4-Hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH) (1a) and its derivatives form a new class of compounds which possess norepinephrine (NE) potentiating activity. As a new series of compounds, 1-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines (2a—f) were synthesized by the intramolecular Barbier reaction of N-[2-(2-iodophenyl)ethyl]phenacylamines (6a—f) with n-BuLi as a key reaction step. The potentiating activities of the benzazepines 2a—f on the contraction of rat anococcygeus muscle induced by NE were tested. Among the compounds tested in this study, compound 2a showed moderate potentiating activity (the activity ratio was 7.3-fold at 3×10⁻⁵ M).

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The preparation of some new spiro-substituted 4-hydroxypyranoquinolinones and their corresponding dihydropyrano cis-diols is described. The free radical scavenging activity of the compounds was determined by means of their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the superoxide anions generated by the enzymic xanthine–xanthine oxidase system. The spiroadamatylpyranoquinolinone analogue proved to be the most efficient free radical scavenger.

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Pluronic F127 (PF127) is a copolymer which forms thermosensitive hydrogels. Hyaluronic acid (HA) was grafted to PF127 to form a new hydrogel matrix (HP) for delivery of cisplatin and carboplatin. The physicochemical properties and drug delivery of the graft were examined in this study. HP system (20% HP copolymer in water) exhibited a similar sol–gel transition temperature (28.3 °C) as PF127 system (20% PF127 copolymer in water) but with a shorter gelling process. A stronger structure was obtained by HP system according to scanning electron microscopic (SEM) images and viscosity kinetics. In vitro release test showed the sustained-release characteristics of hydrogels entrapped with cisplatin and carboplatin. The drug release rate from HP hydrogel was slower than that from PF127 hydrogel. The reduction of drug release by HP system as compared to the control solution was more significant for cisplatin than for carboplatin. Such a thermosensitive hydrogel may be advantageous as an injectable therapeutic formulation for anticancer treatment.

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The stability of a moisture-sensitive drug in lyophilized products was investigated under conditions with varying water content and temperature using two model formulations: a formulation containing inositol (IF) as the excipient and a formulation containing mannitol (MF) as the excipient. IF showed better chemical stability (a lower hydrolysis rate) than MF when both formulations contained 2% water. However, in the case of formulations with 8% water, MF showed similar or better stability than IF. From the results of hygroscopicity and phase transition experiments for both formulations, it was assumed that this stability profile was exhibited because 1) more water was taken up into the amorphous inositol in IF than into the crystalline Form-III mannitol in MF at a low water content, so that drug hydrolysis in IF was suppressed compared with MF and 2) when the water content increased, the amorphous inositol crystallized to anhydrate in IF causing expulsion of absorbed water from the excipient, meaning that IF lost its superior chemical stability due to the highly mobile water generated by the crystallization. This assumption was supported by the results of the ²H-NMR measurement, which estimated water mobility from the signal shape and the spin–lattice relaxation time (T₁) of deuterium oxide.

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Hot-melt coating process (HMCP) was applied to develop a lipid based oral controlled release matrix system (tablet) to deliver highly aqueous soluble drugs using paracetamol as a model drug. Granules prepared from paracetamol and particular filler were coated with different levels of lipid and then compressed into tablets to get controlled/sustained delivery of the drug over an optimum period. Process parameters were optimized with particular focus on fluidization pattern during HMCP proposing a ‘design space’ with ‘Quality by Design’ (QbD) concept in mind. The results demonstrated that the granule composition influenced the drug release pattern, and the rate of release could be manipulated by varying the amount of lipid in the formulation. The in vitro release profile of the drug was pH-independent and the most promising release profile was obtained from tablets prepared from granules with the water-soluble filler, lactose, and coated at 9% (w/w) level with a lipid, glyceryl behanate. In vivo plasma profiles of the drug were predicted from the in vitro release profile data by convolution analysis which confirmed that the lactose based formulation with 9% (w/w) lipid coating on the granules would be suitable for controlled delivery of the drug over a period of 12 h making the formulation suitable for highly water soluble drug candidates like paracetamol with twice daily dose regimen. Moreover, the dissolution data adequately fitted into Higuchi model suggesting that the drug release occurred predominantly by diffusion.

