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The convergent synthesis of thiophene-3-carboxamide analogues of annonaceous acetogenins was accomplished through the asymmetric alkynylation of a 2-formyl THF ring fragment with an alkyne having a thiophene ring as the key step. Eight stereoisomers of the THF ring moiety were synthesized by this convergent route and their antiproliferative activities against 39 human cancer cell lines were evaluated. It was revealed that derivatives having the threo configuration between C17–C18 positions showed more potent activities than the corresponding erythro ones.

A practical method for the synthesis of chiral β2,3-amino esters having various substituents was developed, which is characterized by an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. We found that a highly face-selective protonation occurred by the quick addition of water to the enolate intermediate derived from the Michael addition reaction to afford N-protected β2,3-amino esters in moderate to excellent yields. This finding was made possible by the facile preparation of geometrically pure trisubstituted (E)-α,β-unsaturated esters, which was established recently by our group. The subsequent deprotection of the amino group in the Michael adduct by using N-iodosuccinimide (NIS) efficiently provided β2,3-amino esters having various substituents.

Homotypic fusion of early endosomes is important for efficient protein trafficking and sorting. The key controller of this process is Rab5 which regulates several effectors and PtdInsPs levels, but whose mechanisms are largely unknown. Here, we report that vicenistatin, a natural product, enhanced homotypic fusion of early endosomes and induced the formation of large vacuole-like structures in mammalian cells. Unlike YM201636, another early endosome vacuolating compound, vicenistatin did not inhibit PIKfyve activity in vitro but activated Rab5-PAS pathway in cells. Furthermore, vicenistatin increased the membrane surface fluidity of cholesterol-containing liposomes in vitro, and cholesterol deprivation from the plasma membrane stimulated vicenistatin-induced vacuolation in cells. These results suggest that vicenistatin is a novel compound that induces the formation of vacuole-like structures by activating Rab5-PAS pathway and increasing membrane fluidity. Vicenistatin is a novel compound that induces the formation of vacuole-like structures by activating Rab5-PAS pathway and increasing membrane fluidity.

A skeletal transformation of α-pyrones having electron-withdrawing groups at the 3,5-positions into dihydrofurans was developed. Using dimethylsulfoxonium methylide as the methylene-transfer reagent, the α-pyrones were converted into dihydrofurans as major products and 1-methylthiopyran-1-oxides as minor products. The selectivity of the dihydrofuran formation was improved by optimizing the reaction conditions.

2,2′-Binaphthyl-3,3′-dicarbonyl cyanide possessing two reaction sites was designed and synthesized as a new chromophoric reagent for exciton-coupled circular dichroism (ECCD), which is more effective in determination of the absolute stereochemistry of the target chiral alcohols than 2,2′-binaphthyl-3-methoxycarbonyl-3′-carbonyl cyanide, which contains only one reaction site. The CD spectra of the 2,2′-binaphthyl diesters derived from chiral secondary alcohols show bisignate curves centered at 240 nm, of which the Δe value was roughly twice as large as that of the binaphthyl methyl monoester.

The syntheses of three thiophene-3-carboxamide analogs of annonaceous acetogenins were accomplished, where the obtained analogs bear ethylene glycol units that enhance their water solubilities. Evaluation of their growth inhibitory activities across 39 human cancer cell lines revealed that the analog bearing one ethylene glycol unit in the vicinity of its tetrahydrofuran ring moiety exhibited a comparable potent growth inhibitory activity to the lead compound, and the growth inhibitory patterns of these analogs are similar to those of mitochondrial complex I inhibitors. This result indicates the possibility of discovering new water-soluble antitumor agents derived from acetogenins through the introduction of ethylene glycol units.

Pyrrolophenanthridinone derivatives including the natural products were readily synthesized by samarium(II)-mediated reductive cyclization of aryl radical onto a benzene ring under mild reaction conditions. This methodology was applied to the concise synthesis of anhydrolycorinone, a natural pyrrolophenanthridinone and a precursor of hippadine and anhydrolycorine.

An asymmetric intramolecular Heck reaction that involves the dynamic kinetic resolution of an atropisomer as the substrate furnished a product in high yield with high enantioselectivity. DFT calculations (Spartan'10, B3LYP/6-31G*) confirmed that the reaction proceeded via atropisomerization involving a conformational transformation (half-chair form/distorted-boat form) of the substrate.

