Studies on Instructive Construction of exo-Olefin Terminated Five- and Six-Membered Nitrogen Heterocycles: SmI-Mediated Intramolecular Cyclization of Haloalkynals.

Stereoselective construction of exo-olefin terminated pyrrolidine and piperidine frameworks was developed by employing SmI-mediated intramolecular radical cyclization of haloalkynaks. The radical cyclization affording 2,3-disubstituted pyrrolidines and piperidines proceeded in a highly stereoselective manner. However, decreasing stereoselectivety was observed in the preparation of 2,4-disubstituted pyrrolidine and 3,4-disubstituted piperidine derivatives in the cyclization.

Covalent anthocyanin-flavonol complexes from the violet-blue flowers of Allium 'Blue Perfume'.

Three covalent anthocyanin-flavonol complexes (pigments 1-3) were extracted from the violet-blue flower of Allium 'Blue Perfume' with 5% acetic acid-MeOH solution, in which pigment 1 was the dominant pigment. These three pigments are based on delphinidin 3-glucoside as their deacylanthocyanin and were acylated with malonyl kaempferol 3-sophoroside-7-glucosiduronic acid or malonyl-kaempferol 3-p-coumaroyl-tetraglycoside-7-glucosiduronic acid in addition to acylation with acetic acid. By spectroscopic and chemical methods, the structures of these three pigments 1-3 were determined to be: pigment 1, (6(I)-O-(delphinidin 3-O-(3(I)-O-(acetyl)-β-glucopyranoside(I))))(2(VI)-O-(kaempferol 3-O-(2(II)-O-(3(III)-O-(β-glucopyranosyl(V))-β-glucopyranosyl(III))-4(II)-O-(trans-p-coumaroyl)-6(II)-O-(β-glucopyranosyl(IV))-β-glucopyranoside(II))-7-O-(β-glucosiduronic acid(VI)))) malonate; pigment 2, (6(I)-O-(delphinidin 3-O-(3(I)-O-(acetyl)-β-glucopyranoside(I))))(2(VI)-O-(kaempferol 3-O-(2(II)-O-β-glucopyranosyl(III))-β-glucopyranoside(II))-7-O-(β-glucosiduronic acid(VI)))); and pigment 3, (6(I)-O-(delphinidin 3-O-(3(I)-O-(acetyl)-β-glucopyranoside(I))))(2(VI)-O-(kaempferol 3-O-(2(II)-O-(3(III)-O-(β-glucopyranosyl(V))-β-glucopyranosyl(III))-4(II)-O-(cis-p-coumaroyl)-6(II)-O-(β-glucopyranosyl(IV))-β-glucopyranoside(II))-7-O-(β-glucosiduronic acid(VI)))) malonate.

Investigation of innovative synthesis of biologically active compounds on the basis of newly developed reactions.

Synthesis of biologically active compounds, including natural products and pharmaceutical agents, is an important and interesting research area since the large structural diversity and complexity of bioactive compounds make them an important source of leads and scaffolds in drug discovery and development. Many structurally and also biologically interesting compounds, including marine natural products, have been isolated from nature and have also been prepared on the basis of a computational design for the purpose of developing medicinal chemistry. In order to obtain a wide variety of derivatives of biologically active compounds from the viewpoint of medicinal chemistry, it is essential to establish efficient synthetic procedures for desired targets.

Alkenylresorcinols and cytotoxic activity of the constituents isolated from Labisia pumila.

Phytochemical investigation on the leaves of Labisia pumila (Myrsinaceae), an important medicinal herb in Malaysia, has led to the isolation of 1-O-methyl-6-acetoxy-5-(pentadec-10Z-enyl)resorcinol (1), labisiaquinone A (2) and labisiaquinone B (3). Along with these, 16 known compounds including 1-O-methyl-6-acetoxy-5-pentadecylresorcinol (4), 5-(pentadec-10Z-enyl)resorcinol (5), 5-(pentadecyl)resorcinol (6), (-)-loliolide (7), stigmasterol (8), 4-hydroxyphenylethylamine (9), 3,4,5-trihydroxybenzoic acid (10), 3,4-dihydroxybenzoic acid (11), (+)-catechin (12), (-)-epicatechin (13), kaempferol-3-O-α-rhamnopyranosyl-7-O-β-glycopyranoside (14), kaempferol-4'-O-β-glycopyranoside (15), quercetin-3-O-α-rhamnopyranoside (16), kaempferol-3-O-α-rhamnopyranoside (17), (9Z,12Z)-octadeca-9,12-dienoic acid (18) and stigmasterol-3-O-β-glycopyranoside (19) were also isolated. The structures of these compounds were established on the basis of 1D and 2D NMR spectroscopy techniques (¹H, ¹³C, COSY, HSQC, NOESY and HMBC experiments), mass spectrometry and chemical derivatization.

