Oxidation reactions consist of a number of important transformations in organic synthesis. However, in spite of their utility in both laboratory- and industrial-scale production, oxidations are among the most problematic processes regarding the factors of safety, environmental friendliness, operational simplicity, etc. As oxidants, hypervalent iodines, such as phenyliodine(III) diacetate (PIDA) and phenyliodine(III) bis(trifluoroacetate) (PIFA), are among promising reagents for developing environmentally benign oxidation reactions due to their low toxicities, mild reactivity, ready availability, high stability, and easy handling. Our research objective is, largely in consideration of economic and environmental viewpoints, to enhance the synthetic values of these reagents as useful alternatives to highly toxic heavy-metal oxidants and even rare transition metals by pioneering their efficient utilization methods and unique reactivities. During this study, we have succeeded in the development of new recyclable reagents 1 and their catalytic utilization, and the design of a new chiral reagent 2 and its application to perform asymmetric oxidations. Accordingly, the recycling and catalytic use of a hypervalent iodine reagent became possible in many representative types of oxidative bond-forming reactions, some of which even include key transformations for natural product synthesis. A summary of these important achievements in hypervalent iodine chemistry are described in this review.

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This paper introduces a new delivery system for rapid and controlled drug release. Mixture of hydrophilic, (poly vinyl alcohol, PVA, and randomly methylated β-cyclodextrin, RM β-CD), and hydrophobic (poly D,L-lactide, PLA, and poly D,L-lactide-co-glycoside, PLGA) polymers were electrospun to make a multi-layered/multicomponent nanofiber mat. The release characteristics of the drug were modified using the layer by layer approach to help compensate the limitation of the individual materials. Incorporation of RM β-CD to the PVA solution was able to significantly decrease the degradation rate of the resulting fiber mat from a few weeks to a few seconds. Hydrophilic polymer mat (PVA-RM β-CD) can dissolve in the release media instantly and provide rapid release of the drug. This characteristic makes such carriers suitable as sublingual delivery systems in the treatment of acute disorders. Polyesters, PLA and PLGA, can control drug release via hydrolysis of the polymer and provide sustained and controlled release of the drug. Blends of these hydrophilic and hydrophobic polymers can effectively prolong drug release and decrease physiological toxicity resulting from fast release of drugs. These carriers may be suitable for the treatment of chronic disease where sustained release of the drug is required.

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Methotrexate (MTX) is one of the most common anticancer drugs used for chemotherapy so far. However some problems such as high toxicity and short plasma half-life, have limited its use. To overcome these limitations, conjugation with polymers such as polyethylene glycol (PEG) is one the efficient approaches which has been attempted in recent years. The aim of the present study is to synthesize esters of MTX with PEGs of different molecular weights and to characterize their physicochemical properties. Polymeric esters (MTX-PEGs) of MTX with low, medium and high molecular weight PEGs (750 D, 5000 D and 35000 D, respectively) were synthesized using dicyclohexylcarbodiimide (DCC) as coupling agent and triethylamine (TEA) as catalyst. The purification was carried out using preparative TLC. Purified esters were characterized by UV, IR and ¹H-NMR spectroscopy methods and their thermal behavior was studied by differential scanning calorimetry (DSC). Also, an isocratic HPLC method with three mobile phase systems was set to determine the partition coefficient of the esters (log P). Gel permeation chromatography (GPC) was utilized for molecular weight determination of esters, which proved 1 : 1 conjugation of drug with each polymer. The stability and solubility of esters were determined in different pH values. The spectroscopy results indicated that esteric bond between MTX and PEGs were formed. The sharp endothermic peaks for MTX-PEGs were obtained in DSC which are similar to pure polymers, whilst a wide peak was observed for MTX. The values of log P for MTX-PEGs (+4.3, obtained by HPLC method) were remarkably different from log P of MTX (−1.4, obtained by shake-flask method). The stability results showed a pH range of 3—4 and an optimum polymer mw of 5000 for maximum stability of esters. A parabolic profile obtained from solubility studies that indicated the more solubility of MTX in alkaline condition (pH>5) and MTX-PEGs in acidic conditions (pH<5). Based on our results, it is concluded that MTX-PEGs were formed on an equimolar ratio of MTX and PEGs. The higher log P observed for the esters indicated dramatic physicochemical differences between MTX and its PEG conjugates and the higher stability and solubility in acidic medium showed a promising approach to improve the drug delivery of the conjugates, specially MTX-PEG5000 in the future.

