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Malaria disease remains a serious worldwide health problem. In South-East Asia, one of the malaria infection "hot-spots," medicinal plants such as Piper betle have traditionally been used for the treatment of malaria, and allylpyrocatechol (1), a constituent of P. betle, has been shown to exhibit anti-malarial activities. In this study, we verified that 1 showed in vivo anti-malarial activity through not only intraperitoneal (i.p.) but also peroral (p.o.) administration. Additionally, some analogs of 1 were synthesized and the structure-activity relationship was analyzed to disclose the crucial sub-structures for the potent activity.

Africa Trypanosomiasis remains a serious health problem, but the approved drugs for this disease are so few that novel trypanocidal compounds are demanded. In search for trypanocidal principles from medicinal plants, we found MeOH extracts of Meliae Cortex with potent activity through the screening from about 300 kinds of methanolic extract. By bioassay-guided fractionation from this extract through the liquid-liquid partition and subsequent chromatographic technique using silica gel and ODS, finally we disclosed toosendanin (1) and its relatives as active principles. These active congeners showed not only potent trypanocidal activity but also little cytotoxicity to display the excellent selective index. Taking the isolated amount as well as trypanocidal activity into consideration, 1 was disclosed to be the responsible active principle in Meliae Cortex. Additionally, the derivatives of 1 were chemically prepared from 1 and bioactivity of them were also evaluated. Through the comparison with their trypanocidal activity among the isolated relatives and the synthesized derivatives of 1, the epoxide moiety was revealed to be essential for their potent trypanocidal activity. Furthermore, 3-O-acetyl group and 7-hydroxyl group were presumed to be important functional groups and introduction of methylpropionyl group into hemiacetal hydroxy moiety was clarified to enhance their typanocidal activity.

Malaria disease remains a serious worldwide health problem. In South-East Asia, one of the malaria infection "hot-spots," medicinal plants such as Piper betle have traditionally been used for the treatment of malaria, and allylpyrocatechol (1), a constituent of P. betle, has been shown to exhibit anti-malarial activities. In this study, we verified that 1 showed in vivo anti-malarial activity through not only intraperitoneal (i.p.) but also peroral (p.o.) administration. Additionally, some analogs of 1 were synthesized and the structure-activity relationship was analyzed to disclose the crucial sub-structures for the potent activity.

Africa Trypanosomiasis remains a serious health problem, but the approved drugs for this disease are so few that novel trypanocidal compounds are demanded. In search for trypanocidal principles from medicinal plants, we found MeOH extracts of Meliae Cortex with potent activity through the screening from about 300 kinds of methanolic extract. By bioassay-guided fractionation from this extract through the liquid-liquid partition and subsequent chromatographic technique using silica gel and ODS, finally we disclosed toosendanin (1) and its relatives as active principles. These active congeners showed not only potent trypanocidal activity but also little cytotoxicity to display the excellent selective index. Taking the isolated amount as well as trypanocidal activity into consideration, 1 was disclosed to be the responsible active principle in Meliae Cortex. Additionally, the derivatives of 1 were chemically prepared from 1 and bioactivity of them were also evaluated. Through the comparison with their trypanocidal activity among the isolated relatives and the synthesized derivatives of 1, the epoxide moiety was revealed to be essential for their potent trypanocidal activity. Furthermore, 3-O-acetyl group and 7-hydroxyl group were presumed to be important functional groups and introduction of methylpropionyl group into hemiacetal hydroxy moiety was clarified to enhance their typanocidal activity.

The envelope proteins of the hepatitis C virus (HCV), E1 and E2, have been revealed to be essential for invasion of HCV. Thus, we were engaged in the search for the inhibitors against HCV invasion through the assay system using the model virus expressing recombinant HCV envelopes, E1 and E2. Now, we disclosed dimeric hydrolysable tannin oenothein B (1) from MeOH extract of Oenothera erythrosepala as an active principle for inhibition of HCV invasion and its potency was almost the same as that of monomeric hydrolysable tannin, tellimagrandin I (2). Furthermore, by use of stereoselectively prepared 1-β- and 1-α-O-methyl tellimagrandin Is (4 and 5), the introduction of methyl moiety into 1-hydroxy group of 2 was clarified to result in slightly reduction of activity and β-isomer was revealed to exhibit a little stronger activity than α-one.

