To improve powder flow of a high-dose direct compression formulation (drug content 30%), we compared a two-step operation for mixing glidants with a conventional one-step glidant mixing process. This two-step mixing operation was studied with two kinds of mixtures; an active pharmaceutical ingredient (API)-glidant combination and a direct compression excipient-glidant combination. The two-step operation permitted the selection of the optimum glidant type and concentration in each glidant-mixing procedure even though the formulation had different powder properties such as micronized API and enlarged direct compression vehicles, whereas the conventional approaches forced the selection of a certain glidant type and concentration at one-step mixing. The addition of 0.5% nonporous silica markedly improved API flow. In contrast, 1.0% porous silica was the appropriate glidant to enhance excipient flow at direct compression excipient-glidant mixing. The two-step operation dominantly enhanced powder flow when the appropriate API-glidant mixture and the suitable direct compression excipients-glidant mixture were blended compared to the one-step operation with its optimum glidant concentration. The results showed that the angle of repose was 43° and the critical orifice diameter was 10 mm in the two-step operation, whereas it was 47° and 16 mm in the one-step operation. The two-step operation of glidant mixing enhanced powder flow of the high-dose direct compression formulation compared with the one-step operation. The two-step operation eliminates the bottleneck of powder flow and allows direct compression to be more worth applying for formulation and process development trials.

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To prove the presence of a hydrogen–deuterium (H–D) exchange reaction, ¹H- and ¹³C-NMR spectra of warfarin were measured in solvents containing D₂O and H₂O. In D₂O or D₂O/dimethyl sulfoxide (DMSO)-d₆ solvent, signal pattern changes were observed on H12 and H11 as well as 14 methyl protons over time while no changes were observed on H₂O or H₂O/DMSO-d₆ solvent. The observed changes in the solvents containing D₂O were concluded to be caused by the H–D exchange reaction on H12, the process of CH₂→CHD→CD₂. MS spectroscopy also confirmed these H–D exchanges. The kinetics of this reaction were analyzed as the successive reaction, and the mechanism was also proposed.

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A spray freeze drying (SFD) method was developed to prepare the composite particles of poorly water-soluble drug. The aqueous solution dissolved drug and the functional polymer was sprayed directly into liquid nitrogen. Then, the iced droplets were lyophilized with freeze-dryer to prepare solid particles. Tolbutamide (TBM) and hydroxypropylmethylcellulose (HPMC) were used as a model drug and water-soluble polymeric carrier in this study, respectively. The morphological observation of particles revealed that the spherical particles having porous structure could be obtained by optimizing the loading amount of drug and polymer in the spray solution. Especially, SFD method was characterized that the prepared particles had significantly larger specific surface area comparing with those prepared by the standard spray drying technique. The physicochemical properties of the resultant particles were found to be dependent on the concentration of spray solution. When the solution with high content of drug and polymer was used, the particle size of the resulting composite particles increased and they became spherical. The specific surface area of the particles also increased as a result of higher concentration of solution. The evaluation of spray solution indicated that these results were dependent on the viscosity of spray solution. In addition, when composite particles of TBM were prepared using the SFD method with HPMC as a carrier, the crystallinity of TBM decreased as the proportion of HPMC increased. When the TBM : HPMC ratio reached 1 : 5, the crystallinity of the particles completely disappeared. The dissolution tests showed that the release profiles of poorly water-soluble TBM from SFD composite particles were drastically improved compared to bulk TBM. The 70% release time T₇₀ of composite particles prepared by the SFD method in a solution of pH 1.2 was quite smaller than that of bulk TBM, while in a solution of pH 6.8, it was slightly lower. In addition, the release rates were faster than those of standard spray dried (SD) composite particles for solutions of pH 1.2 and 6.8, respectively. When composite particles were prepared from mixtures with various composition ratios, T₇₀ was found to decrease as the proportion of HPMC increased; the release rate was faster than that of bulk TBM in a solution of pH 6.8, as well as solution of pH 1.2.