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A rapid expansion of supercritical solution (RESS) technology was presented for the micronization of Chinese medicinal material. Magnolia bark extract (MBE) obtained by supercritical carbon dioxide (scCO₂) extraction technology was chosen as the experimental material. RESS process produced 4.7 μm size MBE microparticles (size distribution, 0.2—24.1 μm), which was significantly smaller than the 55.3 μm size particles (size distribution, 8.3—102.4 μm) obtained from conventional mechanical milling. Dissolution rate study showed that drug dissolution was significantly enhanced by the RESS progress. At 90 min, the amount dissolved of mechanical milling MBE was 6.37 mg·l⁻¹, which was significantly lower than that of micronized MBE (14.77 mg·l⁻¹), according to the results of ANOVA (p<0.01). The effect of extraction temperature (30, 40, 50 °C), extraction pressure (200, 250, 300 bar) and nozzle size (50, 100, 200 μm) on the size distribution of microparticles was investigated. The characteristics of microparticles were also studied by differential scanning calorimetry (DSC), infrared spectroscopy (IR), scanning electron microscopy (SEM), and image analysis. This study demonstrates that RESS is applicable for preparing microparticles of MBE at low operating temperature; the process is simple without residual solvent.

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A series of thirteen new thiadiazole compounds were synthesized and evaluated for in vitro antifungal and antibacterial activity. All compound tested showed significant antifungal activity against all the micromycetes, compared to the commercial fungicide bifonazole. Differences in their activity depend on the substitution of different reactive groups. More specifically, best antifungal activity was shown for the synthetic analogue with methylpiperazine reactive group. Furthermore, it is apparent that different compounds reacted on different ways against bacteria. An effort was made to correlate the above mentioned differences in activity with lipophilicity studies. Furthermore, NMR and molecular modelling were used to obtain the main conformational features of a potent analogue, for future in silico studies.

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We designed 1-alkyloxygenipins with the aim of improving the stability of genipins based on the structural and electronic properties of genipins, and prepared 1-alkyloxygenipins and examined their neuritogenic activities in PC12h cells. All genipin-derivatives exhibited electronic properties similar to those of genipin and induced significant neurite outgrowth. These compounds will be classified as nitric oxide synthase (NOS) activators (neuritogenic active compounds) since their lowest unoccupied molecular orbital (LUMO)-energies are similar to that of tetrahydrobiopterin (H4B). (1R)-isoPropyloxygenipin showed activity comparable to that of genipin, and unlike the parent compound genipin, it was found to be physiologically stable in rat liver homogenate.

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Further study of constituents from the aerial parts of Asclepias tuberosa afforded twenty-two new steroidal glycosides along with tuberoside B₅ and G₅. These glycosides were confirmed to contain 8,12;8,20-diepoxy-8,14-secopregnanes, tuberogenin and its congeners, as their aglycones. The structure of each of these compounds was elucidated based on the interpretation of NMR and MS measurements and from chemical evidence.

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Selecting the best quality model from a set of predicted structures is one of the most important aspects of protein structure prediction. We have developed model quality assessment programs that select high quality models which account for both the Cα backbone and side-chain atom positions. The new methods are based on the consensus method with consideration of the side-chain environment of a protein structure and the secondary structure agreement. This Side-chain Environment Consensus (SEC) method is compared with the conventional consensus method, 3D-Jury (Ginalski K. et al., Bioinformatics, 19, 1015—1018 (2003)), which takes into account only the Cα backbone atoms of the protein model. As the result, it was found that the SEC method selects the models with more accurate positioning of the side-chain atoms than the 3D-Jury method. When the SEC method was used in combination with the 3D-Jury method (3DJ+SEC), models were selected with improved quality both in the Cα backbone and side-chain atom positions. Moreover, the CIRCLE (CCL) method (Terashi G. et al., Proteins, 69 (Suppl. 8), 98—107 (2007)) based on the 3D–1D profile score has been shown to select the best possible models that are the closest to the native structures from candidate models. Accordingly, the 3DJ+SEC+CCL method, in which CIRCLE is used after reducing the number of candidates by the 3DJ+SEC consensus method, was found to be very effective in selecting high quality models. Thus, the best method (the 3DJ+SEC+CCL method) includes the consensus approaches of the Cα backbone and the side-chains, the secondary structure agreement and the 3D–1D profile score which corresponds to the free energy-like score in the residues of the protein model. In short, new algorithms are introduced in protein structure evaluation methods that are based on a side-chain consensus score. Additionally, in order to apply the 3DJ+SEC+CCL method and indicate the usefulness of this method, a model of human Cabin1, a protein associated with p53 function and cancer, is created using various internet modeling and alignment servers.

