Amodiaquine (AQ) is an antimalarial which is effective against chloroquino-resistant strains of Plasmodium falciparum but whose clinical use is severely restricted because of associated hepatotoxicity and agranulocytosis. “One-pot” synthesis of formamidines likely to be transformed into AQ derivatives is reported. Compared with AQ, the new compounds were devoid of in vitro cytotoxicity upon human embryonic lung cells and mouse peritoneal macrophages. One showed a potent in vivo activity in mice infected with P. berghei. Transformation of this compound by reductive amination led to a new type of AQ derivatives that displayed an in vitro activity similar to that of AQ but did not lead to toxic quinone-imines.

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Five new polyacetylene glucosides, bidensyneosides A₁, A₂, B, C (1-4), and 3-deoxybidensyneoside B (5), have been isolated from the air-dried whole plant of Bidens parviflora WILLD. The structures were identified based on spectroscopic analysis, physicochemical properties, and application of the modified Mosher method to be 3(R), 8(E)-8-decene-4, 6-diyne-1, 3-diol 1-O-β-D-glucopyranoside (1), deca-3(R), 8(Z) 8-decene-4, 6-diyne-1, 3-diol 1-O-β-D-glucopyranoside (2), 3(R)-deca-4, 6, 8-triyne-1, 3-diol 1-O-β-D-glucopyranoside (3), 3(R), 8(E)-8-decene-4, 6-diyne-1, 3, 10-triol 1-O-β-D-glucopyranoside (4), and 8(E)-8-decene-4, 6-diyne-1, 10-diol 1-O-β-D-glucopyranoside (5), respectively. These compounds inhibited nitric oxide (NO) production in lipopolysaccharide and interferon-γ activated murine macrophages (RAW264.7) and also inhibited histamine release from rat mast cells stimulated by the antigen-antibody reaction.

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The reaction of probucol with superoxide (O₂^·-) was investigated in acetonitrile using both electron spin resonance (ESR) and electrochemical techniques. The formation of phenoxyl radical was observed during the reaction of probucol with O₂^·- by ESR spectroscopy. The reaction of probucol with O₂^·- in acetonitrile was followed by cyclic voltammetry. With the addition of probucol, the oxidation peak current of O₂^·- decreased concentration dependently. This suggests that probucol reacts with O₂^·-, that is, probucol scavenges O₂^·- in acetonitrile, 2,6-Di-tert-butyl-p-benzoquinone was identified as the major product of the reaction of probucol with O₂^·- in acetonitrile. Electrochemical oxidation of probucol was also performed. Probucol gives an irreversible oxidation peak at ca. +1.4 V vs. the saturated calomel electrode in the cyclic voltammogram. Controlled-potential electrolysis was carried out at +1.2 V in a divided cell. 2,6-Di-tert-butyl-p-benzoquinone, 4,4'-dithiobis(2,6-di-tert-butylphenol), and 4,4'-trithiobis(2,6-di-tert-butylphenol) were identified as the products of anodic oxidation. These redox properties of probucol may correlate with the physiological activities.

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Vitamin E glycosides were synthesized and enzymatic hydrolysis was examined for use as potential prodrugs, however, the glycoside bond was found to be stable. On the other hand, among the glycosides synthesized, dl-α-tocopherylglucoside (6b) and dl-α-tocopherylmannoside (6c) showed strong inhibitory action on histamine release from mast cells. In addition, 6c also showed a suppressive action on IgE antibody formation. Thus, tocopheryl glycoside showed new properties compared to tocopherol (vitamin E). In particular, 6c was shown to be a novel lead compound with excellent manifold anti-allergic activity and anti-inflammatory activity.

