A growing number of functionally divergent the chalcone synthase (CHS) superfamily type III polyketide synthases (PKSs) have been cloned and characterized, which include recently obtained pentaketide chromone synthase (PCS) and octaketide synthase (OKS) from aloe (Aloe arborescens). Recombinant PCS expressed in Escherichia coli catalyzes iterative condensations of five molecules of malonyl-CoA to produce a pentaketide, 5,7-dihydroxy-2-methylchromone, while OKS carries out sequential condensations of eight molecules of malonyl-CoA to yield aromatic octaketides, SEK4 and SEK4b, the longest polyketides generated by the structurally simple type III PKS. The two enzymes share 91% amino acid sequence identity, maintaining most of the active-site residues of CHS including the Cys-His-Asn catalytic triad. One of the most characteristic features is that the conserved Thr197 of CHS (numbering in Medicago sativa CHS) is uniquely replaced with Met207 in PCS and with Gly207 in OKS, respectively. Site-directed mutagenesis and X-ray crystallographic studies clearly demonstrated that the chemically inert single residue lining the active-site cavity controls the polyketide chain length and the product specificity depending on the steric bulk of the side chain. Finally, on the basis of the crystal structures of both wild-type and M207G-mutant PCS, a triple mutant PCS F80A/Y82A/M207G was constructed and shown to catalyze condensations of nine molecules of malonyl-CoA to produce a novel nonaketide naphthopyrone with a fused tricyclic ring system. Structure-based engineering of the type III PKS superfamily enzymes would thus lead to further production of chemically and structurally divergent unnatural novel polyketides.

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In the development of oligoarginine-based prodrugs with self-cleavable spacers for intestinal absorption, we previously reported a series of spacers with variable half-lives of parent compound release based on a neighboring group participation mechanism from an amino acid side-chain structure next to the succinyl moiety. In the present study, to diversify the half-life of the spacer, we first synthesized several additional fluorescein isothiocyanate ethanolamine (FE)-heptaarginine conjugates (4d—g) and evaluated their conversion time. To investigate the overall cellular uptake of FE-heptaarginine conjugates, the cellular uptakes of FE-heptaarginines 4a and 4b possessing the longest and shortest half-lives, respectively, were evaluated using HeLa cells by confocal microscopy and flow cytometry. Conjugate 4a with a longer half-life was more efficiently taken up by the cells than conjugate 4b. However, in term of the transport rate of parent FE 1 in in vitro Caco-2 cell permeation assay, conjugate 4b with a short half-life could function more efficiently that conjugate 4a. To understand the reason for this discrepant finding, fluorescence on the basal side medium after treatment with conjugate 4b in the permeation assay was determined. It became apparent that the fluorescence was mostly from the parent FE 1 itself, and not conjugate 4b, suggesting that the conjugate was cleaved inside the cells. Moreover, the conversion time of conjugate 4b (t_1/2=9.4 min at pH 7.4) was significantly extended in slightly acidic media. These results suggest that the conversion rate was slowed in the relatively acidic endosomal environment where the conjugate was transferred after endocytosis, and resulted in a favorable migration time across the cells. The other conjugates, including conjugate 4a, were more stable inside of the cell, resulting in very long conversion times that were ineffective in increasing the permeation rate. Therefore, spacers with shorter half lives, in order to produce a larger amount of the parent compound inside the cells are promising development for effective oligoarginine-based cargo-transporter systems to enhance intestinal absorption of parent drugs with low permeability.