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Five new lignans, ovafolinins A—E (1—5), were isolated from the wood of Lyonia ovalifolia (Ericaceae). The structures of 1—5 were elucidated based on 2D NMR spectroscopy, X-ray crystallography, and other chemical methods.

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Spray freeze-drying (SFD) technique using four-fluid nozzle (4N), which is a novel particle design technique previously developed by authors, has been further developed to expand its application in pharmaceutical industry. The organic solvent was utilized as a spray solvent to dissolve the poorly soluble drug instead of conventional aqueous solution. Acetonitrile solution of the drug and aqueous solution of the polymeric carrier were separately and simultaneously atomized through 4N, and collided each other at the tip of nozzle edge. The spray mists were immediately frozen in the liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier according to our proprietary method developed before. The resultant composite particles with phenytoin prepared by using acetonitrile (4N-SFD-MeCN system) were deeply characterized compared to those using aqueous solution (4N-SFD-aqua system) from morphological and physicochemical perspectives. The characteristic porous structure was observed in 4N-SFD-MeCN particles as well as 4N-SFD-aqua particles. However, it was found that the size and quantity of pore in 4N-SFD-MeCN particles were smaller than those of 4N-SFD-aqua particles. As a result, the former particles had 2- to 3-times smaller specific surface area than the latter particles independent of the type of carrier loaded. The slight difference of release profiles from the particles prepared between both systems was discussed from the microscopically structural viewpoint. In addition, ciclosporin was applied to organic solvent SFD system because this drug was poorly water soluble and cannot be applied to conventional aqueous SFD system. The release profiles from SFD particles were dramatically improved compared to the bulk material, suggesting that the new SFD technique using organic solvent has potential to develop the novel solubilized formulation for poorly water-soluble active pharmaceutical ingredients (APIs).

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Cannabis sativa L. (cannabis) extracts, vapor produced by the Volcano^® vaporizer and smoke made from burning cannabis joints were analyzed by GC-flame ionization detecter (FID), GC-MS and HPLC. Three different medicinal cannabis varieties were investigated Bedrocan^®, Bedrobinol^® and Bediol^®. Cannabinoids plus other components such as terpenoids and pyrolytic by-products were identified and quantified in all samples. Cannabis vapor and smoke was tested for cannabinoid receptor 1 (CB1) binding activity and compared to pure Δ⁹-tetrahydrocannabinol (Δ⁹-THC). The top five major compounds in Bedrocan^® extracts were Δ⁹-THC, cannabigerol (CBG), terpinolene, myrcene, and cis-ocimene in Bedrobinol^® Δ⁹-THC, myrcene, CBG, cannabichromene (CBC), and camphene in Bediol^® cannabidiol (CBD), Δ⁹-THC, myrcene, CBC, and CBG. The major components in Bedrocan^® vapor (>1.0 mg/g) were Δ⁹-THC, terpinolene, myrcene, CBG, cis-ocimene and CBD in Bedrobinol^® Δ⁹-THC, myrcene and CBD in Bediol^® CBD, Δ⁹-THC, myrcene, CBC and terpinolene. The major components in Bedrocan^® smoke (>1.0 mg/g) were Δ⁹-THC, cannabinol (CBN), terpinolene, CBG, myrcene and cis-ocimene in Bedrobinol^® Δ⁹-THC, CBN and myrcene in Bediol^® CBD, Δ⁹-THC, CBN, myrcene, CBC and terpinolene. There was no statistically significant difference between CB1 binding of pure Δ⁹-THC compared to cannabis smoke and vapor at an equivalent concentration of Δ⁹-THC.

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A series of phthiobuzone analogs, prepared from potassium phthalimide or phthalandione, have been evaluated for their antiviral activities. Among the candidates, compounds 5j and 5k, which contain the substituted 4-halogenated phenyl ring at N-4′,4″ position, show more potent antiviral activity than phthiobuzone against herpes simplex virus 1 (IC₅₀=8.56 and 2.85 μg/ml, respectively) and herpes simplex virus 2 (IC₅₀=1.75 and 4.11 μg/ml, respectively). Compounds 9c and 9d with a propylene linker between the phthalimide and bisthiosemicarbazone moieties display similar antiviral potency against herpes simplex virus 1 (IC₅₀=2.85 and 4.11 μg/ml, respectively).

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A mild and efficient route for the synthesis of quinolines utilizing cuprous triflate (Cu(OTf)₂) as a novel catalyst via Friedländer annulation in excellent yields at room temperature under solvent-free conditions was described.