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Compounds 1-6 were isolated from the AcOEt soluble fraction of leaves of the Brazilian medicinal plant, Cordia multispicata, and their structures were elucidated to be 3β, 25-epoxy-21β-acetoxy-3α, 22β-dihydroxyurs-12-en-28-al (1), 3β, 25-epoxy-28-acetoxy-3α, 21β, 22β-trihydroxyurs-12-ene (2), 21β-acetoxy-22β-hydroxy-3-oxours-12-en-28-al (3), 28-acetoxy-6β, 21β, 22β-trihydroxy-3-oxours-12-ene (4), 21β, 22β-dihydroxy-3-oxours-12-en-28-al (5) and 3β, 21β, 22β-trihydroxyurs-12-en-28-al (6), respectively, by means of spectral data, especially two dimensional NMR techniques. Triterpenes having the hemiketal structure at the A-ring, an acyloxy group at C-22 and/or ketone at C-3 showed potent anti-androgenic activity.

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Application of the fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase segment condensation approach to the preparation of sulfated peptides was investigated through the synthesis of human big gastrin-II, a 34-residue sulfated tyrosine [Tyr(SO₃H)]-containing peptide. Highly acid-sensitive 2-chlorotrityl resin (Clt resin) was exclusively employed as an anchor-resin for the preparation of the three peptide segments having the C-terminal Pro residue as well as of the Tyr(SO₃H)-containing resin-bound segment. By using the PyBOP-mediated coupling protocol [PyBOP=benzotriazolyloxytris(pyrrolidino)phosphonium hexafluorophosphate], we successively condensed each segment and constructed the 34-residue peptide-resin without any difficulty. The final acid treatment of the fully protected peptide-resin at low temperature (90% aqueous TFA, 0 °C for 8 h), which can detach a Tyr(SO₃H)-containing peptide from the resin and remove the protecting groups concurrently with minimum deterioration of the sulfate, afforded a crude sulfated peptide. After one-step HPLC purification, a highly homogeneous human big gastrin-II was easily obtained in 14% yield from the protected peptide-resin. The sulfate form of the C-terminal glycine-extended gastrin (G34-Gly sulfate), a posttranslational processing intermediate of gastrin-II, was also successfully prepared with the segment condensation approach (11% yield). These results demonstrated the usefulness of the segment condensation protocol for preparing lange Tyr(SO₃H)-containing peptides.

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Intercalation compounds of ternary layered inorganic materials, synthetic mica (Na-TSM), with diclofenac sodium (DFS) and its drug release characteristics were investigated. Hygroscopic DFS was selected as a model drug to verify the anti-humidity and anti-oxidation of the intercalation compounds. Na-TSM powder was first mixed with the reduced-type phosphatidylcholine (H-PC) solution of chloroform or ethanol. DFS was then mixed with these solutions and heated at 37 °C to prepare the ternary Na-TSM/H-PC/DFS compound. A remarkable phenomenon was observed in the drug release study. The net amount of DFS from the DFS powder decreased apparently after 20 min arising from the decomposition of DFS in acidic medium. On the other hand, the net amount of the released DFS from the intercalation compound was invariant. Thermal analyses study indicated that DFS powder was hygroscopic and a significant endothermic peak was observed accompanied by a large weight loss due to the dehydration of adsorbed water from 40 to 90 °C. On the other hand, no significant dehydration reaction was observed in the intercalation compounds even in the sample stored under humid conditions. The present results indicated that the ternary intercalation compound was resistant to acid in addition to anti-humidity.

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The synthetically useful approaches to 9-acyloxy 1, 5-dichloroanthracene derivatives are reported. The system selectively reduces the carbonyl group flanked by the peri substituents of the anthracenediones to give the corresponding 1, 5-dichloro-9(10H)-anthracenone. Simple regioselective acylation of anthracenone is applied with appropriate acyl chlorides in CH₂Cl₂ with catalytic amount of pyridine to give the novel 9-acyloxy 1, 5-dichloroanthracene derivatives. Considerable interest has developed in the mechanism of how anthracenone achieves this desirable selectivity. In an attempt to understand the mechanism of this reaction, solid-state structures of anthracene derivatives have been obtained. In addition, the inhibition of lipid peroxidation in model membranes was determined as was their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerase enzyme. In contrast to (+)-α-tocopherol, 3b, 3c, 3d, 3g, and 3i do not enhance lipid peroxidation in model membranes. Implications for 9-acyloxy 1, 5-dichloroanthracene analogues as potential anticancer agents are discussed.