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Three different sensitive and accurate spectroscopic procedures were developed for the determination of three angiotensin-converting enzyme inhibitors, namely, ramipril, enalapril maleate and fosinopril. The first two spectrophotometric (extractive and non-extractive) procedures were based on ternary complex formation with molybdenum(V) thiocyanate. The formed complex can be determined by extraction with chloroform measured at λ_max 517 nm Beer's law was obeyed in the concentration range from (10—90 μg ml⁻¹) for ramipril and fosinopril and (4—36 μg ml⁻¹) for enalapril maleate with molar absorptivity 1.2×10⁴, 2×10⁴ and 3.4×10⁴ l mol⁻¹ cm⁻¹, respectively, or by direct measurement after addition of benzalkonium chloride as surfactant and measuring the formed ternary complex at λ_max 545 nm with a linear relationship in the concentration range from (8—72 μg ml⁻¹), (3—27 μg ml⁻¹) and (8—72 μg ml⁻¹) for ramipril, enalapril maleate and fosinopril with molar absorptivity 1.5×10⁴, 5×10⁴ and 2.1×10⁴ l mol⁻¹ cm⁻¹, respectively. The third procedure is atomic absorption measurement through the quantitative determination of molybdenum content of the complex. These methods hold their accuracy and precision well when applied to the determination of ramipril, enalapril maleate and fosinopril in their dosage forms.

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A novel naringenin Schiff base ligand (1,2-di(4′-iminonaringenin)ethane, H₆L) and its three transition metal complexes [Cu(II) complex (1), Zn(II) complex (2), and Ni(II) complex (3)] have been prepared and characterized on the basis of elemental analysis, molar conductivity, ¹H-NMR, mass spectra, UV–vis spectra, and IR spectra. The DNA-binding properties of the ligand and its complexes have been investigated by absorption spectroscopy, fluorescence spectroscopy, ethidium bromide (EB) displacement experiments, and viscosity measurement. The results indicated that the ligand and its complexes can bind to DNA. The binding affinity of the Cu(II) complex (1) is higher than that of the ligand and the other two complexes. The intrinsic binding constant (K_b) of the complex (1) is 3.3×10⁶. In addition, the suppression ratio for O₂^−· and HO^· was determined. The 50% inhibition obtained for the ligand and its three complexes demonstrates that, compared to the ligand, the complexes exhibit higher antioxidative activity in the suppression of O₂^−· and HO^·.

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In bioassay-guided searches for novel bioactive natural products from higher plants of the Egyptian flora, two new eudesmane sesquiterpene derivatives, 3α-hydroxyilicic acid methyl ester (1) and 2α-hydroxy-4-epi-ilicic acid (2), together with 11 known sesquiterpenes were isolated from bioactive fractions of the active epigeal parts extracts of Dittrichia graveolens (L.) GREUTER (Asteraceae) growing in the coastal regions of northwestern Egypt. Four other known sesquiterpene lactones with different carbon skeletons, named 2α-hydroxy-2R-xanthalongin (8), 4-epi-isoinuviscolide (9), 8-epi-helenalin (10), and bigelovin (11), were also isolated for the first time from the same source. The stereochemical structures of the isolated compounds were elucidated on the basis of physical and spectroscopic methods including UV, IR, ¹H-, ¹³C-NMR, distortionless enhancement by polarization transfer, 2D NMR, ¹H–¹H correlation spectroscopy, ¹H–¹³C heteronuclear single-quantum coherence, ¹H–¹³C heteronuclear multiple-bond connectivity, ¹H–¹H nuclear Overhauser effect spectroscopy experiments, and high-resolution mass spectrometry, as well as some chemical transformations. The antimicrobial, antiinflammatory, and antipyretic activities of D. graveolens extracts and chromatographic fractions were carried out and the various bioactivities of our findings are discussed.

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Chemical examination of the n-butanol extract of the root of Codonopsis tangshen led to the isolation of four new compounds named codonosides A (1) and B (2) and codonopyrrolidiums A (3) and B (4), with seven known compounds [(Z)-2-(β-glucopyranosyloxy)-3-phenylpropenoic acid (5), lobetyolin (6), lobetyol (7), luteolin (8), friedelin (9), 5,6,9-trihydroxy-octadec-7-enoic acid (10), and adenosine (11)]. Based on spectroscopic evidence, the structures of codonosides A (1) and B (2) were established as phenolic glycosides, and those of codonopyrrolidiums A (3) and B (4) as pyrrolidines. The relative configuration of 3 was determined by X-ray crystallographic analysis.