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3,4-Methylenedioxymethamphetamine (MDMA), one of the most popular illicit recreational drugs, is metabolized primarily into 4-hydroxy-3-methoxymethamphetamine (HMMA) by drug-metabolizing enzymes. HMMA is further metabolized by phase II enzymes to give the glucuronide or sulfate which is excreted into urine. In the present study, enzyme kinetic studies with various microsomes showed that rat liver microsomes pretreated with Aroclor 1254 were most suitable for the enzyme-assisted synthesis of the glucuronide (HMMA-Gluc). This method selectively produced the β-anomer of HMMA-Gluc in a very high, isolated yield (71%), and with a purity that was sufficient for use in an analysis of MDMA intake and for enzyme kinetic studies. We also identified, by an LC-MS method, the human uridine 5′-diphosphate-glucuronosyltransferase (UGT) isoforms that catalyze the glucuronidation of HMMA. Among 12 isoforms of human recombinant UGT expressed in insect cells, UGT2B15 was the only isoform that showed adequate enzymatic activity in catalyzing HMMA glucuronidation with K_m and V_max values of 3.8 mM and 1.6 nmol/min/mg protein, respectively. The finding that UGT2B15 is capable of HMMA glucuronidation suggests this isoform may have an important in vivo role in human MDMA metabolism.

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trans- and cis-Icosyl, docosyl, and tetracosyl p-coumarates, constituents of Artemisia annua L., and their structurally-related compounds were synthesized and evaluated for inhibitory activity on DNA polymerases α and β. Among 30 compounds synthesized, octadecyl trans- and cis-p-coumarates and octadecyl p-hydroxyphenylpropiolate showed strong inhibitory activity on DNA polymerases α and β.

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Hoechst 33258 belongs to bisbenzimidazole class of molecules having anticancer properties for their ability to inhibit topoisomerase and many other cellular processes. The aim of the present study is to understand the nature of Hoechst 33258-bovine serum albumin (BSA) binding interactions by using absorption, fluorescence and circular dichrorism (CD) measurements under simulative physiological conditions. The absorption spectra of BSA indicated the binding of Hoechst 33258 with BSA. The analysis of fluorescence data indicated the presence of both dynamic and static quenching mechanism in the binding. The associative binding constant and number of binding sites were found to be K=2.08=10⁷ M⁻¹ and n=1.36 respectively. Biexponential fluorescence lifetime distribution of Hoechst 33258 in the presence of BSA has altered viz. τ₁ was increased significantly from 0.3 ns (60%) to 1.2 ns (13%) whereas a marginal increase in τ₂ from 3.6 ns (40%) to 4.0 ns (87%). Fluorescence anisotropy value of Hoechst 33258 has increased from 0.14 to 0.34 upon the addition of BSA. Thermodynamic parameters were also calculated using Van't Hoff plot by conducting fluorescence titration at four different temperatures, ΔH=+102.785 kJ mol⁻¹, ΔS=+490.18 kJ mol⁻¹, ΔG=−491.708 kJ mol⁻¹. The CD spectrum of BSA revealed that the binding of Hoechst 33258 to BSA causes loss in the secondary structure but increases the thermal stability of the protein. The results indicated that hydrophobic interactions were the predominant intermolecular forces in stabilizing BSA-Hoechst 33258 complex. The possible implications of these results will be on designing better therapeutic minor groove binding drug molecules.