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Following the characterization of hypoglycemic, gastric emptying inhibitory, and gastroprotective principles and the structure elucidation of calendasaponins A, B, C, and D, two new ionone glucosides (officinosides A and B), and two sesquiterpene oligoglycosides (officinosides C and D), were isolated from the flowers of Egyptian Calendula officinalis. The structures of the officinosides were elucidated on the basis of chemical and physicochemical evidence.

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A synthesis of 6, 7-dimethoxy-3-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (14a) and 7, 8-dimethoxy-2-phenyl-1, 2, 4, 5-tetrahydro-3H-3-benzazepine (14b) was achieved via the cyclization of N-(3, 4-dimethoxyphenyl)methyl-1-phenyl-2-(phenylsulfinyl)ethylformamide (6a) and N-2-(3, 4-dimethoxyphenyl)ethyl-1-phenyl-2-(phenylsulfinyl)-ethylformamide (6b) using the Pummerer reaction as a key step, respectively. The Pummerer reaction of 6a, b under usual conditions using trifluoroacetic anhydride yielded the vinyl sulfides (8a, b), non-cyclized products, as a major product. The cyclization proceeded when boron trifluoride diethyl etherate was used as an additive reagent, thus giving rise to the corresponding cyclized products (7a) and (7b) in moderate yields. We propose that the enhancing effect of the Lewis acid on the cyclization may be attributable to the involvement of a dicationic intermediate, sulfonium-carbenium dication (23).

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Three new carotenoids with a 3-methoxy-5-keto-5, 6-seco-4, 6-cyclo-β end group (1-3) have been isolated from the seeds of Pittosporum tobira. Their structures were elucidated by detailed analyses of nuclear magnetic resonance and UV data.

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A novel series of 3-(2-substituted-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridines (5-38) were synthesized and evaluated for their in vitro adenosine A₁ and A_2A receptor binding activities, and in vitro metabolism by rat liver in order to search for orally active compounds. Most of the test compounds were potent adenosine A₁ receptor antagonists with high A₁ selectivity and the A₁ affinity and A₁ selectivity of carbonyl derivatives (5-11) was particularly high. In particular, compound 7 was an extremely potent and selective adenosine A₁ antagonist with high A₁ selectivity (Ki=0.026 nM, A_2A/A₁=5400). In terms of metabolic stability, 2-oxopropyl (5), 2-hydroxypropyl (12), N-methylacetamide (16), 2-(piperidin-1-yl)ethyl (28) and 1-methylpiperidin-4-yl (32, FR194921) were the most stable compounds in this series of analogues. Further in vivo evaluation indicated that compounds 5, 13, 17, 28 and 32 were detected in both plasma and brain after oral administration in rats. In particular, 32 displayed good plasma and brain concentrations (dose: 32 mg/kg (n=3); after 30 min, plasma conc.=3390±651 nM, brain conc.=3670±496 nM; after 60 min, plasma conc.=1580±348 nM, brain conc.=2143±434 nM), and a good brain/plasma ratio (1.11±0.060 (30 min), 1.39±0.172 (60 min)). As a result, we could show that 32 is a good candidate for an orally active adenosine A₁ receptor antagonist with high blood-brain barrier permeability and good bioavailability (Ki=6.6 nM, A_2A/A₁=820, BA=60.6±4.9% (32 mg/kg)).

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Five new triterpenoid saponins, fargosides A, B, C, D, and E, were isolated from the roots of Holboellia fargesii. The structures of fargosides A-E were elucidated on the basis of chemical and physicochemical evidence and found to be 3β, 20α-dihydroxy-29-norolean-12-en-28-oic acid 3-O-β-D-xylopyranosyl-(1→2)-β-D-glucopyranoside (1), 3β, 20α, 24-trihydroxy-29-norolean-12-en-28-oic acid 23-O-β-D-fucopyranosyl-(1→2)-[α-L-arabinopyranosyl-(1→3)]-β-D-glucopyranoside (2), 3β, 23-dihydroxy-30-norolean-2, 20(29)-dien-28-oic acid 3-O-α-L-arabinopyranosyl-(1→2)-[β-D-glucopyranosyluronic acid-(1→3)]-α-L-arabinopyranoside (3), 3β, 23-dihydroxy-30-norolean-12, 20(29)-dien-28-oic acid 3-O-methyl β-D-glucopyranosyluronate-(1→3)-α-L-arabinopyranoside (4), and 3β, 23-dihydroxy-olean-12-en-28-oic acid 3-O-methyl β-D-glucopyranosyluronate-(1→3)-α-L-arabinopyranoside (5), respectively.

