This review highlights author's recent study on allenic compounds. In the first section, organocopper-mediated ring-opening reaction of ethynylaziridines and palladium-catalyzed reductive synthesis of allenes including those which are not accessible by other means, are described. In the second section, palladium-catalyzed stereoselective cyclization of allenes and tandem reaction leading to aziridines, pyrrolidines, benzoisoindoles, and cyclopropanes are presented. The final section presents aziridination and medium-ring formation by intramolecular reaction of bromoallenes, which are scarcely investigated until quite recently. The latter reaction is based on our recent discovery that bromoallenes can act as allylic dication equivalents in the presence of a palladium catalyst and alcohol.
Pre-formulation studies constitute the first step of any pharmaceutical product development and manufacture. Establishment of a comprehensive library of critical physical, chemical, biological and mechanical properties of all materials used for a formulation can be costly, tedious and time consuming, despite its importance in quality manufacturing management. This study seeks to demonstrate the pharmaceutical application of multidimensional scaling (MDS) by incorporating it as a pre-formulation tool for grouping an expanded range of microcrystalline celluloses (MCC). MDS presents the various MCC grades in two-dimensional space based on their torque rheological properties; thus conferring an extra dimension to the pre-formulation tool to facilitate the visualization of the relative positions of each MCC grade. Through this work, the utility of MDS for expediting pre-formulation studies, in particular, grouping of excipients that are available in different brands and grades can be amply exemplified.
Three new naturally occurring anthraquinones, ophiohayatone-A (1), -B (2), and -C (3), together with four known anthraquinones, were isolated from Ophiorrhiza hayatana OHWI (Rubiaceae). Structures of these new compounds were established by spectral methods.
Design, synthesis, and structure–activity relationships for 3,4-dihydropyridopyrimidin-2(1H)-one derivatives, which are aza-3,4-dihydro-2(1H)-quinazolinone derivatives, as the sodium/calcium (Na+/Ca2+) exchanger inhibitors are discussed. These studies based on 3,4-dihydro-2(1H)-quinazolinone derivatives led to the discovery of a structurally novel and potent Na+/Ca2+ exchanger inhibitor, 3,4-dihydropyridopyrimidin-2(1H)-one derivative (26), with an IC30 value of 0.02 μM. Compound 26 directly inhibited the Na+-dependent Ca2+ influx via the Na+/Ca2+ exchanger after Na+-free treatment in cardiomyocytes.
In the present study, we prepared solid dispersions of the poorly water-soluble drug nitrendipine (NIT) using the twin screw extruder method with high-molecular-weight substances, hydroxypropylmethylcellulosephthalate (HPMCP) and Carbopol (CAR), as carriers. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) evaluation showed that solid dispersions can be formed when NIT–HPMCP and NIT–CAR mixtures are treated with the twin screw extruder method. Fourier Transformation IR Spectroscopy (FT-IR) obtained with NIT–HPMCP and NIT–CAR solid dispersions indicated the presence of hydrogen bonding between the drug and the carriers. NIT–CAR solid dispersions were found to give somewhat higher dissolution than crystalline NIT and physical mixtures, while the dissolution of NIT–HPMCP solid dispersions was markedly decreased compared with the crystalline NIT and physical mixtures. These findings indicated that CAR has a greater ability to improve the dissolution of NIT than HPMCP when a twin screw extruder was employed to prepare the solid dispersions. The twin screw extruder method can be used as a simple and effective method for the preparation of solid dispersions to improve the dissolution properties of poorly water-soluble drugs when choosing proper polymers as carriers.