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Lichens are an important source of phenolic compounds and have been intensively investigated for their biological and pharmacological activities. Lecanoric acid (1), a lichen depside, was isolated from a Parmotrema tinctorum specimen and treated with alcohols to produce orsellinic acid (2) and orsellinates (3) to (9) (2,4-dihydroxy-6-n-methyl benzoates). Free radical scavenging activity of methyl (3), ethyl (4), n-propyl (5), n-butyl (6), iso-propyl (7), sec-butyl (8), tert-butyl (9) orsellinates was evaluated using 2,2′-diphenyl-1-picrylhydrazyl (DPPH) method. Results showed that chain elongation of methyl (3) to n-butyl (6) causes a rise in the antioxidant activity. However, iso-propyl (7) and tert-butyl (9) were more active than the correspondent linear compounds, although sec-butyl (8) was less active among the chain ramified compounds. All the orsellinates were less active than lecanoric acid (1) and orsellinic acid (2). Orcinol (10) and resorcinol (11) were also determined for comparison with activities of orsellinates. Gallic acid (12) was used as control.

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The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC₅₀=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED₅₀=7 mg/kg).

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The 4-(dihydroxyphenylthio)-2H-chromen-2-one derivatives have been synthesized by direct electrochemical oxidation of catechols in the presence of 4-mercaptocoumarin as a nucleophile in water/acetonitrile (50/50) solution, in a one-pot process, at carbon rod electrode, in an undivided cell and in constant current conditions, through an EC mechanism. The products are characterized by spectra data. Besides, the difference in electrochemical oxidation of catechol in the presence of 4-hydroxycoumarin and 4-mercaptocoumarin explained by computational structure, natural bond orbital (NBO) analysis and density functional theory (DFT: B3LYP/6-31G*//B3LYP/6-31G*) based methods, using the GAUSSIAN 98 package of programs.

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An enantioselective intramolecular Heck-type reaction of chloroformamides has been developed for the synthesis of 3,3-disubstituted piperidones. The desired piperidone was formed in the presence of a palladium catalyst, an optically active phosphoramidite ligand, K₃PO₄ and Ag₃PO₄. The obtained piperidone was converted to epieburnamonine.

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A series of novel unsymmetrically N,N′-substituted ureas were synthesized from dehydroabietic acid and their structures were characterized by IR, ¹H-NMR, ¹³C-NMR spectroscopy and single crystal X-ray diffraction. Three six-membered rings of urea 4c exhibited plane, half-chair and chair configurations, respectively. Their cytotoxicity activities against SMMC7721 liver cancer cells were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The results showed that the title compounds exhibited highly effective cytotoxicity activities against SMMC7721 cells. Their IC₅₀ values are between 8.8 and 14.2 μmol/l. The change of N′ substituted groups resulted little difference to the cytotoxicity activities of ureas, which indicated that the cytotoxicity of this kind of ureas depend strongly on the tricyclic hydrophenanthrene structure.

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The salting-out taste-masking system is a multiparticulate system consisting of a drug core, a salting-out layer containing salts and water-soluble polymers, and a water-penetration control layer containing water-insoluble materials. The system generates a long lag time (time when released drug is less than 1%) for numbness masking, and a subsequent immediate drug release for high bioavailability. Aiming to contain the system and drugs that cause numbness in oral disintegrating tablets, the system was optimized to reduce the particle size and contain drugs with high water solubility in this study. The amount of coating on the layers, the coating solvent, and the positioning of the components were also optimized. The findings in this study will lead to the provision of numbness-masked oral disintegrating tablets to patients.