We found out 2′,3′-dihydroxypuberulin from South American medicinal plant, V. thapsus L., as a candidate of an anti-allergic lead which inhibits the expression of high-affinity receptor of IgE (FceRI) on the surface of mast cells. Furthermore, the analysis of structure-activity relationship by using synthesized 2′,3′-dihydroxypuberulin analogs revealed that both hydroxy groups in the side chain and both of methyl moieties on phenolic hydroxy groups were crucial for potent activity, but absolute configuration of C-3′ position wasn’t. The active principle, 2′,3′-dihydroxypuberulin, was disclosed to down-regulate the mRNA level of β-chain of FceRI, different from previous reported active natural product reducing γ-chain level.

A new synthetic strategy for obtaining artificial receptors that selectively regulate and/or control specific protein/protein interactions was developed based on the template-assisted and the self-activating click reaction applied to a combinatorial library. Synthetic mimics of the Grb2-SH2 domain, examined as a model case, selectively bound to a target signaling protein to induce cytotoxicity and inhibit tumor growth in vivo.

Nuclear export signal (NES)-mediated export of MEK and Rev from the nucleus to the cytoplasm is revealed to be essential for proliferation of tumor cells and viral multiplication of HIV. In this context, we have been engaged in explore medicinal leads by using medicinal plant originated natural products with inhibitory potency for nuclear export of NES-containing proteins as seed principles. By use of the bioassay monitoring MEK directly, the unprecedented NES non-antagonistic MEK-export inhibitor, peumusolide A (5), was disclosed. Furthermore, this principle was shown to act in the NES non-antagonistic mode by the synthesized probe and display selective cytotoxicity for MEK-activated tumor cells. Additionally, we developed the stereo-controlled synthesis of the core structure of 5, presenting all four stereoisomers from the common starting material. By application of this procedure, the first total synthesis of 5 as well as exploration of the antitumor leads with the novel mechanism of action has been accomplished. With respect to Rev-export inhibitor valtrate (3), the synthesis of 5,6-dihydroanalog (24), rationally designed with the aid of MO calculation, presented the alternative bioisosteric seed principle. By utilizing this bioisotere as the scaffold, the new anti-HIV lead with enhanced Rev-export inhibitory potency in comparison with 3 and 24 has been disclosed.

Many pathogenic viruses, such as the influenza virus and the Human Immunodeficiency Virus (HIV)-1, are a threat to humans, thus leading to thousands of deaths annually. The development of antiviral drugs is urgent, and it is an essential strategy for the suppression of these infectious diseases. However, regardless of the rapid emergence of many infectious diseases, the development of novel antiviral drugs has been slow, except for the case of the AIDS. In addition, several viruses can easily mutate and escape the inhibitory activity of anti-viral drugs. It was already well-established that HIV escapes from anti-viral drug effects because of the lack of proofreading activity in its reverse transcriptase. It is known that the influenza virus, which is resistant to Tamiflu, is already spread all over the world. Viruses utilize the host cell environment and cellular factors to propagate. Therefore, the development of novel drugs which inhibit viral protein-host protein interactions or cellular functions appear to be good candidates. The influenza virus is unique in replicating in host nuclei, and we therefore focused on the nuclear export processes for the development of anti-influenza viral drugs. We previously reported that leptomycin B (LMB), which inhibited the nuclear export processes via the nuclear export signal (NES) inhibited the nuclear export of influenza viral RNP (vRNP), and resulted in the inhibition of influenza viral propagation. We herein examined novel CRM1 inhibitors, valtrate from Valerianae Radix, and 1'-acetoxychavicol acetate (ACA) from Alpinia galanga as potent inhibitors for the influenza virus replication.

The first total synthesis of peumusolide A (1) has been achieved by combination of regio- and stereo-selective aluminum-mediated hydroiodination to 2-yn-1-ol and enantioselective reduction of 4-en-1-yn-3-one with the chiral oxazaborolidine as the key reactions. This total synthesis has unequivocally established our proposed absolute structure of 1.

