate that Seco-CB is a novel actin polymerization inhibitor.

Total Synthesis of (+)-Cytosporolide A via a Biomimetic Hetero-Diels-Alder Reaction.

The first total synthesis of (+)-cytosporolide A was achieved by a biomimetic hetero-Diels-Alder reaction of (-)-fuscoatrol A with o-quinone methide generated from (+)-CJ-12,373. The dienophile, highly oxygenated caryophyllene sesquiterpenoid (-)-fuscoatrol A, was synthesized from the synthetic intermediate in our previous total synthesis of (+)-pestalotiopsin A. The o-quinone methide precursor, isochroman carboxylic acid (+)-CJ-12,373, was synthesized through a Kolbe-Schmitt reaction and an oxa-Pictet-Spengler reaction. The hetero-Diels-Alder reaction of these two compounds proceeded with complete chemo-, regio-, and stereoselectivity to produce the complicated pentacyclic ring system of the cytosporolide skeleton. This total synthesis unambiguously demonstrates that natural cytosporolide A has the structure previously suggested.

Total synthesis of (+)-vibsanin A.

The first total synthesis of (+)-vibsanin A, an 11-membered vibsane diterpenoid, was achieved, unambiguously establishing its relative and absolute stereochemistry. Highlights of the synthesis include the stereoselective formation of an all-carbon quaternary stereocenter by a zinc-mediated Barbier-type allylation in an aqueous medium, and the efficient construction of an 11-membered ring skeleton by a combination of an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction and a Mitsunobu reaction.