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The methanolic extracts from the wood and bark of Cotylelobium melanoxylon were found to inhibit plasma glucose elevation after sucrose loading in rats and triglyceride elevation after olive oil loading in mice. A new stilbene dimer, melanoxylin A, together with the known stilbene dimers [(+)-ampelopsin F, (+)-isoampelopsin F, and (+)-ε-viniferin] and a trimer (vaticanol G) and a lignan [(+)-lyoniresinol] were isolated from the wood extract, and a new stilbene trimer, melanoxylin B, together with the known stilbene dimers [(+)-ε-viniferin and cis-(+)-ε-viniferin] and trimers (vaticanols A, E, and G) were isolated from the bark extract of C. melanoxylon. The principal constituents, vaticanols A, E, and/or G, inhibited plasma glucose and triglyceride elevation after sucrose loading in rats and olive oil loading in mice, respectively. In addition, vaticanols A, E, and/or G inhibited the enzyme activities of rat intestinal α-glucosidase, porcine pancreatic lipase, and rat lens aldose reductase.

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Four novel prenylflavonols, macaranones A—D (1—4), were isolated from the leaves of Macaranga sampsonii. Their structures were elucidated on the basis of spectroscopic data. Macaranones C (3) and D (4) represent first two examples of flavonols having an unusual peltogynoid skeleton which is formed from a 2′-geranylflavonol by cyclization between 3-OH and C-1″ of the 2′-geranyl substituent of the flavonol. Compounds 1—4 were evaluated for the cytotoxicity against several human cancer cell lines.

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The C-terminal domain of apolipoprotein (apo) A-I plays an important role in lipid binding. ApoA-I Nichinan, a naturally occurring human apoA-I variant with a deletion of E235 located in the C-terminus, is associated with low high-density lipoprotein (HDL) cholesterolemia. In the present study, a series of variant peptides corresponding to residues 220—241 of human apoA-I were examined to clarify the influences of E235 deletion (ΔE235) on the structure and lipid interaction of the C-terminal region. NMR studies demonstrated that in trifluoroethanol, apoA-I 220—241/ΔE235 peptide forms the α-helical structure similar to wild-type (WT) peptide. Circular dichroism measurements revealed that the interaction with phospholipid vesicles induced structural changes from random coil to α-helix both in apoA-I 220—241 WT and E235A, a variant with a negative charge ablation, peptides. These peptides also showed abilities to form HDL-like particles through microsolubilization of phospholipid vesicles, indicating that the negative charge ablation in E235 has no effect on the lipid interaction. By contrast, neither lipid binding-induced α-helix formation nor microsolubilization of vesicles were observed in apoA-I 220—241/ΔE235 and L230P, a helix-breaking variant, peptides. In addition, fluorescence measurements showed that tryptophan fluorescence intensity of apoA-I 220—241/F225W greatly increased upon lipid binding, while only a little increase was observed for the corresponding ΔE235 variant. Taken together, these results suggest that the deletion of E235 causes defective lipid binding of apoA-I Nichinan because of the impaired helix-forming ability of the C-terminal residues.

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Three new Daphniphyllum alkaloids, daphnezomines T—V (1—3), were isolated from the leaves and branches of Daphniphyllum humile (Daphniphyllaceae). The structures and relative stereochemistry of 1—3 were elucidated on the basis of spectroscopic data. Daphnezomine T (1) is the first alkaloid without a branched C₁ unit at C-5 among all Daphiniphyllum alkaloids reported so far.

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A practical large-scale synthesis of monomethyl malonate and monoethyl malonate, which are among the most commonly applied half-esters in organic synthesis, is described, applying the highly efficient selective monohydrolysis of symmetric diesters we reported before. The optimal conditions with regard to the type of base, equivalent, co-solvents, and the reaction time have been examined for large-scale reactions. Monomethyl malonate and monoethyl malonate were obtained in high yields with near 100% purity within only half a day. The conditions of this selective monohydrolysis reaction are environmentally benign and straightforward, as it requires only water, a small proportion of a volatile co-solvent, and inexpensive reagents, and produces no hazardous by-products, and therefore the synthetic utility of this reaction in process chemistry is expected.

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Ni-Et-Duphos-catalyzed 1,2-addition of potassium aryltrifluoroborates to α,β-unsaturated aldehydes is described.

