The ability of nanoparticles to manipulate the molecules and their structures has revolutionized the conventional drug delivery system. The chitosan nanoparticles, because of their biodegradability, biocompatibility, better stability, low toxicity, simple and mild preparation methods, offer a valuable tool to novel drug delivery systems in the present scenario. Besides ionotropic gelation method, other methods such as microemulsion method, emulsification solvent diffusion method, polyelectrolyte complex method, emulsification cross-linking method, complex coacervation method and solvent evaporation method are also in use. The chitosan nanoparticles have also been reported to have key applications in parentral drug delivery, per-oral administration of drugs, in non-viral gene delivery, in vaccine delivery, in ocular drug delivery, in electrodeposition, in brain targeting drug delivery, in stability improvement, in mucosal drug delivery in controlled drug delivery of drugs, in tissue engineering and in the effective delivery of insulin. The present review describes origin and properties of chitosan and its nanoparticles along with the different methods of its preparation and the various areas of novel drug delivery where it has got its application.

View full abstract

(23E)-25-Methylcycloart-23-en-3β-ol (1), a cycloartane-type triterpenoid featuring an unusual skeleton of 31 carbon atoms, (17E)-cycloart-17,26-dien-3β-ol (2), a new cycloartane-type triterpenoid, and the other two new compounds 4R-hydroxy-4-(9S-hydroxy-12-methylhexan-6-yl)-3-methylcyclopent-2-enone (6) and 7-hydroxy-5-(2′-hydroxy-4′,5′-dimethoxyphenyl)-2-methoxy-6-methyl-1,4-naphthoquinone (7), together with three known cycloart-3β-ol triterpenoids (3—5) were isolated from aerial parts of Aphanamixis grandifolia. Their structures were elucidated by spectroscopic analysis, and that of 1 was confirmed by single-crystal X-ray diffraction. The absolute configuration of two carbon stereocenters of compound 6 was determined to be 4R,9S by means of circular dichroism (CD) and auxiliary chiral α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) derivatives, respectively. The compound 3 exhibited significant cytotoxicities against HL-60, Hep G2 and HeLa, and compounds 1, 2, 5, 6 and 7 exhibited modest cytotoxicities. No activity of compound 4 could be due to the absence of the hydroxyl group at C-24.

View full abstract

A series of novel glutarimide compounds were synthesized and their antiviral activities were evaluated. The compounds displaying the strongest antiviral activities included 5, 6f, 7e and 9 against coxsackievirus B3 (Cox B3), 10 and 6f against influenza virus A (influenza A) and 7a against herpes simplex virus 2 (HSV-2). However, most of the synthetic glutarimides showed comparatively much weaker activity against influenza A, Cox B3 and HSV-2 than the natural glutarimide compounds tested. Based on the results, it seemed likely that a conjugated system at the β-substituted moiety provides stronger antiviral activity.

View full abstract

New potent antioxidants conjugating the catechol (=pyrocatechol; pyrCat) group to two N-termini of modified double-stranded tyrosine residues were synthesized and showed radical scavenging activity with 2,2-diphenyl-1-picrylhydrazyl radical (DPPH radical, DPPH˙) as a free radical model, second-order rate constants for the DPPH˙ scavenging reaction, and the results from electron spin resonance (ESR) studies. It was found that the tyrosine (Tyr) residue and pyrCat containing new antioxidants developed in the study have about 3—20 times more potent antioxidative activity than Trolox, pyrCat, and L-ascorbic acid (VC). In order to elucidate the relationship between antioxidant activity and the molecular orbital states, and to design potent antioxidants we present an interesting approach using an absolute hardness (η)–absolute electronegativity (χ) diagram based on chemical hardness. It was shown that quantum chemicals were required to develop potent antioxidants.