The convergent synthesis of the dansyl-labeled probe of the thiophene-3-carboxamide analogue of annonaceous acetogenins, which shows potent antitumor activity, was accomplished by two asymmetric alkynylations of the 2,5-diformyl THF equivalent with an alkyne having a thiophene moiety and another alkyne tagged with a dansyl group. The growth inhibitory profiles toward 39 human cancer cell lines revealed that the probe retained the biological function of its mother compound, and would be useful for studying cellular activity.

A skeleton transformation of 5-aryl-α-pyrones into dihydrofurans was developed. In the course of our study of the skeleton transformation reaction of α-pyrones by using dimethylsulfoxonium methylide, α-pyrones having an aryl group at the 5-position were converted into corresponding dihydrofurans as major products and bicyclo[3.1.0]hexanes as minor products. Selectivity for dihydrofurans was improved by optimizing the reaction conditions and investigating the substituent effect.

The first asymmetric total synthesis of (+)-taiwaniaquinol D and (−)-taiwaniaquinone D isolated from Taiwania cryptomerioides was attained by using the intramolecular asymmetric Heck reaction. The reaction provided a tricyclic intermediate that would be available for the asymmetric total synthesis of various abeo-abietane-type diterpenoids.

By applying a skeleton transformation reaction using dimethylsulfoxonium methylide, a novel reaction was identified by which 5,6,7,8-tetrahydrocoumarin with the electron-withdrawing group at C3 was led to the spirobicyclo[3.1.0]hexane-cyclohexane derivative. Moreover, by establishing the scope of this reaction, it was confirmed that it is possible to apply this reaction to not only ring-fused α-pyrone derivatives but also alkyl-chain-substituted α-pyrone derivatives in moderate to good yields.

The first total synthesis of (±)-adunctin B ( 1 ), a natural product isolated from Piper aduncum (Piperaceae) and having antibacterial activity, was achieved in 1.26% overall yield in 15 steps from 5,7-dimethoxycoumarin-3-carboxylate ( 8 ).

We report a samarium(II)-mediated tandem spirocyclization reaction to provide dispiro[4.2.4.2]tetradecadiene and dispiro[4.2.5.2]pentadecadiene skeletons. The reaction was achieved by intramolecular addition of a ketyl radical onto an aromatic ring bearing an electrophilic moiety followed by reductive capture of the spirohexadienyl radical intermediate with SmI2 in the presence of HMPA.

A novel method for indole skeleton synthesis under mild conditions mediated by samarium(II) diiodide has been developed. The reaction of N-allenyl-2-iodoaniline derivatives with SmI2 in the presence of HMPA and i-PrOH at 0 °C afforded indole derivatives in high yields.

C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH–ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural acetogenins.

Circular dichroism (CD) spectra of the 2,2′-binaphthyl ester derived from Δ 5 -sterols showed not bisignate CD but diagnostic CD bands at around 210 and 240 nm. These bands might be attributable to an interaction between an olefinic chromophore and a binaphthyl one. Various types of unsaturated sterols were thus derivatized followed by complete hydrogenation, to give saturated sterols. As a result, CD spectra of the binaphthyl derivatives of the saturated sterols showed bisignate curves centered at 240 nm (3 S (β): positive chirality; 3 R (α): negative one). This suggested a straightforward and practical method for discriminating the absolute stereogenic center at the C-3 positions of sterols based on an induced CD. This finding should contribute significantly to the analysis of metabolites of various types of sterols.

Background and aims A number of previous studies had revealed the association between trace elements in serum and bronchial asthma. However, only a few researches had focused on serum concentration of trace elements in a general population. In this study, an association between trace elements in serum and bronchial asthma was investigated in a general population. Methods Subjects were 1025 volunteers (385 males and 640 females between ages 19 and 82 years old) who had participated in the Iwaki Health Promotion Project 2005. Bronchial asthma was diagnosed based on the European Community Respiratory Health Survey II according to the self-questionnaires on health conditions of subjects. The serum concentrations of certain trace elements (manganese, copper, zinc, selenium and iron) were measured and compared. Also, an association between serum trace elements level and neutrophil-related functions (oxidative burst activity, phagocytic activity, serum opsonic activity) were determined. Results In males, no significant differences were seen in any serum trace elements concentrations. In females, serum zinc level was significantly higher in bronchial asthma group than in control. A positive correlation was seen between serum concentration of zinc and serum opsonic activity in both genders. Conclusions In female asthmatics, increase of oxidative stress was suggested to be caused by superoxide dismutase pathway (elimination system of reactive oxygen species) rather than serum opsonic activity (production system of reactive oxygen species from neutrophils) pathway, as the zinc concentration in bronchial asthma group was higher than that in control.