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Coloration of mefenamic acid (MFA) was investigated in the presence of mesoporous silica FSM-16 with 16.0 Å (Oc) and 45.0 Å (Doc) pore diameter. The color change of MFA/FSM-16 physical mixture from white to deep blue was observed by sealed-heating (SH) and the subsequent humidification (HU). The coloration and the color difference were caused by the changes of chroma and lightness. In the case of MFA/FSM-16 (Oc), coloration was not observed by SH treatment only. Powder X-ray diffraction data indicated that difference of the dispersed states of MFA molecules in FSM-16 mesopore affected the coloration. MFA adsorbed on the silica surface and MFA in the mesopore were differentiated by thermogravimetric analysis. Solid-state ¹³C-NMR showed that the molecular mobility of MFA was increased in the dispersed state in FSM-16 mesopores compared to the crystalline state. Structural changes of silanol groups in FSM-16 by humidification were observed by solid-state ²⁹Si-NMR. MFA adsorption in FSM-16 mesopore by SH as well as changes of the surface state of FSM-16 by HU affected the coloration of MFA.

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Experimental solubilities of acetaminophen and ibuprofen in polyethylene glycol 600–water, ethanol–polyethylene glycol 600, and polyethylene glycol 600–water–ethanol mixtures at 25 °C are reported. The solubilities of drugs in the presence of ethanol and polyethylene glycol 600 were increased. The Jouyban–Acree model was used to fit the solubility data of each drug in the binary mixtures in which the overall mean relative deviations (OMRDs) for acetaminophen and ibuprofen were 2.9% and 4.3%, respectively. The OMRDs for ternary solvent mixtures for acetaminophen and ibuprofen were 16.8% and 22.4%, respectively. Generally, the errors associated with ibuprofen are larger than that of acetaminophen in both binary and ternary solvent mixtures. The solubilities were predicted using previously trained versions of the Jouyban–Acree and log-linear models with the OMRDs of 38.8% and 52.1%, respectively. Density of the mixed solvents in the absence of the solute was measured and used to train the model and then the density of the saturated solutions was predicted using the trained model and the density of the saturated solutions in mono-solvent systems with the OMRD of 3.2%.

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Four novel octanorcucurbitane triterpenes, octanorcucurbitacins A—D (1—4), together with one known octanorcucurbitane triterpene, kuguacin M (5), were isolated from the methyl alcohol extract of the stems of Momordica charantia. Their structures were elucidated on the basis of extensive spectroscopic analyses. Compound 3 inhibited tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity against HepG2 cells.

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The aim of this study was to improve wettability and dissolution rate of a poorly water-soluble drug, cilostazol, using the supercritical antisolvent (SAS) process. The solid state of particles precipitated from dichloromethane containing additives, including poloxamer 188, poloxamer 407, TPGS 1000, Gelucire^® 44/14 and Gelucire^® 50/13, in supercritical CO₂ medium were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), FT-IR, particle size analysis, contact angle, and dissolution. Interestingly, the morphology of SAS particles processed with TPGS 1000, Gelucire^® 44/14 and Gelucire^® 50/13 changed to plate- or leaflet-shaped. Furthermore, the particle sizes of cilostazol processed with Gelucire^® 44/14 and Gelucire^® 50/13 were increased compared to cilostazol processed without additives. Poloxamer 188 and poloxamer 407 were superior in increasing the dissolution rate due to decreased particle size, the resulting increased surface area, and improved wettability. Micronization with the supercritical antisolvent process resulted in a significant decrease in mean particle size, and wettability of cilostazol was increased by using small amounts of hydrophilic additives.

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Two new daphnane-type diterpene esters, yuanhuahine (1) and yuanhualine (2), were isolated from the flowers of Daphne genkwa (Thymelaeaceae) along with three known diterpene esters, yuanhuacine (3), yuanhuadine (4), and yuanhuagine (5). Their structures were determined by a combination of 1D and 2D NMR experiments, including correlation spectroscopy (COSY), heteronuclear multiple quantum correlation (HMQC), heteronuclear multiple bond correlation (HMBC), and rotating frame Overhauser enhancement spectroscopy (ROESY) sequences, and mass spectrometry. All the isolated compounds were tested against A549 human lung cancer cells and MRC-5 human normal lung epithelial cells. Compounds 1—5 exhibited potent anti-proliferative effects against A549 lung cancer cells with IC₅₀ values of 12—53 nM, whereas these compounds were relatively non-cytotoxic against MRC-5 normal lung epithelial cells.