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The complexations of sulfasalazine (H₃Suz) with some of transition metals have been investigated. Three types of complexes, [Mn(HSuz)⁻²(H₂O)₄] · 2H₂O, [M(HSuz)⁻²(H₂O)₂] · xH₂O (M=Hg(II), ZrO(II) and VO(II), x=4, 8 and 6, respectively) and [M(HSuz)⁻²(Cl)(H₂O)₃] · xH₂O (M=Cr(III) and Y(III), x=5 and 6, respectively) were obtained and characterized by physicochemical and spectroscopic methods. The IR spectra of the complexes suggest that the H₃Suz behaves as a bidentate ligand. The thermal decomposition of the complexes as well as thermodynamic parameters (ΔE*, ΔH*, ΔS* and ΔG*) were estimated using Coats–Redfern and Horowitz–Metzger equations. In vitro antimicrobial activities of the H₃Suz and the complexes were tested.

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Simultaneous determination of polydatin and its metabolite in excrement samples using high-performance liquid chromatography (HPLC) with UV detection was accomplished. After extracted them by C₁₈ solid phase extraction, the samples were separated on a reversed-phase column. Detection wave-lengths were set at 306 nm. The separation was carried out with a gradient elution. The mobile phase was acetonitrile–water (containing 0.1% formic acid) at a flow rate of 1.0 ml·min⁻¹. The identities of the peaks were accomplished by comparing retention times, UV and mass data with reference compounds under the same conditions. The standard curve was rectilinear in the range of 0.803—642.6 μg·ml⁻¹ (r=1.0000) for polydatin, 0.407—325.8 μg·ml⁻¹ (r=1.0000) for resveratrol. The recoveries of the markers listed above were 102.2% and 97.3%, respectively. The verified method can be used to determine the contents of two compounds in samples of stomach, small intestine, caecum, and large intestine (including excrement) of rats fed with polydatin. The analytical results demonstrated that the metabolism of polydatin is mainly processed in the intestines; polydatin can be transformed into resveratrol by de-sugaring process.

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The present study was aimed at developing safe and effective bioadhesive gelling systems of ketorolac tromethamine, a potent non-narcotic analgesic with moderate anti-inflammatory activity for nasal systemic delivery. Chitosan and pectin based gelling systems were prepared with variables like polymer concentration and type. These systems were characterized in terms of their physical properties, in vitro bioadhesion, in vitro drug release and long-term stability. The anti-inflammatory activity and mucosal irritancy of selected gels were also evaluated in rats and these results were compared with per oral, intraperitoneal and nasal solution administration of ketorolac tromethamine. All the prepared formulations gelled immediately at the nasal mucosal pH and showed longer contact time. Addition of hydroxypropyl methylcellulose (HPMC) in both chitosan and pectin based gelling systems increased the viscosity and gel strength. All the formulated gels exhibited pseudoplastic rheology and diffusion-controlled drug release. The results from stability studies revealed that the prepared thermogels showed marginal decrease in viscosity but at the same time, no significant difference in drug content, and in vitro release characteristics were observed before and after accelerated studies. The developed gelling systems produced only mild to negligible irritant effect to nasal mucosae as compared to control group.

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Chemical investigation of the whole plant of Spiranthes australis (R. BROWN) LINDL. resulted in the isolation and characterization of three new flavonoid constituents, 5-hydroxy-4′-[(2-isopentenyl)oxy]-3,7,3′-trimethoxyflavone (1), 3-O-{[O-β-D-xylopyranosyl]-(1→2)-β-D-glucopyranosyl}-8-(p-hydroxy-benzyl)-kaempferol (2) and 3-O-{O-[2-O-(E)-p-coumaroyl-β-D-xylopyranosyl]-(1→2)-β-D-glucopyranosyl}-8-(p-hydroxy-benzyl)-kaempferol (3), together with six known flavonoid compounds. The structures of new compounds were determined on the basis of spectroscopic analysis, including HR-ESI-MS, 1D- and 2D-NMR techniques and chemical methods.