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Calcium pectinate gel (CPG) micrometer-sized beads (microbeads) containing insulin, as a model amphoteric protein, were prepared by ionotropic gelation technique together with an air compressor. The influences of phosphate buffer, pH as well as calcium and pectin concentrations of cross-linking solution on the characteristics and release profiles of microbeads were investigated. With the aid of compressed air flow, the mean diameters of beads were successfully decreased to micron-sized. The results showed that all the factors investigated greatly affected the entrapment efficiencies and release profiles of the microbeads. Suitable formulation concentrations should be considered and great care should be taken to maintain the pH of working solutions at or close to isoelectric point of protein loaded during the whole preparation process. Hence, CPG microbeads of perfect spherical shape, uniform sizes, enhanced mechanical strength, good entrapment efficiencies and delayed release profiles were prepared for a load of amphoteric protein and peptide drugs, without any use of organic solvents or harsh ingredients. Therefore, CPG microbeads could be a promising carrier for oral controlled-release systems of amphoteric protein and peptide drugs.

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Fourteen new bisnor- and norditerpene dilactones, makilactones E—R, having a 7α : 8α-epoxy-9,11-enolide substructure, were isolated from a methanolic extract of the root and the bark of Podocarpus macrophyllus D. DON (Podocarpaceae) with thirteen known bisnor- and norditerpenoids, and the structures of those new bisnor- and norditerpenoids were determined on the basis of their spectroscopic studies. Of the thirteen known ones isolated, the structures of two, i.e., podolactone B and inumakilactone B, were revised on the basis of X-ray crystallographic analysis and spectroscopic analysis. Many of the compounds of this type isolated in this study showed potent cytotoxic activities against P388 murine leukemia cells.

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A series of isopropyl fatty esters having different chain length (C₁₃—C₂₃) were synthesized and formulated in lipid nanoparticles based on Precirol^® ATO to evaluate their effect on the physicochemical properties of these latter. Moreover, drug loading and skin permeation of Econazole nitrate, chosen as a lipophilic model drug, were evaluated as well. The obtained nanosystems, prepared by high shear homogenization method, had a mean diameter ranging from 180 to 280 nm and showed an encapsulation efficiency of about 100%. Ex vivo permeation results demonstrated a parabolic correlation between permeation effect and chain length of the fatty esters present in the lipid nanoparticles formulated in hydrophilic gels. The maximum flux of drug was observed for the nanoparticles containing esters with 17 and 19 carbon atoms, suggesting that these formulations may constitute a potential carrier for topical delivery of econazole nitrate.

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A new series of bis-[4-methoxy-3-[3-(4-fluorophenyl)-6-(4-methylphenyl)-2-(aryl)-3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d][1,3]thiazol-5-yl]phenyl]methanes 6a—r was synthesized by the reaction of arylidine derivative of methylene-bis-thiazolidinones 5a—c with aryl/alkyl hydrazines. Chemical structures of all the new compounds were established by IR, ¹H-NMR, ¹³C-NMR, MS and elemental data. The compounds 6a—r were evaluated for their nematicidal activity against Ditylenchus myceliophagus and Caenorhabdites elegans by aqueous in vitro screening technique. Amongst them compounds containing N-benzylpyrazole moiety (6d, 6j, 6p), and N-methylpyrazole moiety (6f, 6l, 6r) showed significant nematicidal activity against both the test nematodes with LD₅₀ 160—210 ppm, almost equal to the oxamyl standard. Further, these compounds 6a—r were screened for their antibacterial (MZI, MIC and MBC) activity against three representative Gram-positive bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11), Staphylococcus aureus (MTCC 96) and three Gram-negative bacteria viz. Pseudomonas aeruginosa (MTCC 741), Klebsiella aerogenes (MTCC 39), Chromobacterium violaceum (MTCC 2656) and also screened for their antifungal (MZI, MIC and MFC) activity against four fungal organisms viz. Candida albicans (ATCC 10231), Aspergillus fumigatus (HIC 6094), Trichophyton rubrum (IFO 9185) and Trichophyton mentagrophytes (IFO 40996). Most of these new compounds showed appreciable activity against test bacteria and fungi, and emerged as potential molecules for further development.