Bioassay-guided separation of the extract of the medicinal plant, Puerariae Flos, disclosed the two isoflavones tectorigenin (1) and genistein (2) as the inhibitors for expression of IgE receptor (FcepsilonRI), the key molecule triggering the allergic reactions, on human mast cells. As a result of analysis of structure-activity relationship of the naturally occurring and synthesized isoflavones, 7-O-methyl glycitein (11) was disclosed as the more potent inhibitor than tectorigenin (1). These isoflavone ingredients suppressed expression of FcepsilonRI more potently than the active flavonoids found previously. In addition, tectorigenin (1) was clarified to particularly reduce generation of gamma-chain subunit to suppress expression of FcepsilonRI among the three subunits.

By use of the fission yeast expressing the model fusion protein comprised of GST, SV40 T antigen NLS, GFP, and Rev-NES in the bioassay, the prenylcoumarin osthol (1) was disclosed as the new Rev-export inhibitor from the MeOH extract of Cnidii Monnieris Fructus. Furthermore, 1 was also found to inhibit export the genuine Rev in HeLa cells by indirect fluorescent antibody technique. By the competitive experiment using the biotinylated probe 3, osthol (1) was revealed to inhibit nuclear export of Rev through a NES non-antagonistic mode. Structure-activity relationship analysis of several analogs of 1 clarified that both prenyl side chain and double bond adjacent to the lactone carbonyl residue play an important role in the Rev-export inhibitory potency of 1.

Stereo-controlled construction of the core structure of peumusolide A ( 1 ), α-alkylidene-β-hydroxy-γ-methylenebutyrolactone, was developed by a combination of regio- and stereo-selective hydroiodination of 2-yn-1-ol and asymmetric reduction of 1-yn-4-en-3-one as the key reactions. By using this protocol, all the four stereoisomers of the analog of 1 were synthesized from the common starting material.

Exploration for inhibitors against expression of IgE receptor (Fc epsilonRI) on human mast cell, a significant trigger to acute and chronic allergic symptoms, disclosed epigallocatechin gallate (EGCG), epicatechin gallate, and gallocatechin gallate as active principles. Additionally, the anthocyanidin, delphinidin, and the flavone, tricetinidin, possessing a pyrogallol function were also revealed to suppress expression of Fc epsilonRI. Structure-activity relationship analysis among catechins, anthocyanidins, and flavones revealed the pyrogallol moiety to be crucial for biological potency. Furthermore, EGCG was clarified to reduce generation of gamma-chain subunit to suppress expression of Fc epsilonRI on human mast cells.

In the course of search for the robust analogs of 1′-acetoxychavicol acetate (ACA, 1 ), the Rev-export inhibitor from the medicinal plant Alpinia galanga , we clarified formation of the quinone methide intermediate ii to be essential for exerting the inhibitory activity of 1 . Based on this mechanism of action, the rational design from the MO calculation of the conclusive activation energy to ii resulted in the four halogenated analogs with more potent activity than ACA ( 1 ). In particular, the difluoroanalog 20d exhibited approximately four-fold potent activity as compared with 1 .

A new polyketide peumusolide A was disclosed as an unprecedented NES non-antagonistic inhibitor for nuclear export of MEK, a promising scaffold for antitumor agents with novel mechanism of action, from Peumus boldus Molina. The absolute stereostructure as well as optical purity was established by use of the two synthesized enantiomeric model lactones. In addition, the Δe values in their CD spectra were demonstrated to be the conclusive index for determination of not only configuration at C-3 but also optical purity of natural congeneric polyketides. Peumusolide A was revealed to show NES non-antagonistic action by the biotinylated probe and to inhibit proliferation of MEK-activated tumor cells selectively.