View full abstract

The aim of this work was to investigate the effect of altered water activity on Hoechst 33258–calf thymus DNA (CtDNA) interaction by using osmotic stress approach. Water activity was changed by using osmolytes viz., sucrose and triethylene glycol (TEG). We have reported the results of thermal denaturation, absorption and fluorescence spectroscopy and binding affinity measurements as a function of osmolytes concentration. TEG dramatically lowered the thermal stability of CtDNA, ΔT_m=−16 °C whereas sucrose induced very little decrease. Hoechst 33258 increases the stability of CtDNA, but in the presence of TEG, the ΔT_m was −37 °C and a marginal decrease was observed with sucrose. Binding affinity of Hoechst 33258 with CtDNA was found to be reduced from 4.75×10⁷ to 0.16×10⁷ M⁻¹ in TEG and this was accompanied with the increased uptake of 74±2 water molecules. In the presence of sucrose this uptake of water molecules was found to be 30±1. Method of continuous variation suggests that the osmolytes lowered the stoichiometry of Hoechst 33258–CtDNA complex. On the contrary, van't Hoff plot revealed the hydrophobic interaction (ΔS=130.66 J mol⁻¹ K⁻¹) between the Hoechst 33258 and CtDNA. The detailed absorption and fluorescence spectral measurements including the fluorescence lifetime and anisotropy indicated bound state of Hoechst 33258 in osmotic stress condition. Fluorescence lifetime measurement revealed that the contribution from the planar conformer of Hoechst 33258 dominated the binding interaction with CtDNA in presence of TEG. These results can be useful for understanding of interaction of Hoechst 33258 with genomic DNA in a complex environment having altered water activity.

View full abstract

Breviscapine is a Traditional Chinese Medicine treating cardiovascular diseases by promoting blood circulation and removing blood stasis. The major active component of breviscapine has low aqueous solubility, poor chemical stability, short biological half-life and rapid elimination rate from the plasma. The use of a lipid emulsion formulation containing breviscapine might improve chemical stability, increase drug loading, exhibit sustained release profile. In the present study, we developed an optimized formulation and technological method for the preparation of sterile and stable breviscapine lipid emulsion (Bre-LE) for intravenous infusion. The average particle size, polydispersity index, zeta potential, stability constant (K_s) value and content of final product were (225.3±8.8) nm, 0.221±0.020, (−29.6±1.5) mV, (24.3±2.9)% and (94.5±0.6)% respectively (n=3). The results of in vitro release experiment suggest that lipid emulsion as breviscapine carrier showed a desirable sustained release profile. Dilution stability and long-term stability were also researched in the present paper. The results show the carrier could protect drug from degradation after dilution by phosphate buffered saline and fetal calf serum. And Bre-LE was stable for up to 6 months at room temperature storage condition. The biodistribution of drug in heart of mice increased dramatically after encapsulation into lipid emulsion which was beneficial to heart disease therapy.

View full abstract

The objective of this work was to develop a safe and effective delivery vehicle for topical treatment of gemcitabine. The physicochemical properties, drug release rate, drug level in plasma and bladder, and histological changes of tissue after drug administration were investigated. The electrical conductivity, mean size, and viscosity of drug-loaded microemulsions were 0.8—102.0 μS/cm, 116.8—322.5 nm, and 42.9—105.0 cps×10³, respectively. Gemcitabine loaded microemulsions showed a slower and sustained release. After intravesical administration of aqueous control and microemulsions treated, the drug concentrations in plasma were 15.11 μg/ml and 2.81—12.82 μg/ml, respectively, and the accumulation in bladder were 18.27 μg and 9.12—64.16 μg, respectively. Microemulsions slightly decreased the systemic absorption and significantly enhanced the accumulation in bladder tissue. Moreover, the preliminary toxicity studies revealed no overt adverse histological changes or tissue irritation by the microemulsion application. Therefore, the microemulsions were suggested to be a promising drug carrier for intravesical chemotherapy.

View full abstract

Transdermal patches of meloxicam (MX) and lornoxicam (LX) were aimed to be prepared in order to overcome their side effects by oral application. The strategy was formulation of optimized films to prepare transdermal patches by determination of physical properties and investigation of drug–excipient compatibility. As the next step, in vitro drug release, assesment of anti-inflammatory effect on Wistar Albino rats, ex vivo skin penetration and investigation of factors on drug release from transdermal patches were studied. Hydroxypropyl methylcellulose (HPMC) was concluded to be suitable polymer for formulation of MX and LX transdermal films indicating pharmaceutical quality required. MX and LX transdermal patches gave satisfactory results regarding to the edema inhibition in the assessment of anti-inflammatory effect. MX was found out to be more effective compared to LX on relieving of edema and swelling. These results were supported by data obtained from ex vivo penetration experiments of drug through rat skin. Indicative parameters like log P, molecular weight and solubility constraint on penetration rate of drugs also indicated good skin penetration. Transdermal patches of MX and LX can be suggested to be used especially for the immediate treatment of inflammated area since it displays anti-inflammatory effect, soon.