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Interactions of certain amino acids with some metal ions have significant consequences in biological systems. Metal ions can act as co-factors in the regulation of enzymatic reactions. Interactions of metal ions with amino acid side chains or with different organic complexes is also essential for many biological events. In this study, the stability constants of 1 : 1 : 1 ternary complexes of Cu(II) with 1,10-phenanthroline (Phen) as the primary ligand, and 2,2′-bipyridyl (Bpy) and some selected α-amino acids [(glycine (Gly), leucine (Leu), glutamine (Gln)] as secondary ligands, were identified in I=0.1 M ionic medium at t=(25±0.1) °C in aqueous solutions, by potentiometry. The protonation constants of the free ligands and the stability constants of the binary and ternary systems were also determined under the same experimental conditions. The protonation constants of all of the ligands and the stability constants of the formed complexes were evaluated by using the BEST computer program. The stabilities of the ternary complexes have been quantitatively compared with those of the corresponding binary complexes in terms of the some parameters. The concentration distributions of the complexes in solution were also evaluated. Species distributions as a function of pH reveal that the MAB ternary complexes predominate over a pH range, where M=Cu(II); A=Phen; B=Bpy, Gly, Leu and Gln.

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It is shown that o-carboxyphenylglyoxal, which is converted from ninhydrin by alkali, produces a chemiluminescent lucigenin reaction under alkaline conditions when with reacted with guanidino compounds. It is also demonstrated that phenylglyoxal, which is a model compound of o-carboxyphenylglyoxal, produces a strong chemiluminescent lucigenin reaction under alkaline conditions when reacted with guanidino compounds. Moreover, ESR spectra showed the presence of 5,5-dimethyl-1-pyrroline N-oxide (DMPO)–spin adducts of superoxide anions in a mixture of phenylglyoxal and guanidino compounds under alkaline conditions. It was confirmed that the superoxide anions were generated by the reaction of phenylglyoxal with guanidino compounds under alkaline conditions, thereby causing lucigenin chemiluminescence. The chemiluminescent reaction of lucigenin in a mixture of phenylglyoxal and the guanidino compounds was applied to HPLC for guanidino compounds. The present chemiluminescence-HPLC system has a 2-fold greater sensitivity than chemiluminescence-HPLC using ninhydrin. Arginine, guanidine and methylguanidine were detected in serum from a hemodialysis patient with chronic renal failure.

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In this study, chemical feature-based 3-dimensional (3D) pharmacophore models of Checkpoint kinase 1 (Chk1) inhibitors were developed based on the known inhibitors of Chk1. The best pharmacophore model Hypo1 was characterized by the best correlation coefficient (0.9577), and the lowest root mean square deviation (0.8871). Hypo1 consists of one hydrogen-bond acceptor, one hydrogen-bond donor, and two hydrophobic features, as well as one excluded volume. This pharmacophore model was further validated by both test set and cross validation methods. A comparison analysis of Hypo1 with chemical features in the active site of Chk1 indicates that the pharmacophore model Hypo1 can correctly reflect the interactions between Chk1 and its ligands. Then Hypo1 was used to screen chemical databases, including Specs and Chinese Nature Product Database (CNPD) for potential lead compounds. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking study to refine the retrieved hits. Finally some of the most potent (estimated) compounds were selected from the final refined hits and suggested for further experimental investigation.

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The facile and clean oxidative biaryl coupling reaction of thiophenes and pyrroles has been achieved using the recyclable hypervalent iodine(III) reagents having adamantane or methane structures. These iodine(III) reagents could be recovered from the reaction mixtures by a simple solid–liquid separation, i.e., filtration.