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A new ionone glucoside, pisumionoside, a phenethyl glycoside, sayaendoside, and two acylated flavonol oligoglycosides, pisumflavonosides I and II, were isolated from the young seedpods of garden peas, Pisum sativum L., together with quercetin and kaempferol 3-O-(6-O-trans-p-coumaroyl)-β-D-glucopyranosyl (1→2)-β-D-glucopyranosyl (1→2)-β-D-glucopyranosides and quercetin and kaempferol 3-sophorotriosides. The structures of pisumionoside, sayaendoside, and pisumflavonosides I and II were determined on the basis of chemical and physicochemical evidence, respectively. Quercetin 3-sophorotrioside, a principle component, was found to show protective effects on liver injury induced by D-galactosamine and lipopolysaccharide and by carbon tetrachloride in mice.

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Structure activity studies of N-phenylrolipram derivatives have led to the identification of highly potent PDE4 inhibitors. The potential of these inhibitors for cellular activity was routinely assessed in an assay of fMLP induced oxidative burst in human eosinophils. Since first generation PDE4 inhibitors have been plagued with a number of unwanted side effects, parallel structure activity studies for competition with the [³H]-rolipram binding site in rat brain were performed. In this fashion 5-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-3-(3-methoxybenzyloxy)benzoic acid N',N'-dimethylhydrazide (22) was identified as a potent inhibitor of PDE4 which exhibits >1000 fold selectivity versus PDE3, and is a nanomolar inhibitor in all the cellular assays tested. Studies on the streoselectivity of PDE4 inhibition of this class of rolipram based compounds revealed, that for example (S)-11 is a more potent inhibitor than (R)-11. This effect can also be observed in primary human cells where the (S)-enantiomer is about 10 fold more potent than the corresponding (R)-enantiomer.

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The synthetic route for a uterine relaxant, bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl}amino)-1, 2, 3, 4-tetrahydronaphthalen-7-yl]oxy}-N, N-dimethylacetamide) sulfate (KUR-1246), was established by the coupling of optically active components, the bromohydrin 14 and the amine 24. We now describe the practical synthesis of these two optically active components. Bromohydrin 14 was obtained by the asymmetric borane reduction of the prochiral phenacyl bromide 13 using a catalyst prepared from aluminum triethoxide and a chiral amino alcohol. The other optically active component 24 was prepared from (S)-AMT.

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Three new dammarane triterpenes and semialactic acid were isolated from the stem bark of Rhus javanica. The structures of these triterpenes, named semialactone, isofouquierone peroxide and fouquierone, were elucidated by 2D-NMR analysis (HMQC, ¹H-¹H COSY and HMBC), and the ¹³C-NMR data of semialatic acid is revised.

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The stable free radical 2, 2, 6, 6-tetramethylpiperidine-N-oxyl-4-amino-4-carboxylic acid (TOAC) is the only spin labeled amino acid that has been used to date to successfully label peptide sequences for structural studies. However, severe difficulty in coupling the subsequent amino acid has been the most serious shortcoming of this paramagnetic marker. This problem stems from the low nucleophilicity of TOAC’s amine group towards the acylation reaction during peptide chain elongation. The present report introduces the alternative β-amino acid 2, 2, 5, 5-tetramethylpyrrolidine-N-oxyl-3-amino-4-carboxylic acid (POAC), potentially useful in peptide and protein chemistry. Investigations aimed at addressing the stereochemistry of this cyclic molecule through X-ray diffraction measurements of crystalline and bulk samples revealed that it consists only of the trans conformer. The 9-fluorenylmethyloxycarbonyl group (Fmoc) was chosen for temporary protection of the POAC amine function, allowing insertion of the probe at any position in a peptide sequence. The vasoactive octapeptide angiotensin II (AII, DRVYIHPF) was synthesized by replacing Pro with POAC. The reaction of Fmoc-POAC with the peptidyl-resin occurred smoothly, and the coupling of the subsequent amino acid showed a much faster reaction when compared with TOAC. POAC⁷-AII was obtained in good yield, demonstrating that, in addition to TOAC, POAC is a convenient amino acid for the synthesis of spin labeled peptide analogues. The present findings open the possibility of a wide range of chemical and biological applications for this novel β-amino acid derivative, including structural investigations involving its differentiated bend-inducing characteristics.