View full abstract

Exenatide (synthetic exendin-4), a 39-amino acid peptide, was encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) microspheres as a sustained release delivery system for the therapy of type 2 diabetes mellitus. The microspheres were prepared by a double-emulsion solvent evaporation method and the particle size, surface morphology, drug encapsulation efficiency, in vitro release profiles and in vivo hypoglycemic activity were evaluated. The results indicated that the morphology of the exenatide PLGA microspheres presented as a spherical shape with smooth surface, and the particle sizes distributed from 5.8 to 13.6 μm. The drug encapsulation efficiency tested by micro-bicinchoninic acid (BCA) assay was influenced by certain parameters such as inner and outer aqueous phase volume, PLGA concentration in oil phase, polyvinyl alcohol (PVA) concentrations in outer aqueous phase. Moreover, in vitro release behaviors were also affected by some parameters such as polymer type, PLGA molecular, internal aqueous phase volume, PLGA concentration. The pharmacodynamics in streptozotocin (STZ)-induced diabetic mice suggested that, exenatide microspheres have a significant hypoglycemic activity within one month, and its controlling of plasma glucose was similar to that of exenatide solution injected twice daily with identical exenatide amount. In conclusion, this microsphere could be a well sustained delivery system for exenatide to treat type 2 diabetes mellitus.

View full abstract

To evaluate the usability of silk protein (sericin, SC) as a sustained-release material, the physicochemical properties of SC and the release profiles of model drugs from SC gel, sponge and film were studied. Heat aids the dissolution of SC. The molecular weight of SC tended to decrease as the heating temperature and heating time increased. The gel and sponge formed by SC were moldable and consisted of high molecular weight SC polymers (250 kDa and about 400 kDa). SC film was easily broken and exhibited elastic distortion. The addition of moisture-retaining plasticizer (glycerin and sorbitol) improved the film-forming characteristics of SC. The results suggested that SC is practical as a moldable gel and sponge, and as a tensible film. To evaluate the release profiles of small molecules, fluorescein isothiocyanate-dextran ((1) FD4, 4 kDa and (2) FD70, 70 kDa) were used as two model drugs with significantly different molecular weights, and fluorescein isothiocyanate-albumin ((3) FA, 66 kDa) was used as a charged drug. Each was formulated in SC gel, sponge and film. In each preparation, the release rate of the model drugs tended to be FA<FD70<FD4. FA, which has a large molecular weight and negative charge, was released for the longest period of time (≥1 week) from each preparation. The results suggest that SC is usable as an aqueous sustained-release material for high molecular weight drugs. Furthermore, if the drug is charged, its release can be sustained for an extended time.

View full abstract

A new geranylated coumarin, (E)-4-(1-hydroxypropyl)-5,7-dihydroxy-6-(3,7-dimethyl-2,6-octadienyl)-8-(3-methyl-1-oxobutyl)coumarin (named surangin D), was isolated from the bark of Mammea siamensis collected in Vietnam, along with four known coumarins, surangins B and C, and theraphins B and C, and seven xanthones, 1,7-dihydroxyxanthone, 7-hydroxy-1-methoxyxanthone, 1,7-dimethoxyxanthone, 1,7-dimethoxy-6-hydroxyxanthone, 1,6,7-trihydroxyxanthone, 1,3,7-trihydroxyxanthone, and 1,7-dihydroxy-3-methoxyxanthone. Their structures were determined by spectroscopic methods (mainly 1D- and 2D-NMR) and preparation of methylated derivatives. The four coumarins, surangins C and D and theraphins B and C, were tested for inhibition of cell proliferation in DLD-1 (colon cancer), MCF-7 (breast adenocarcinoma), HeLa (human cervical cancer) and NCI-H460 (human lung cancer) cell lines using the sulforhodamine B (SRB) assay. In all four cell lines, theraphin C showed the strongest activity (IC₅₀ in the range of 1.6—5.7 μM). Testing the anti-proliferative effect of the methylated derivatives showed reduced cellular effects of all derivatives, indicating that the number and position of free hydroxyl groups were very important for the anti-proliferative effect.