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We constructed a minilibrary using a solution-phase synthesis through coupling of three core amino compounds (5′-amino-5′-deoxy uridine, 5′-amino-2′,5′-di-deoxy arabinosyl uridine, and butan-1-amine) with 30 carboxylic acids via amide bond formation. The simplified structural core compound butan-1-amine was selectively coupled with 9 carboxylic acids as control. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay of the crude mixtures showed that analogues derived from fenbufen, butylfenbufen C15; ethacrynic acid, butyl ethacrynic amide C18; and sphingosines, Sph-1, Sph-2 and U27 had an increased cytotoxicity against MCF-7 cells as well as A549 cells. Structural elucidation with molecular docking suggested that cytotoxicity of these compounds is mainly due to the inhibition of enzymes regulating cellular apoptosis.

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Two new guaiane-type sesquiterpene (1, 2), 2 new phenylpropanoid derivatives (3, 4), and 5-oxo-11-hydroxy-8(Z)-undecenoic acid 11-O-glucoside (5), together with 17 known compounds have been isolated from the whole plants of Youngia japonica (L.) Dc., which have been known to be used as folk medicines to treat people suffering from atopy. The guaiane-type sesquiterpene, grosheimin (17) exhibited strong antiallergic and antioxidant activities.

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Six new triterpene glycosides (1—6), together with 11 known ones (7—17), have been isolated from a glycoside-enriched fraction prepared from the tubers of Anemone coronaria L. (Ranunculaceae). On the basis of extensive spectroscopic analysis, including 2D NMR data, and the results of hydrolytic cleavage, the structures of 1—6 were determined to be 3β-[(O-β-D-glucopyranosyl-(1→4)-O-[α-L-rhamnopyranosyl-(1→2)]-α-L-arabinopyranosyl)oxy]-2β,23-dihydroxyolean-12-en-28-oic acid (1), 3β-[(O-β-D-glucopyranosyl-(1→3)-O-α-L-rhamnopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-α-L-arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid (2), 3β-[(O-β-D-glucopyranosyl-(1→4)-O-[α-L-rhamnopyranosyl-(1→2)]-α-L-arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester (3), 3β-[(O-β-D-glucopyranosyl-(1→4)-O-[α-L-rhamnopyranosyl-(1→2)]-α-L-arabinopyranosyl)oxy]-2β,23-dihydroxyolean-12-en-28-oic acid O-α-L-rhamnopyranosyl-(1→4)-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester (4), 3β-[(O-β-D-glucopyranosyl-(1→4)-O-[α-L-rhamnopyranosyl-(1→2)]-α-L-arabinopyranosyl)oxy]-2β-hydroxyolean-12-en-28-oic acid O-α-L-rhamnopyranosyl-(1→4)-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester (5), and 3β-[(O-β-D-glucopyranosyl-(1→4)-O-[α-L-rhamnopyranosyl-(1→2)]-α-L-arabinopyranosyl)oxy]-23-hydroxyolean-18-en-28-oic acid O-α-L-rhamnopyranosyl-(1→4)-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester (6), respectively. Furthermore, the isolated compounds were evaluated for their cytotoxic activity against HSC-2 cells.

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Four acyclic diterpene glycosides were extracted from Habanero, the fruits of Capsicum chinense JACQ., which is known as one of the hottest peppers in existence. Two of these glycosides were identified as capsianoside XIII and capsianoside XV. The other two were new ones and were characterized as 3-O-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl 17,19-dihydroxy-6E,10E,14Z-(3S)-geranyllinalool 17-O-β-D-glucopyranosyl-(1→4)-α-L-rhamnopyranosyl-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside and 3-O-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl 6E,10E,14Z-(3S)-17-hydroxy-geranyllinalool 17-O-[3-O-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl 6′E,10′E,14′Z-(3′S)-13′R,19′-dihydroxy-geranyllinalool-16′-oyl (16′→2)-[α-L-rhamnopyranosyl-(1→3)]-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside.

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A new acridone alkaloid, 1,3-dihydroxy-4-methoxy-10-methylacridone (1), was isolated from leaves of the plant Micromelum integerrimum, together with two known carbazole alkaloids, glycozolinol (2) and methyl carbazole-3-carboxylate (3). Their structures were elucidated by extensive spectroscopic analysis.