Red ginger (Zingiber officinale var. Rubra) has been prescribed as an analgesic for arthritis pain in Indonesian traditional medicine. The surface color of the rhizome is purple because of the anthocyanidins in its peel. We prepared 40% ethanolic extract from dried red ginger (red ginger extract [RGE]) and evaluated its anti-inflammatory activity using acute and chronic inflammation models. In an acetic acid-induced mouse writhing model, RGE (10-100 mg/kg) suppressed both the frequency of writhing and the increase in permeability of abdominal capillaries. On the other hand, continuous treatment with RGE (10 mg/kg) significantly (P.05) suppressed footpad edema in a rat adjuvant arthritis model. To clarify the anti-inflammatory mechanism of RGE, we examined the effect on prostaglandin (PG) and nitric oxide (NO) production from mouse leukemic monocytes (RAW264 cells) stimulated by lipopolysaccharide. RGE (3 and 10 microg/mL) significantly (P.05) suppressed PGE(2) production, while it also suppressed NO production at 100 microg/mL. After bioassay-guided separation of RGE, we found that [6]-shogaol and gingerdiols suppressed NO production. Red dye fractions presumed to be proanthocyanidins also suppressed NO production at 100 microg/mL. Consequently, we found a potent suppressive effect of RGE on acute and chronic inflammation, and inhibition of macrophage activation seems to be involved in this anti-inflammatory effect. [6]-Shogaol, gingerdiols, and proanthocyanidins were identified as constituents that inhibited NO production.

Two analogues possessing steric hindered substituents on C-15 of arenastatin A (1), a potent cytotoxic spongean depsipeptide, were synthesized and shown to enhance stability in mouse serum. Notably, 15-tert-butylanalogue (6) with higher cytotoxicity exhibited in vivo anti-tumor activity through iv administration different from 1. Additionally, conformation analysis among the two analogues and arenastatin A (1) indicated that the torsion angle from C-14 to C-20 is a conclusive factor for the potent cytotoxicity of 1.

On the basis of a comparative analysis for stability in mouse serum between 15-O-acetylbruceolide and bruceolide 15-methyl carbonate, several 3,15-dialkyl carbonates of bruceolide were synthesized and their in vitro antimalarial activity was assessed. Methyl, ethyl, and isopropyl carbonates with pronounced in vitro activity were further evaluated for in vivo antimalarial potency. Both the methyl and ethyl carbonates significantly increased the life span of mice as compared with 3,15-di-O-accetylbruceolide and chloroquine.

Two new long-chain acetylene alcohols named lembehynes B ( 2 ) and C ( 3 ) were isolated from an Indonesian marine sponge of Haliclona sp. Lembehynes B ( 2 ) and C ( 3 ), which have different types of long carbon-chain parts compared with that of lembehyne A ( 1 ), also exhibited neuritogenic activity against a neuroblastoma cell line, Neuro 2A. For structure–activity relationship study of lembehynes, analogue-I ( 4 ), analogue-II ( 5 ) and analogue-III ( 6 ), which have different types of long carbon-chain parts, were synthesized from suitable fatty acids. As a result of neurite outgrowth assay for these related compounds, it was revealed that the carbon-chain length is important for neuritogenic activity, while the unsaturated bonds in the long-chain part are not. On the other hand, analogue-IV ( 7 ) with 3 S configuration showed much weaker activity than analogue-III ( 6 ) with 3 R configuration and the same type of long carbon-chain part. This indicates the importance of the stereochemistry of the hydroxyl group at C-3 in lembehynes for neuritogenic activity.

In an explorative study for new anti-malarial substances using the methyl esters (1 and 2) of peroxyplakoric acids A(3) and B(3) as scaffolds, 6-carbomethoxymethyl-3-methoxy-3-pentyl-1,2-dioxane, which has been readily synthesized from 6-keto-alpha,beta-unsaturated ester, was found to exhibit potent anti-malarial activity with high selective toxicity.

Facile construction of 6-carbomethoxymethyl-3-methoxy-1,2-dioxane, the core structure of spongean anti-malarial peroxides, has been developed by combination of Sc(OTf) 3 -mediated peroxyhemiacetalization of keto-ester and Michael addition of the resultant peroxyhemiacetal in the fluorinated alcohol.