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Two new steroid derivatives, (22E, 24R)-3α-ureido-ergosta-4, 6, 8(14), 22-tetraene (1) and (22E, 24R)-5α, 8α-epidioxyergosta-6, 9, 22-triene-3β-ol 3-O-β-D-glucopyranoside (2) were isolated from the fruit bodies of Chlorophyllum molybdites (Agaricaceae). The structures were established by spectroscopic and chemical methods. These compounds exhibited cytotoxicity against Kato III cells.

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Three quinone-type podocarpanes, 3β-hydroxy-13-methoxy-8, 12-podocarpadiene-11, 14-dione (1), 18-hydroxy-13-methoxy-8, 12-podocarpadiene-11, 14-dione (2), and 13-methoxy-8, 12-podocarpadiene-2, 11, 14-trione (3) were isolated from the bark of Taiwania cryptomerioides. Their structures were elucidated using spectral methods.

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Eight phenolic compounds including two new lignan glucopyranosides together with a known alkaloid were isolated from the stems of Cynomorium songaricum RUPR. (Cynomoriaceae). Their chemical structures were elucidated on the basis of spectral and chemical evidence. The chemotaxonomic significance of these metabolites is discussed.

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From the aerial parts of Phlomis spinidens, two new flavonol bisglycosides, phlomisflavosides A (1) and B (2), were isolated together with the known compounds, astragalin, isoquercitrin, lamiridoside, phlomoside A, shanzhiside methyl ester, 8-O-acetylshanzhiside methyl ester, phlorigidoside C, rodioloside (=salidroside), forsythoside B, citroside A and lariciresinol-4'-O-β-D-glucoside. The structures of the new compounds were elucidated based on spectral and chemical evidence.

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Further search for cytotoxic compounds contained in the bulbs of Galtonia candicans (Liliaceae) led to the isolation of four potent cytotoxic cholestane glycosides (1-4) based upon 3β, 16β, 17α-trihydroxycholest-5-en-22-one, three of which (2-4) have not been reported previously. A new cholestane bisdesmoside (5) and a new rearranged cholestane glycoside (6) were also isolated. The structural assignment of the new constituents was carried out by spectroscopic analysis and a few chemical transformations.

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2-O-α-D-Glucopyranosyl-6-O-octanoyl-L-ascorbic acid was enzymatically synthesized from 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) and vinyl octanoate with a protease from Bacillus subtilis in pyridine. Furthermore, with various linear saturated fatty acid vinylesters as acyl donors, AA-2G was also converted to their corresponding 6-O-acyl AA-2G in the same manner. The reactivities of transacylation decreased with increasing length of the acyl groups. Thus, short chain acyl groups were transferred to AA-2G by this protease more efficiently than were long chain acyl groups. This enzymatic method is recommended for the synthesis of 6-Acyl-AA-2G with short or medium length chain acyl groups.

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2, 7-Dichlorodibenzo-p-dioxin (DCDD) was found to evaporate easily with water vapor from a heated solution. Steam distillation was also effective for the removal of DCDD from DCDD-applied soil; its concentration (250 μg/50 g soil) in the original soil decreased to less than 5% after steam distillation for only 20 min. Actual dioxin-polluted soil in Tokorozawa City was partially decontaminated using the same method. These results suggest that steam distillation could be a new remedial method for soils contaminated with persistent environmental pollutants, such as dioxins and polychlorinated biphenyls.

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