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Uric acid of human plasma concentration accelerated nitrosation of N-acetylcysteine by diethylamine NONOate at neutral pH, but diminished that of N-acetyltryptophan. Uric acid also accelerated nitrosation of N-acetylcysteine by N-acetyl-N-nitrosotryptophan, having a nitroso group on the nitrogen atom of the indole ring. N-Acetyl-S-nitrosocysteine was stable even in the presence of uric acid and N-acetyltryptophan at neutral pH, while decomposition of N-acetyl-N-nitrosotryptophan was accelerated by uric acid and N-acetylcysteine. The results indicate that uric acid receives a nitroso group from diethylamine NONOate or N-acetyl-N-nitrosotryptophan, and passes it to the thiol group of N-acetylcysteine resulting in N-acetyl-S-nitrosocysteine. This implies that uric acid may act as an effective transporter of nitric oxide to thiols resulting in accumulation of nitrosothiols in humans.

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Phytochemical investigation of the leaves of Tamarix nilotica (Tamaricaceae) has led to isolation of methyl ferulate 3-O-sulphate (1) for the first time from natural sources. In addition, coniferyl alcohol 4-O-sulphate (2), kaempferol 4′-methyl ether (3), tamarixetin (4) and quercetin 3-O-β-D-glucupyranuronide (5) were isolated from the n-butanol soluble fraction of the extract. The pentacyclic triterpenoid, 3α-(3″,4″-dihydroxy-trans-cinnamoyloxy)-D-friedoolean-14-en-28-oic acid (6) was isolated from the n-hexane soluble fraction of the extract. The structures of these compounds were determined on the basis of spectroscopic analyses including 2 dimensional NMR. Compounds 3, 4 and 6 exhibited 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity with IC₅₀ values of 35.2, 37.0 and 21.2 μM, respectively.

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Two new flavonoid dimers (1, 2) consisting of flavan-chalcone together with three known compounds (3—5) were isolated from the ethanol extract of the whole plants of Sarcandra hainanensis. Their structures were determined by extensive spectroscopic analysis. Human immunodeficiency virus-1 integrase inhibition activities of compounds 1 and 2 were evaluated and they showed weak activities with IC₅₀ at 18.05 and 25.27 μM, respectively.

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A new characteristic steroidal glycoside of the 23S,26R-hydroxylated spirostanol-type named indioside F was isolated from the fruit of Solanum indicum, along with indioside A and protodioscin. On the basis of spectroscopic analysis, the structure of indioside F was found to be 3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D-glucopyranosyl (β-chacotriosyl) (22R,23S,25R,26R)-spirost-5-ene-3β,23,26-triol.

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The molecular structure of the double Diels–Alder (DDA) adduct derived from three-step thermal cascade reactions of 2,5-bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone with ethyl sorbate is elucidated by single crystal X-ray analysis. The structural features and the reaction mechanism of the adduct are discussed on the basis of density functional theory (DFT) calculation results.

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Two ways for the synthesis of binaphthyl were examined based on a chiral ligand-mediated asymmetric conjugate addition of 1-naphthyllithium to naththalene-2-carboxylic acid 2,6-di-t-butyl-4-methoxyphenyl esters. The one pot method by conjugate addition-elimination gave a relatively higher enantioselectivity than the two step synthesis based on addition and subsequent oxidative aromatization.

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Reaction of some fused tricyclic 3-(2-bromoethyl)pyrimidin-4(3H)-ones with primary alkyl amines gave abnormal fused 3-alkyl-4-alkyliminopyrimidines via a Dimroth-type rearrangement, as well as normal substituted 3-(2-alkylaminoethyl) derivatives in methanol. This abnormal rearrangement reaction depended on reaction solvent.

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Besides 12 known glycosides, five new steroidal glycosides have been isolated from the stems of Solanum sodomaeum L. (Solanaceae). The chemical structures of these five glycosides were determined on the basis of spectroscopic data as well as chemical evidence, and the structure of one known steroidal glycoside was corrected.

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