In order to produce stable analogs in blood of arenastatin A, a potent cytotoxic depsipeptide from the marine sponge Dysidea arenaria , we synthesized four analogs in which the 15-20 ester linkage was modified. Among them, the carba analog and 20-deoxo analog showed stability in serum. The conformation of arenastatin A and its three analogs were analyzed by distance-restrained molecular dynamic calculation to elucidate a three-dimensional stereostructure contributing to the extremely potent cytotoxicity of arenastatin A.

The participation of the beta-hydroxyketone part of callystatin A in the potent cytotoxicity was analyzed through the analogue-syntheses and the assessment of their biological potencies. The ketonic carbonyl, the 19-hydroxyl, and the three asymmetric methyl groups located in the beta-hydroxyketone part of callystatin A were revealed to contribute to the cytotoxic potency, respectively. Moreover, the alpha,beta-unsaturated delta-lactone portion was shown to serve as a conclusive functional group for the cytotoxic activity.

By use of the model virus, expressing the HCV envelope proteins E1 and E2, bioassay guided separation of the MeOH extract from Rosa rugosa Thunb. disclosed tellimagrandin I (1) together with eugeniin (2) and casuarictin (3) as the potent HCV invasion inhibitors. Furthermore, structure–activity relationship analysis of some relative tannins including the synthesized analogs elucidated the partial structures crucial for potent activity of 1.

Falcarindiol (1) was isolated as an algicidal principle against the harmful red tide dinoflagellate, Heterocapsa circularisquama, from Notopterygii Rhizoma through bioassay-guided separation. In order to determine the ambiguous absolute structure of this active principle, all three stereoisomers as well as falcarindiol (1) were synthesized. As a result of intensive analysis of their physicochemical properties, the configuration of 1 was revealed to be 3R,8S. On the other hand, (3S,8S)- and (3S,8R)-isomers were found to exhibit more potent algicidal activity than (3R,8S)-falcarindiol (1) isolated from Notopterygii Rhizoma. In addition, the diyne moiety of 1 was established as the crucial structural requirement for algicidal potency.

In order to probe the metabolism of arenastatin A, a potent cytotoxic depsipeptide from the marine sponge Dysidea arenaria, we synthesized three analogs in which the ester linkages were replaced by amide bonds. Triamide analog-II and tetraamide analog, both of which contained a 15,20-amide linkage, showed stability in serum. However, arenastatin A and triamide analog-I, which both contained a 15,20-ester moiety, were readily metabolized in serum. Among the three amide analogs, only triamide analog-II exhibited potent cytotoxic activity against KB cells.

4-Deacetoxyagosterol A was synthesized from ergosterol by utilizing reductive regioselective epoxy cleavage as a key reaction. This synthesized congener of agosterol A, a spongean MDR-modulator, showed similar MDR-modulating activity against KB CV-60 cells overexpressing MRP.

Novel mono- O -alkyl-diglycosylglycerols named myrmekiosides A ( 1 ) and B ( 2 ) were isolated from a marine sponge of Myrmekioderma sp. and their absolute stereostructures were elucidated on the basis of chemical and physicochemical evidence. Myrmekiosides A ( 1 ) and B ( 2 ) reversed the phenotype of melanoma H- ras transformed NIH3T3 cells at 5 μg/ml.

The absolute sterestructure of leptomycin B, an antitumor antibiotic and inhibitor of nuclear protein export, was firstly presumed as 1 having 4 S , 5 R , 10 R , 16 R , 18 S , 19 R , 20 S on the basis of NMR comparison with callystatin A ( 2 ) and then 1 was asymmetrically synthesized. The synthesized leptomycin B ( 1 ) was found identical with the authentic sample in HPLC and CD comparison as well as in other respects. This structural elucidation of the absolute stereostructure and total synthesis are the first example among the leptomycin family as Streptomyces metabolites.

Agosterol A (1) has been isolated from a marine sponge of Spongia sp. and the absolute stereo-structure elucidated. Agosterol A (1) is a novel polyhydroxylated sterol acetate, which completely reverses multidrug resistance in human carcinoma cells caused by overexpression of two kinds of membrane glycoprotein.