View full abstract

The practical synthesis of important natural polyphenolic stilbenes, including resveratrol, piceatannol and oxyresveratrol, through Perkin methodology is described. Starting from 3,5-dihydoxyacetophenone (1), the common intermediate 3,5-dimethoxyphenylacetic acid (3) can be obtained via methylation and Willgerodt–Kindler reaction. Perkin condensations between (3) and substituted phenylaldehydes 4 furnished E-2,3-diarylacrylic acids 5, followed by decarboxylation in Cu/quinoline giving stilbene intermediates 6 which bear the Z-configuration. Finally, through a simultaneous demethylation/isomerization process in AlI₃/CH₃CN system, the target compounds 7a—c can be obtained respectively in good to high overall yields. The synthetic method proved to be more concise, trans-specific, mild, economical and commonly applicable.

View full abstract

Kampo medicines, traditional herbal medicines in Japan, are comprised of multiple botanical raw materials that contain a number of pharmacologically active substances. Conventionally, the quality control of kampo medicines has been performed by analyzing the contents of two or three representative components. However, it is not sufficient to check quality only with a limited number of specific components. We performed HPLC of 287 lots of keishibukuryogan formulas, calculated the areas of 11 components on chromatograms as feature values and made a cluster analysis using self-organizing maps (SOMs). We verified the precision (repeatability and intermediate precision) of clustering results when using the same samples and successfully established an clustering method using SOMs that is capable of precisely clustering differences in HPLC-fingerprints among pharmaceutical manufacturers, differences in HPLC-fingerprints due to the combination ratios of botanical raw materials, and differences in HPLC-fingerprints due to changes in component contents caused by time-course deterioration. Consequently, we could confirm that this method is useful for controlling the quality of multiple component drugs and analyzing quality differences.

View full abstract

The alkaline treatment of the pyridinium salts, readily available from the S-alkylations of 3-amino-4-(1-pyridinio)thiophene-5-thiolates with various alkyl halides, in chloroform at room temperature afforded the corresponding thieno[3′,4′:4,5]imidazo[1,2-a]pyridine derivatives in low to moderate yields via the intramolecular cyclization of the resulting 1,5-dipoles followed by the aromatization of the primary cycloadducts. Interestingly, the reactions using unsymmetrical 3-amino-4-[1-(3-methylpyridinio)]thiophene-5-thiolates afforded only 8-methylthieno[3′,4′:4,5]imidazo[1,2-a]pyridines and the other 6-methyl derivatives were not formed at all. In addition the isolation of a byproduct in the condensation reaction of pyridinium salt with the solvent (CHCl₃) is also discussed.

View full abstract

Stereoselective formal synthesis of (+)-allokainic acid was accomplished starting from L-glutamate by using a thiol-mediated acyl radical cyclization as a key step. The cyclization of a formylalkenoate proceeded in a highly diastereoselective manner to give trans-4,5-disubstituted pyrrolidin-3-one without the production of the cis-isomer. The pyrrolidinone was then converted into the established synthetic intermediate of (+)-allokainic acid via the iron-catalyzed coupling reaction with an isopropenyl Grignard reagent.

View full abstract

Density functional theory (DFT) calculations at the B3LYP/6-31G(d) level demonstrated that sodium O-(3-phenylallyl) dithiocarbonate undergoes [3,3]-sigmatropic rearrangement to sodium S-(1-phenylallyl) dithiocarbonate, which then isomerizes to the more thermodynamically stable sodium S-(3-phenylallyl) dithiocarbonate. The calculations also showed that sodium 2-alkenyl trithiocarbonates and their esters are more labile towards the allylic rearrangement.

View full abstract

There have been few reports wherein drug migration from the interior to the surface of a tablet has been analyzed quantitatively until now. In this paper, we propose a novel, rapid, quantitative analysis of drug migration in tablets using laser induced breakdown spectroscopy (LIBS). To evaluate drug migration, model tablets containing nicardipine hydrochloride as active pharmaceutical ingredient (API) were prepared by a conventional wet granulation method. Since the color of this API is pale yellow and all excipients are white, we can observe the degree of drug migration by visual inspection in these model tablets. In order to prepare tablets with different degrees of drug migration, the temperature of the drying process after tableting was varied between 50 to 80 °C. Using these manifold tablets, visual inspection, Fourier transform (FT)-IR mapping and LIBS analysis were carried out to evaluate the drug migration in the tablets. While drug migration could be observed using all methods, only LIBS analysis could provide quantitative analysis wherein the average LIBS intensity was correlated with the degree of drug migration obtained from the drying temperature. Moreover, in this work, we compared the sample preparation, data analysis process and measurement time for visual inspection, FT-IR mapping and LIBS analysis. The results of the comparison between these methods demonstrated that LIBS analysis is the simplest and the fastest method for migration monitoring. From the results obtained, we conclude that LIBS analysis is one of most useful process analytical technology (PAT) tools to solve the universal migration problem.