Protection against dopaminergic neurodegeneration in Parkinson's disease-model animals by a modulator of the oxidized form of DJ-1, a wild-type of familial Parkinson's disease-linked PARK7.

DJ-1, Parkinson's disease PARK7, acts as an oxidative stress sensor in neural cells. Recently, we identified the DJ-1 modulator UCP0054278 by in silico virtual screening. However, the effect of the peripheral administration of UCP0054278 on an in vivo Parkinson's disease (PD) model is unclear.

The blue anthocyanin pigments from the blue flowers of Heliophila coronopifolia L. (Brassicaceae).

Six acylated delphinidin glycosides (pigments 1-6) and one acylated kaempferol glycoside (pigment 9) were isolated from the blue flowers of cape stock (Heliophila coronopifolia) in Brassicaceae along with two known acylated cyanidin glycosides (pigments 7 and 8). Pigments 1-8, based on 3-sambubioside-5-glucosides of delphinidin and cyanidin, were acylated with hydroxycinnamic acids at 3-glycosyl residues of anthocyanidins. Using spectroscopic and chemical methods, the structures of pigments 1, 2, 5, and 6 were determined to be: delphinidin 3-O-[2-O-(β-xylopyranosyl)-6-O-(acyl)-β-glucopyranoside]-5-O-[6-O-(malonyl)-β-glucopyranoside], in which acyl moieties were, respectively, cis-p-coumaric acid for pigment 1, trans-caffeic acid for pigment 2, trans-p-coumaric acid for pigment 5 (a main pigment) and trans-ferulic acid for pigment 6, respectively.

Integral stereocontrolled synthesis of a spiro-norlignan, sequosempervirin A: revision of absolute configuration.

A novel synthetic path to sequosempervirin A was established by employing a samarium diiodide promoted intramolecular Barbier-type reaction of the lactonic iodide, in which the key structural feature, a spiro[4.5]decane ring system, could be constructed by controlling the stereochemistry of the hydroxyl group at the 8-position. The absolute configuration of natural sequosempervirin A was revised to be 4S based on this synthesis.

Total synthesis of a novel tetracyclic alkaloid, cassiarin F from the flowers of Cassia siamea.

A novel alkaloid, cassiarin F (1), which showed potent antiplasmodial activity against Plasmodium falciparum in vitro, was isolated from the flowers of Cassia siamea, and its structure was elucidated on the basis of 2D NMR analyses. A total synthesis of 1 was also achieved by employing the Suzuki coupling constructing biaryl unit, nucleophilic aromatic substitution, and Houben-Hoesch type ring construction as key steps.

Structural features of polyacylated anthocyanins using matrix-assisted laser desorption/ionization and electrospray ionization time-of-flight mass spectrometry.

In our continuing studies to isolate water-soluble vacuolar pigments, we expect to elucidate more structural details using mass spectrometry (MS). Because of its sensitivity, only a small amount of pigment extracted from natural plants is required for MS measurement. Nuclear magnetic resonance is also a useful spectroscopic method for structural determination.

Efficient total synthesis of (-)-stemoamide.

An efficient diastereoselective synthesis of (-)-stemoamide has been accomplished from a pyroglutamic acid derivative in eight steps and with 24% overall yield. The synthesis features an intramolecular samarium diiodide-promoted 7-exo-trig cyclization of a ketyl radical generated from the corresponding aldehyde.

Diastereoselective syntheses of functionalized five-membered carbocycles and heterocycles by a SmI2-promoted intramolecular coupling of bromoalkynes and alpha,beta-unsaturated esters.

An intramolecular coupling of bromoalkynes with alpha,beta-unsaturated esters afforded functionalized five-membered carbocycles and heterocycles with high diastereoselectivities in excellent yields. The vinyl bromides newly generated as the products serve as adequate intermediates for further chemical modification.

Vasodilator effect of Cassiarin A, a novel antiplasmodial alkaloid from Cassia siamea, in rat isolated mesenteric artery.

The aim of this study was to investigate the vasorelaxant effect induced by cassiarin A, a novel antiplasmodial alkaloid from Cassia siamea, in rings cut from rat superior mesenteric arteries. In rings precontracted with phenylephrine, cassiarin A induced a concentration-dependent relaxation. This relaxation was attenuated: 1) after removal of the endothelium or after pretreatment of rings with 100 microM of N(G)-nitro-L-arginine (nitric oxide synthase inhibitor) or 10 microM of 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (guanylyl cyclase inhibitor), but not after pretreatment with 10 microM of indomethacin (cyclooxygenase inhibitor); and 2) after pretreatment of preparations with either a nonselective or selective inhibitor of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels [1 mM of tetraethylammonium or 100 nM of iberiotoxin, respectively].

Synthesis and structure-activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity.

Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria.