The purpose of this study was to investigate the possibility of parenteral delivery of poorly water-soluble lipophilic drugs using a phospholipid-based microemulsion system. Ibuprofen eugenol ester (IEE), a highly lipophilic compound, was synthesized from ibuprofen and eugenol, and isolated as an amorphous whitish solid with a melting point at 40.2±0.1 °C, which structure was confirmed by IR, 1H-NMR and MS spectra. A pharmaceutically acceptable microemulsion system using Miglyol 812, soybean phosphatidylcholine (SbPC) and poly (ethylene glycol) (660)-12-hydroxystearate (Solutol® HS-15), and PEG400 and ethanol as oil phase, surfactants and cosurfactants, respectively, was presented and characterized in terms of stability, droplet size distribution (DSD) and their solubilization capacity of IEE. The solubility of IEE in the optimized microemulsion formulation consisting of 6.4% ibuprofen eugenol, 9.6% Miglyol 812, 6% SbPC, 6% HS-15, 8.4% PEG400, 3.6% ethanol and 60% distilled water (w/w) was about 21000 times higher than that in water. The ibuprofen blood concentration after intravenous administration of microemulsions was determined and compared with that of ibuprofen solution. It was concluded that the presented microemulsion system might be a promising intravenous dosage form of poorly water-soluble lipophilic drugs.
In this study, a simple and sensitive fluorimetric method was described for the determination of Ascorbic Acid (AA). The procedure is based on the reaction between AA and Methylene Blue (MB). The fluorescence intensity of MB was measured at excitation and emission of 664 and 682 nm, respectively. MB concentration was decreased as a function of decreasing fluorescence intensity due to forming colorless form of MB (Leuco-MB) in the reaction between AA and MB. A linear relationship was obtained between the decreasing fluorescence intensity and the concentration of AA in the range of 3.0×10−7—6.0×10−6 mol·l−1. The detection limit was 2.5×10−7 mol·l−1. The proposed method was applied successfully for the determination of AA in Vitamin C tablets.
A new glucocerebroside, linckiacerebroside A (1) and a known glucocerebroside S-2a-3 (2), have been isolated from the cerebroside molecular species obtained from the less polar fraction of the CHCl3/MeOH extract of the starfish Linckia laevigata, together with three pseudo homogeneous glucocerebroside, 3, 4, and 5. The structures of these cerebrosides were determined on the basis of chemical and spectroscopic evidence.
The solvolysis reaction of (4,5)-anti-4-aryl-5-tosyloxy-2(E)-hexenoates 4a—k gave (4,5)-anti-4-aryl-5-hydroxy-2(E)-hexenoates 2a—k and (4,5)-anti-5-aryl-4-hydroxy-2(E)-hexenoates 5a—k along with the complete inversion. This 1,2-aryl migration was induced by treatment with heating in water-saturated nitromethane. On the basis of the substituent effect on the aromatic ring, this 1,2-aryl migration is thought to proceed via the σ-bridged phenonium ion. The product selectivity between 2a—k and 5a—k was found to be subtly governed by the substituent and substitution pattern in the aromatic ring of the substrates 4a—k.
The direct activation of C–O bonds in allylic alcohols by palladium complexes has been accelerated by carrying out the reactions in the presence of titanium(IV) isoproxide and 4 Å molecular sieves. The acidic and less nucleophilic anilines such as diphenylamine, phenothiazine, 4-cyanoaniline, and nitroanilines are efficiently allylated under palladium catalysis using allylic alcohols as allylating reagents.
Separation of the enantiomers of each of three different racemates, neutral rac-α-tetralol, acidic rac-2-phenylpropionic acid, and basic rac-1-phenylethylamine, using subcritical and supercritical fluid chromatography with two different chiral stationary phases, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (Sumichiral OA-7500 column) and tris(3,5-dimethylphenylcarbamate) of amylose (Chiralpak AD-H column), was compared. The elution order of the enantiomers of the three racemates was determined, and the effects of the type of alcohol modifier, column oven temperature, mobile phase composition, flow rate, and pressure were examined. The most appropriate column oven temperature depended on both the type of alcohol modifier and the compound analyzed. Lower alcohol content improved the peak separation of both rac-α-tetralol on the Sumichiral OA-7500 column and rac-1-phenylethylamine on the Chiralpak AD-H column, while the same phenomenon was not observed with either rac-α-tetralol or rac-2-phenylpropionic acid on the Chiralpak AD-H column. Decreasing outlet pressure improved the peak separation obtained with rac-2-phenylpropionic acid, but had little effect on either rac-α-tetralol or rac-1-phenylethylamine.