Novel benzofuro[2,3-d]pyridazinium chlorides fused with thiazole 5a, imidazole 5b-c and pyrimidine 5d-f were prepared starting from 4-chloropyridazino[4,5-b]benzofuran 3a. Treatment of 5b, 5d and 5e with 10% potassium carbonate solution provided the corresponding free bases 6a-c. Ring closure of methyl rotenononate 1b with amidines proceeded in the presence of sodium methoxide to give 1,3-diazepino[5,6-b]benzofuran-5-ones 7a-c. Compound 5d showed cytotoxicity against P388 and L1210 leukemia cells.

A first total synthesis of callystatin A ( 1 ), a potent cytotoxic polyketide from the marine sponge Callyspongia truncata , has been achieved by use of an E -selective Wittig olefination and asymmetric Evans aldol condensation as the key reactions. Thus, the absolute stereostructure of 1 previously established by us was confirmed.

Novel camphor-1,2,4-triazines fused with imidazole 2–3, thiadiazole 4, 1,2,4-triazole 7, pyrimidine 9–13 and 1,3,5-triazine 14, were synthesized starting from (5R,8S)-3-amino-5,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methano-1,2,4-benzotriazine 1. Evaluation of central nervous system stimulant activity demonstrated that the presence of a N-N group at C-3 position of 1,2,4-benzotriazine will be essential for the activity.

Several O -acylated derivatives of bruceolide ( 2 ) were synthesized and their anti-malarial activities together with selective toxicities were examined. It was found that 3,15-di- O -acetyl- ( 3c ), 3,15-di- O -propionyl- ( 3d ) and 15- O -propionylbruceolide ( 3b ), as well as bruceine B ( 3a ), exhibited potent anti-malarial activities with high selective toxicities.

5,8-Methanoquinazolines fused with imidazoles 4a-4b, thiadiazoles 5–6, pyrimidines 7, 9, 11 and 12, and 1,3,5-triazine 13 were prepared starting from (5R,8S)-2-amino-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanoquinazoline 3. Most compounds possessed central nervous system stimulant activities.

The absolute stereostructures of panaxytriol (1) and panaxydol (2), two polyacetylenic constituents of the oriental medicine, Ginseng Radix Rubra, were determined by applying the modified Mosher method, CD exciton chirality method, and chemical conversion to be expressed as (3R,9R,10R)-heptadec-1-ene-4,6-diyne-3,9,10-triol and (3R,9R,10S)-9,10-epoxy-heptadec-1-ene-4,6-diyn-3-ol, respectively. Panaxytriol (1), the characteristic constituent of Ginseng Radix Rubra, was presumed to be formed from panaxydol (2), during the processing of the crude drug, via a regioselective hydrolysis of the epoxy moiety in 2.

Callystatin A (1) has been isolated from the marine sponge, Callyspongia truncata, and the plane structure, including parts of the absolute configurations, is elucidated. Callystatin A (1) is a novel polyketide with a terminal α,β-unsaturated δ-lactone and exhibited potent cytotoxicity against KB cells at IC50 0.01 ng/ml.

Following the characterization of notoginsenosides-A, -B, -C, and -D, new dammarane-type triterpene oligoglycosides, notoginsenosides-E, -G, -H, -I, and -J, and a novel acetylenic fatty acid glycoside, notoginsenic acid β-sophoroside, were isolated from the glycoside fraction with hepatoprotecting activity obtained from the dried roots of Panax notoginseng (BURK.) F. H. CHEN. Their chemical structures were elucidated on the basis of chemical and physicochemical evidence as follows : notoginsenoside E; 3-O-[β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl]-20-O-(β-D-glucopyranosyl)-3β, 12β, 20(S)-trihydroxy-25-hydroperoxydammar-23-ene, G; 3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl]-20-O-(β-D-glucopyranosyl)-3β, 7β, 20(S)-trihydroxydammar-5, 24-diene, H; 6-O-[β-D-xylopyranosyl(1→2)-β-D-glucopyranosyl]-20-O-(β-D-glucopyranosyl)-3β, 6α, 12β, 20(S), 25-pentahydroxydammar-23-ene, I; 3-O-[β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl]-20-O-[β-D-glucopyranosyl(1→6)-β-D-glucopyranosyl]-3β, 20(S)-dihydroxydammar-24-ene, J; 6-O-(β-D-glucopyranosyl)-20-O-(β-D-glucopyranosyl)-3β, 6α, 12β, 20(S), 24ζ, 25-hexahydroxydammarane, and notoginsenic acid β-sophoroside; 10-hydroxydaca-4, 6-diynoic acid 10-O-β-D-glucopyranosyl (1→2)-β-D-glucopyranoside, respectively.