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Three new monoterpenes, comosoxide A (1), comosoxide B (2), and comososide (3), were isolated from the methanolic extract of the rhizomes of Curcuma comosa cultivated in Thailand. Their structures were elucidated on the basis of chemical and physicochemical evidence.

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Four new and two known ether-soluble resin glycosides were isolated from popular sweet potato (the roots of Ipomoea batatas L. LAM., Kokei 14 go, Convolvulaceae) in Japan. Unlike ester-type dimers, batatins I and II, obtained from other sweet potato (Ipomoea batabas var. batatas), the glycosides were tetra or pentasaccharide monomers in which the sugar moieties are partially acylated by organic acids and combine with the aglycone, jalapinolic acid, to form a macrocyclic ester.

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The first chemical synthesis of two metabolites ((1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-1) and (1R,2S,5R,6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane (SC-2)) of sesamin was achieved by a simple two-step approach from sesamin. The approach consists of acetoxylation of the methylenedioxy moiety(ies) with lead(IV) tetraacetate and acid hydrolysis of the resulting hemiorthoester to SC-1 and SC-2.

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Three new lupane-type saponins, acankoreosides F—H (1—3) were isolated from the methanol extract of the leaves of Acanthopanax koreanum NAKAI. The structures of these three saponins were established by chemical and spectroscopic analysis as 3α,30-dihydroxylup-20(29)-en-23,28-dioic acid 28-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (1), 3α,30-dihydroxylup-23-al-20(29)-en-28-oic acid 28-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (2), and (20S) 3α-hydroxylup-23-al-28,29-dioic acid 28-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (3), respectively. The effects of the isolates (1—3) on the lipopolysaccharide-induced production of nitric oxide and prostaglandin E₂ were evaluated in RAW 264.7 macrophages.

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A simple, clean and efficient method for the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5′-pyrrolo[2,3-d]pyrimidine]-pentaone derivatives by condensation reaction of 6-amino-uracils and isatins in aqueous media is reported. These products were evaluated in vitro for their antibacterial activities.

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Two new halimane-type diterpenoids, viteagnusins A and B, and three new labdane-type diterpenoids, viteagnusins C, D, and E, were isolated from the fruit of Vitex agnus-castus L. (Chasteberry, Verbenaceae) along with two known diterpenoids. Their chemical structures were determined on the basis of spectroscopic data.

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Two new cycloartane glycosides, named aquilegiosides K and L, have been isolated from the dried underground parts of Aquilegia vulgaris. Their structures were determined by two dimensional (2D) NMR spectroscopic analysis and chemical evidence.

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The methanolic extract from the flowers of Punica granatum L. (Punicaceae) was found to show inhibitory effect on tumor necrosis factor-α (TNF-α, 1 ng/ml)-induced cytotoxicity in L929 cells. By bioassay-guided separation, a new taraxastane-type triterpene, punicanolic acid (1), was isolated from the active fraction (ethyl acetate-soluble fraction) together with four triterpenes (2—5), two galloyl glucoses (6, 7), two flavones (8, 9), and β-sitosterol. Among the constituents, 1, oleanolic acid (2), maslinic acid (4), 1,2,6-tri-O-galloyl β-D-glucopyranoside (6), 1,2-di-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl β-D-glucopyranoside (7), and luteolin (8) significantly inhibited TNF-α-induced cytotoxicity in L929 cells at 30 μM.

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A catalytic hypervalent iodine oxidation of p-dialkoxybenzenes using 4-iodophenoxyacetic acid (1) and 2KHSO_{5 · KHSO}4 · K₂SO₄ (Oxone^®) was developed. Reaction of p-dialkoxybenzenes (2) with a catalytic amount of 1 in the presence of Oxone^® as a co-oxidant in 2,2,2-trifluoroethanol–water (1 : 2) gave the corresponding p-quinones (3) in excellent yields without purification. This procedure was applied to synthesis of blattellaquinone (9), the sex pheromone of the German cockroach, Blattella germanica.

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