This paper concerns a synthetic study of the right-hand segment of complestatin, an inhibitor of gp120-CD4 receptor. The effective synthesis of four important precursors for the right-hand segment of complestatin is described. Two of them are the precursor tripeptides for macrolactamization to the right-hand segment of complestatin at the last step and the other two are the precursor tripeptides for ring-closing reaction using Suzuki and Stille coupling, respectively, to the right-hand segment of complestatin at the last step. These compounds and the synthetic procedure will serve for both the synthesis of the right-hand segment and total synthesis of complestatin in the near future. In addition, consideration of the smooth acidic isomerization of complestatin to chloropeptin was carried out by density functional theory (DFT) calculation.
The crystal structures of a series of three palladium(II) ternary complexes of 5-halogeno-2-aminobenzoic acid (5-X-AB, where X=Cl, Br and I) with 1,10-phenanthroline [Pd(5-Cl-AB)(phen)] (1), [Pd(5-Br-AB)(phen)] (2) and [Pd(5-I-AB)(phen)] (3) have been determined, and their coordination geometries and the crystal architecture characterized. All of the complexes are an isostructure in which each Pd(II) atom has basically similar square planar coordination geometry. The substitute halogen group at 5-position of AB plays an important role in producing the coordination bonds of the carboxylate and amino groups in which the carboxylate O atom and the amino N atom act as the negative monodentate ligand atoms. The coordination bond distances of O–Pd increase in the order 1<2<3, while those of N–Pd decrease in the same order. The binding of the complexes to the calf thymus DNA has also been studied by the fluorescence method. Each of the complexes shows high binding propensity to DNA which can be reflected as the relative order 1<2<3.
Selection of suitable solvent is essential for crystallization of pharmaceuticals. Based on chemical structures of 6397 compounds and 15 single solvents that were used to obtain their single crystals, correlations between the molecular characteristics and the solvents have been investigated by cheminformatics methods. Decision-tree and Bayesian-probability methods have been applied to make classification models. These two models are complementary in character in the present case. It has been proven that the prediction of the solvent rankings for particular compounds by use of the classification models is satisfactory from the practical point of view. The present study has demonstrated that cheminformatics methods could greatly help rational crystallization of small organic molecules such as pharmaceuticals.
From the CH2Cl2 extract of seed kernels of Caesalpinia crista from Myanmar, two rare and biogenetically interesting methyl migrated cassane-type furanoditerpenes [caesalpinins MM (1) and MN (2)] and two normal cassane-type furanoditerpenes [caesalpinins MO (3) and MP (4)] have been isolated, together with eight known cassane-type diterpenes, 1-deacetoxy-1-oxocaesalmin C (5), 1-deacetylcaesalmin C (6), caesalmin C (7), bonducellpin C (8), caesaldekarin e (9), 2-acetoxycaesaldekarin e (10), 2-acetoxy-3-deacetoxycaesaldekarin e (11), and norcaesalpinin E (12). Among the known compounds, compounds 5 and 6 were for the first time isolated from a natural source. The structures of these compounds were elucidated by the use of spectroscopic techniques.
A series of four non-peptidic renin inhibitors have been designed and synthesized. All of them contain in their molecule (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), a hydrophobic portion at the C-terminus and a second dipeptide-like transition state analog or unnatural dipeptidic fragment at the N-terminus. Inhibitory activity of the compounds was measured in vitro by high performance liquid chromatography (HPLC). Their IC50 (M/l) values were: <10−3 (12), 1.0×10−6 (19), 4.0×10−4 (23) and 1.0×10−6 (29), respectively. All the compounds are stable against chymotrypsin.