Six new furostanol saponins called trigoneosides Ia, Ib, IIa, IIb, IIIa, and IIIb were isolated from a medicinal foodstuff, fenugreek seed, the seed of Trigonella foenum-graecum L. (Leguminosae) originating from India, together with two known saponins, glycoside D and trigofoenoside A. The structures of trigoneosides Ia, Ib, IIa, IIb, IIIa, and IIIb were determined on the basis of chemical and physicochemical evidence as 26-O-beta-D-glucopyranosyl-(25S)-5 alpha-furostane-2 alpha,3 beta,22 zeta,26-tetraol 3-O-[beta-D-xylopyranosyl (1 --> 6)]-beta-D-glucopyranoside, 26-O-beta-D-glucopyranosyl-(25R)- 5 alpha-furostane-2 alpha,3 beta,22 zeta,26-tetraol 3-O-[beta-D-xylopyranosyl (1-->6)]-beta-D-glucopyranoside, 26-O-beta-D-glucopyranosyl-(25R)-5 beta-furostane-3 beta,22 zeta,26-triol 3-O-[beta-D-xylopyranosyl (1 --> 6)]-beta-D-glucopyranoside, 26-O-beta-D-glucopyranosyl-(25R)-5 beta-furostane-3 beta,22 zeta,26-triol 3-O-[beta-D-xylopyranosyl (1-->6)]-beta-D-glucopyranoside, 26-O-beta-D-glucopyranosyl-(25S)-5 alpha-furostane-3 beta,22 zeta,26-triol 3-O-[alpha-L-rhamnopyranosyl(1 --> 2)]-beta-D-glucopyranoside, and 26-O-beta-D-glucopyranosyl-(25R)-5 alpha-furostane-3 beta,22 zeta,26-triol 3-O-[alpha-L-rhamnopyranosyl (1 --> 2)]-beta-D-glucopyranoside, respectively.

To search for possible antitumor-promoters, two digalactosyl diacylglycerols (DGDGs), which were obtained from the freshwater cyanobacterium Phormidium tenue and possessed a single pair of acyl residues, were evaluated for their inhibitory effects on the two-stage carcinogenesis test in mouse skin. Papillomas in mouse skin were initiated with 390 nmol of 7,12- O -dimethylbenz[ a ]anthracene and 1 week later, were promoted twice a week with 1.7 nmol of 12- O -tetradecanoylphorbol-13-acetale (TPA).Two DGDGs effectively inhibited tumor formation in the sensitive mouse stock even when these compounds were given 1 h before TPA treatment.

Two bioactive cyanoglycosides, rhodiocyanosides A and B, and two oligoglycosides, rhodioflavonoside [gossypetin 7-O-beta-D-glucopyranosyl(1--3)-alpha-L-rhamnopyranoside] and rhodiooctanoside [octyl alpha-L-arabinopyranosyl(1--6) beta- D-glucopyranoside), were isolated from the Chinese natural medicine "Si Lie Hong Jing Tian" (Shiretsukoukeiten in Japanese), the underground part of Rhodiola quadrifida (Pall.) Fisch. et Mey., together with four known compounds: rhodioloside, n-hexyl beta-D-glucopyranoside, gossypetin 7-O-alpha-L-rhamnopyranoside, and tricetin. The chemical structures of new glycosides were determined on the basis of chemical and physicochemical evidence. Rhodiocyanosides A and B exhibited inhibitory activity on the histamine release from rat peritoneal exudate cells sensitized with anti-2,4-dinitrophenyl IgE. Additionally, rhodiocyanoside A, the major constituent of this natural medicine, was also found to show antiallergic activity in a passive cutaneous anaphylaxis test in rat.