Analyses of biologically active steroids: antitumor active OSW-1 and cardiotonic marinobufotoxin, by matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight tandem mass spectrometry.

Naturally occurring constituents of biological or pharmaceutical interest often exist in the form of glycosides or conjugates. Mass spectral investigations of these compounds require soft ionization techniques if information on molecular mass, sugar sequence, or conjugate content is desired. In this study, matrix-assisted laser desorption/ionization (MALDI) quadrupole ion trap (QIT) time-of-flight tandem mass spectrometry (TOF-MS(n)) was used to identify both OSW-1, an acetylated cholestane diglycoside showing antitumor activity, and the cardiotonic steroid, bufotoxin.

An unusual acylated malvidin 3-glucoside from flowers of Impatiens textori Miq. (Balsaminaceae).

Acylated malvidin 3-glucoside was isolated from the purple flowers of Impatiens textori Miq. as a major anthocyanin component along with malvidin 3-(6''-malonyl-glucoside). Its structure was elucidated to be malvidin 3-O-[6-O-(3-hydroxy-3-methylglutaryl)-beta-glucopyranoside] by chemical and spectroscopic methods.

Efficient diastereoselective synthesis of trifarane-type sesquiterpenes, trifarienols A and B.

Diastereoselective total synthesis of trifarienols A and B, trifarane-type sesquiterpenes isolated from the Malaysian Cheilolejeunea trifaria, was achieved via an intramolecular Hosomi-Sakurai reaction of the aldehyde to construct a substituted bicyclo[3.3.1]nonane skeleton having the exo-methylene moiety of the target compounds in one step.

Facile synthesis of a benzindenoazepine alkaloid, bulgaramine, via samarium diiodide promoted ring expansion of an alpha-aminocarbonyl compound.

A novel synthetic path to a benzindenoazepine alkaloid was established by employing a samarium diiodide promoted ring expansion reaction of an alpha-aminocarbonyl compound as a key reaction, in which a regioselective carbon-nitrogen bond cleavage followed by ring-closing reactions occurred to give the basic ring skeleton of the target compound. Bulgaramine was synthesized from the known tetrahydroisoquinoline derivative in 5 steps in 50% overall yield.

Protection against oxidative stress-induced neurodegeneration by a modulator for DJ-1, the wild-type of familial Parkinson's disease-linked PARK7.

Although a loss-of-function type mutation was identified in familial Parkinson's disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we found a DJ-1 modulator UCP0054278 by in silico virtual screening. In this study, we determined the neuroprotective effects of UCP0054278 against focal ischemia-induced neurodegeneration in rats.

Practical ruthenium-catalyzed cyclocarbonylation of allenyl alcohols in 2,4,6-collidine leading to alpha,beta-unsaturated lactones: concise stereoselective synthesis of (+)-isomintlactone.

We have found that ruthenium-catalyzed cyclocarbonylation of allenyl alcohols in 2,4,6-collidine under atmospheric pressure of carbon monoxide smoothly proceeds to afford alpha,beta-unsaturated five- and six-membered lactones in moderate to good yields. Furthermore, we have completed a highly stereoselective synthesis of (+)-isomintlactone by the cyclocarbonylation of allenyl alcohol using 2,4,6-collidine.

Diastereoselective synthesis of N-Boc-norpandamarilactonine-B and pandamarilactonine-A.

Optically pure N-Boc-norpandamarilactonine-B was diastereoselectively synthesized starting from L-serine by employing a double ring closing metathesis (RCM) of a tetraene derivative as a key reaction. N-Boc-norpandamarilactonine-B obtained was further converted to pandamarilactonine-A.

Chrobisiamone A, a new bischromone from Cassia siamea and a biomimetic transformation of 5-acetonyl-7-hydroxy-2-methylchromone into cassiarin A.

A new bischromone, chrobisiamone A (1) with an antiplasmodial activity has been isolated from the leaves of Cassia siamea and the structure was elucidated by 2D NMR analysis. Cyclization of 5-acetonyl-7-hydroxy-2-methylchromone (2) in the presence of ammonium acetate resulted in generation of cassiarin A (3) with an unprecedented tricyclic skeleton, supporting a biogenetic pathway proposed for 3.

Tetra-acylated cyanidin 3-sophoroside-5-glucosides from the flowers of Iberis umbellata L. (Cruciferae).

The structures of 11 acylated cyanidin 3-sophoroside-5-glucosides (pigments 1-11), isolated from the flowers of Iberis umbellata cultivars (Cruciferae), were elucidated by chemical and spectroscopic methods. Pigments 1-11 were acylated with malonic acid, p-coumaric acid, ferulic acid, sinapic acid and/or glucosylhydroxycinnamic acids. Pigments 1-11 were classified into four groups by the substitution patterns of the linear acylated residues at the 3-position of the cyanidin.