View full abstract

Based on our structure–activity relationship study of liver X receptor (LXR) ligands, we designed and synthesized fluorescent LXR antagonists containing an unsubstituted or substituted amino group on a phthalimide unit.

View full abstract

New 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine and 1,3-thiazole derivatives incorporating indole nucleus were prepared using 3-acetylindole as precursor and evaluated for their antiviral activity against herpes simplex type 1 (HSV-1).

View full abstract

Two new phenolic amides, pharnilatins A (1) and B (2), were isolated from the seeds of Pharbitis nil. These new compounds possess a p-coumaroyl unit with a structurally unique side chain, (2S,3S)-2,3-dihydroxyputrescine. The chemical structures and absolute stereochemistries of the new compounds were determined on the basis of spectroscopic analyses including 1D- and 2D-NMR experiments and chemical reactions. Compounds 1 and 2 exhibited cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 human tumor cells. However, none of the compounds inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-activated microglia cells.

View full abstract

N-(3,5-Dihydroxybenzoyl)-6-hydroxytryptamine (2) was a novel inhibitor of L-3,4-dihydroxyphenylalanine (DOPA) oxidase activity of human HMV-II melanoma tyrosinase. The IC₅₀ values for 2 and three reference compounds, N-(3,5-dihydroxybenzoyl)serotonin, 6-hydroxyindole, and kojic acid, were 9.1, 842, 22, and 310 μM, respectively, indicating that the 6-hydroxyindole moiety was more effective than 5-hydroxyindole as the pharmacophore of polyphenolic tyrosinase inhibitors and that the inhibitory activity of 6-hydroxyindole was strengthened by the link with a resorcinol group. Furthermore, compound 2 exhibited a unique property of inactivating the human tyrosinase in the presence of low concentrations of DOPA. This inactivation was attenuated by high concentrations of DOPA and for the most part was irreversible as confirmed by activity stain in native polyacrylamide gel electrophoresis and by removal of 2 and DOPA using gel permeation chromatography. Tyrosinase is the enzyme that oxidizes tyrosine to DOPA and further oxidizes DOPA to the melanin precursor dopaquinone. A compound such as 2 that inactivates the enzyme in the presence of a small amount of DOPA is therefore attractive as a new type of tyrosinase inhibitor. Unfortunately, 2 hardly suppressed the melanogenesis in melanoma cell culture. However, the above strong inhibitory activity and the unique property in the combination with DOPA suggest that this compound is a useful lead in designing new antimelanogenic agents.

View full abstract

Four new ursane-type triterpenes, olibanumols K (1), L (2), M (3), and N (4), were isolated from traditional Egyptian medicine olibanum, the exuded gum-resin from Boswellia carterii BIRDW. Their structures were elucidated on the basis of chemical and physicochemical evidence.

View full abstract

Two new butenolides, butyrolactones VI (1) and VII (2), were isolated together with six known compounds, butyrolactones I (3), II (4), IV (5), and V (6), aspernolide B (7), and bisdethiodi(methylthio)acetylaranotin (8) from the fungus Aspergillus terreus BCC 4651. Compound 8, exhibiting a minimum inhibitory concentration (MIC) value of 1.56 μg/ml against Mycobacterium tuberculosis H37Ra, proved to be the antimycobacterial principle from the culture of this fungus. On the other hand, butyrolactone V (6) showed antiplasmodial activity against Plasmodium falciparum K1 with an IC₅₀ of 7.9 μg/ml.

View full abstract

In a search for natural products with activity to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance, we performed the bioassay-guided fractionation of a semi mangrove, Pongamia pinnata, collected from Bangladesh, and isolated a new compound, (2S)-(2″,3″:7,8)-furanoflavanone (1), along with six known flavonoids (2—7). Two of the compounds significantly overcame TRAIL-resistance in human gastric adenocarcinoma (AGS) cell lines.

View full abstract

A structure involving the absolute configuration of acinetobactin (1b) was clarified. It was reconfirmed that preacinetobactin (1a) produced 1b by a rearrangement reaction.

View full abstract

Acknowledgments: This work was supported by the RIC Program of the Ministry of Knowledge and Economy (MKE). The authors are grateful to S. H. Kim and collaborators at the Korea Basic Science Institute (Daegu) for measuring the mass spectra.

View full abstract