Five bioactive triterpene oligoglycosides named escins, Ia, Ib, IIa, IIb, and IIIa were isolated from the seeds of horse chestnut tree, Aesculus hippocastanum L. (Hippocastanaceae). The chemical structures of escins Ia, Ib, IIa, IIb, and IIIa were determine on the basis of chemical and physicochemical evidence, which included selective cleavage of the glucuronide linkage using photochemical reaction and lead tetraacetate decarboxylation reaction. Escins Ia, Ib, IIa, and IIb were found to exhibit an ethanol absorption-inhibitory effect and hypoglycemic activity in the oral glucose tolerance test in rats. Some structure-activity relationships are reported.

Lactonization reaction of 2-carboxystilbene mediated by copper(II) chloride proceeded regiospecifically to give the five-membered lactone, while the bromolactonizations using N-bromosuccinimide and anodic oxidation were found to furnish the six-membered lactone. Using these regiospecific lactonization reactions as a key step, antiallergic and antimicrobial isocoumarins and the benzylidenephthalides thunberginols A and F and their 3'-deoxyanalogs were synthesized from phyllodulcin and hydrangenol. Two phthalides called hydramacrophyllols A and B were isolated from Hydrangeae Dulcis Folium and their stereostructures were determined on the basis of physicochemical and chemical evidence, which included the syntheses of hydramacrophyllols A and B from hydrangenol by the application of the lactonization method using copper(II) chloride. In addition, hydramacrophyllols A and B were found to exhibit an inhibitory effect on the histamine release from rat peritoneal exudate cells induced by antigen-antibody reaction.

Two new monogalactosyl diacylglycerols were isolated from the freshwater green alga, Chlorella vulgaris, as anti-tumour promoters, together with three monogalactosyl diacylglycerols and two digalactosyl diacylglycerols. The new monogalactosyl diacylglycerol containing (7Z,10Z)-hexadecadienoic acid showed a more potent inhibitory effect toward tumour promotion than the other glycerolipids isolated.

Convenient synthesis of 1-O-acyl-3-O-(6'-O-acyl-β-D-galactopyranosyl-sn-glycerol was studied. The lipase from Achromobacter sp. catalyzed acylation of 3-O-β-D-galactopyranosyl-sn-glycerol, which contains two primary hydroxyl functions, proceeded regioselectively to furnish 1-O-acyl-3-O-β-D-galactopyranosyl-sn-glycerol.

Total syntheses of myriocin (thermozymocidin, ISP-1, 21) and its analog, Z-myriocin (22), which showed potent immunosuppressive activity, were accomplished starting from 2-deoxy- d -glucose by employing a modified Darzen reaction as a key reaction. The stereoselectivity of the modified Darzen reaction for six-membered cyclic ketones was discussed on the basis of physicochemical evidence including the conformational analyses of the cyclic ketones based on molecular mechanics calculation.

Five new saponins named elatosides G, H, I, J, and K were isolated from a garnish foodstuff "Taranome," the young shoot of Aralia elata SEEM., together with hederagenin-3-O-glucuronopyranoside and elatoside C. Their chemical structures were elucidated on the basis of chemical and physicochemical evidence. Elatosides G, H, and I were found to exhibit potent hypoglycemic activity in the oral glucose tolerance test in rats.

E-Senegasaponins a, b, and c were isolated from Senegae Radix, the root of Polygala senega L. var. latifolia TORREY et GRAY, together with their Z-isomers of the 4"-methoxycinnamoyl moiety, Z-senegasaponins a, b, and c. The structures of E-senegasaponins a and b and Z-senegasaponins a and b have been elucidated on the basis of chemical and physicochemical evidence, and the geometrical isomeric structure of the 4"-methoxycinnamoyl group in each saponin was found to show tautomer-like behavior in methanol solution or under irradiation with fluorescent lamps. E and Z-Senegasaponins a and b were found to exhibit potent inhibitory effects on alcohol absorption and hypoglycemic activity in the oral D-glucose tolerance tests in rats, and some structure-activity relationships of the acylated bisdesmoside-type saponins were clarified.