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To search for secondary metabolites of Alnus hirsuta (Betulaceae), various chromatographic separations of the ethyl acetate soluble fraction of the stem bark of A. hirsuta led to the isolation of a new diarylheptanoid glycoside, (3R)-1,7-bis-(4-dihydroxyphenyl)-3-heptanol 3-O-β-D-glucopyranosyl(1→3)-β-D-xylopyranoside (13) and twelve diarylheptanoid derivatives, namely, oregonin (1), rubranoside A (2), hirsutanonol 5-O-β-D-glucopyranoside (3), rubranoside B (4), rubranoside C (5), hirsutanonol (6), hirsutenone (7), (5S)-O-methylhirsutanonol (8), platyphylloside (9), platyphyllonol 5-O-β-D-xylopyranoside (10), aceroside VII (11) and platyphyllenone (12). Isolates were assessed for their hepatoprotective effects against tert-butylhydroperoxide (t-BHP)-induced toxicity in HepG2 cells. Of these isolates, compounds 1—8 showed significant hepatoprotective effects on t-BHP-induced damage to HepG2 cells, with 8 exhibiting the greatest protective effect (50.7±3.7% at a concentration of 10 μM).

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A series of novel podophyllotoxin (PDT) analogues was synthesized in which the lactone moiety was shifted to C ring. Some of the derivatives were also synthesized with modified A ring. Analogues 23 and 25 exhibited potent in vitro cytotoxicity against colon cancer (CaCO₂) cell line. p-Demethylated E-ring analogues exhibited better potency than the corresponding methylated analogues. These analogues showed toxicity comparable to PDT against human erythrocytes albeit at much higher concentrations (100 μg/ml) than their cytotoxicity values.

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The aim of this study was to examine the effect of D-sorbitol on the gelation characteristics of methylcellulose in aqueous solution. The addition of D-sorbitol at concentrations of between 25 and 30% (w/v) to 1.0—2.0% (w/v) methylcellulose solutions reduced the gelation temperature from approximately 53 °C to values between ambient and 37 °C and increased the strength of the gel. The in vitro release of acetaminophen (paracetamol) from 2.0% (w/v) methylcellulose gels containing 20—30% (w/v) D-sorbitol gel was diffusion-controlled.

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Chemical investigation of the soft coral Sinularia leptoclados has afforded three new sesquiterpenoids, leptocladols A (1), B (2), and 1-epi-chabrolidione A (3). The relative structures of 1—3 were determined on the basis of extensive spectroscopic analysis. The relative configuration of 1 was further confirmed by a single-crystal X-ray diffraction analysis.

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A novel coumarin (1, mucodianin A), three new 2-arylbenzofurans (2—4, mucodianins B—D) along with four known ones were isolated from the vine stems of Mucuna birdwoodiana. Their structures were elucidated on basis of spectral analysis. This is the first report of 7-quinonylcoumarin (1) as stable form in natural products.

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Four new 2-arylbenzofuran derivatives, moracins V—Y (1—4), together with two known compounds, moracin N (5) and moracin P (6), were isolated from the leaves of Morus alba L. Their structures were elucidated by spectroscopic analysis. Moracins X (3) and Y (4) represent unusual substituted group compared with 2-arylbenzofuran derivatives, which were isolated from the genus Morus. Compounds 2—5 were evaluated for cytotoxicity against several human cancer cell lines.

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Tricalysiosides V and W, two new ent-kaurane glycosides with an acylated disaccharide moiety at the C-3 position, were isolated from the roots of Tricalysia okelensis and their structures established by spectroscopic and chemical methods as ent-kauran-3α,16α,17-triol-19-al 3-O-[5-O-vanilloyl-β-D-apiopyranosyl(1→6)]-β-D-glucopyranoside (1) and ent-kauran-3α,16α,17-triol-19-al 3-O-[5-O-E-sinapoyl-β-D-apiopyranosyl(1→6)]-β-D-glucopyranoside (2).

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Enantiomerically enriched sulfonamides were synthesized by the radical addition of an acetal to enantiomerically pure N-sulfinyl imines using dimethylzinc–air and boron trifluoride diethyl etherate. Higher levels of stereocontrol were observed by using a mesitylenesulfinyl group. Furthermore, an amine and an amino alcohol with high enantiomeric purity were obtainable from the sulfonamide product.

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Pyridine-functionalized MCM-41 catalyzed reactions between tetracyanoethylene and various activated CH-acid compounds are described. These reactions afford the corresponding pyran annulated heterocyclic ring systems in high yields at room temperature within a few minutes. The work-up procedure is very simple and the products do not require further purification. The catalyst can be recycled and reused for several times without observable loss of performance.

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