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Four new bibenzyl derivatives, shancigusins A—D (1—4) and five known bibenzyls (5—9) were isolated from the tubers of Pleione yunnanensis (Orchidaceae). The structures of these compounds were determined by extensive analyses of their spectroscopic data.

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Phytochemical investigation of an acetone extract of Upuna borneensis (Dipterocarpaceae) resulted in the isolation of two new resveratrol tetramers, upunaphenols O (1) and P (2). The structures were elucidated by spectroscopic analysis including NMR experiments.

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Ten triterpenoid glycosides, including five new ones (1—5), were isolated from the leaves of Ilex pernyi. The chemical structures of 1—5 were determined on the basis of the chemical and spectroscopic evidence.

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Two new ent-kaurane diterpene derivatives, sculponeatins N (1) and O (2), and a new A-ring contracted oleanane triterpenoid, sculponeatic acid (5), were isolated from the plant Isodon sculponeata. Their structures were elucidated on the basis of extensive spectroscopic analysis. This is the first report of natural occurrence of an A-ring contracted oleanane triterpenoid.

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Two new bile acids, tauroselocholic acid (1) and tauroansocholic acid (2), a new natural bile acid, cygnocholic acid (3) were respectively isolated from bear bile powder Selenaretos thibetanus CUVIER and bile of geese Anser anser domesticus, together with seven known compounds. By spectrum analysis of MS, 1D and 2D NMR, the structures of the new compounds were elucidated as 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid N-[2-sulfoethyl] amide (1), 3α,5,7α-trihydroxy-5β-cholan-24-oic acid N-[2-sulfoethyl] amide (2) and 3α,7α,15α-trihydroxy-5β-cholan-24-oic acid (3).

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Two novel 18, 19-secoursane triterpenoids, kakisaponin B (1) and kakisaponin C (2), an ursane type 28-nortriterpene, kakidiol (3) and one known triterpenoid rosamultin (4), were isolated from the leaves of Diospyros kaki. The structures of compounds 1 and 2 were determined as 28-O-β-D-glucopyranosyl-3α,19,24-trihydoxy-18,19-secours-11,13(18)-dien-28-oic acid (1) and 28-O-β-D-glucopyranosyl-2α,3α,19-trihydoxy-18,19-secours-11,13(18)-dien-28-oic acid (2) by chemical methods and spectra experiments. Kakidiol (3) was characterized as a C₂₉-triterpene with an aromatic E-ring in structure. This is the first report of 18,19-secoursane triterpenoids and 28-nortriterpene from family Ebenaceae.

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3,3′-Diindolylmethane (DIM, 1) and its derivatives have been prepared, and their enhancing effects on chemically-induced HL-60 cell differentiation were analyzed. Among the prepared compounds, IndDIM (12) showed the most potent enhancing effect on HL-60 cell differentiation induced by chemicals, including retinoids, 1,25-dihydroxyvitamin D₃, 12-O-tetradecanoyl phorbol-13-acetate and dimethyl sulfoxide.

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Pegylation technology has been widely used to improve therapeutic efficacies of protein drugs and a number of selective- or randomly-substituted pegylated proteins are on the market. In this study, we prepared a insulin derivative substituted randomly with poly(ethylene glycol) (PEG, MW about 2200) and its polypseudorotaxanes with cyclodextrins (CyDs). The pegylated insulin formed polypseudorotaxanes with α- and γ-CyDs, by inserting one PEG chain in the α-CyD cavity and two PEG chains in the γ-CyD cavity. The pegylated insulin/CyD polypseudorotaxanes were less soluble in water. The release rate of the pegylated protein from its polypseudorotaxanes decreased in the order of drug alone>the γ-CyD polypseudorotaxane>the α-CyD polypseudorotaxane. The pegylated insulin/γ-CyD polypseudorotaxane displayed a significantly higher resistance to proteolysis. The results indicated that the CyD polypseudorotaxanes could be formed with randomly-pegylated insulin and work not only as a sustained release system, but also as a stabilizing agent to enzymatic degradations of pegylated insulin.

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