Phytochemical study of the ethanol extract of the seeds of Aesculus assamica led to the isolation of two new triterpenoid saponins. The structure of the new compounds were elucidated on the basis of spectral data to be 28-O-acetyl-21-O-(4-O-angeloyl)-6-deoxy-β-glucopyranosyl-3-O-[β-glucopyranosyl(1—2)-O-[β-glucopyranosyl(1—4)]-β-glucuronopyranosyl]protoaescigenin (1), and 21-O-(4-O-angeloyl)-6-deoxy-β-glucopyranosyl-3-O-[β-glucopyranosyl(1—2)-O-[β-glucopyranosyl(1—4)]-β-glucuronopyranosyl]protoaescigenin (2). Their in vitro bioactivity against plant pathogenic fungus Pyricularia oryzae and cytotoxicity against K562 and HCT-15 cell lines were evaluated.
Herein we report the development of novel, potent and non-peptide luteinizing hormone releasing hormone (LHRH) antagonists. The optimization towards derivatives free from mechanism-based CYP3A4 inhibition is described. The identification of a main metabolite guided us towards structural modifications of the benzyl moiety, which resulted in significant improvements of the CYP3A4 profile, while maintaining potent LHRH antagonist activity.
Two new triterpene saponins, 3-O-β-D-glucopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D-glucuronopyranosyl-22-O-angeloyl-R1-barrigenol (1) and 3-O-β-D-glucopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D-glucuronopyranosyl-22-O-β,β-dimethylacryloyl-A1-barrigenol (2), were isolated from the roots of Eryngium campestre (Apiaceae). Their structures were established mainly by 2D NMR techniques and mass spectrometry.
Rediocide G (7), a new daphnane diterpenoid, was isolated from the roots of Trigonostemon reidioides (Euphorbiaceae), together with two congeners, rediocide A and rediocide B, (+)-syringaresinol, scopoletin, tomentin and stigmasterol. The structure of the new natural product was elucidated by comparison of its NMR and mass spectral data with those of previously known rediocides and confirmed by extensive 2D NMR spectral analysis. Rediocide G (7) was found to be cytotoxic to various cancer cell lines.
Protein farnesyltransferase of Plasmodium falciparum is a potential target in the treatment of malaria for which increased drug resistance is observed. The design, synthesis and evaluation of a series of N-(4-piperidinyl)benzamides is reported. The most potent compounds showed in vitro activity against the parasite at submicromolar concentrations.
From the twigs of Scleropyrum wallichianum, a new unsaturated carboxylic acid, scleropyric acid (1), two new esters, β-sitosteryl-3-O-scleropyrate (2) and stigmasteryl-3-O-scleropyrate (3), and two well-known sterols, β-sitosterol (4) and stigmasterol (5), were isolated and characterized using spectroscopic methods. Compound 1 exhibited antimycobacterial activity with an MIC value of 25 μg/ml and showed antiplasmodial activity with an IC50 value of 7.2 μg/ml. Compounds 2 and 3 were inactive in both assays.
Three new anthraquinones, 1-hydroxy-2,3-dimethoxy-7-methyl-9,10-anthraquinone, 1,3-dihydroxy-5,6-dimethoxy-2-methyl-9,10-anthraquinone, and 3-hydroxy-1,5,6-trimethoxy-2-methyl-9,10-anthraquinone, along with five known anthraquinones were isolated from the roots of Prismatomeris tetrandra. Their structures were determined on the basis of spectroscopic data.
The absolute configuration of the branched methyl group in ante-iso type side chain moiety on the long chain base of glucocerebroside, HLC-2-A, which was isolated from the sea cucumber Holothuria leucospilota was determined. Oxidation of the glucocerebroside with ozone afforded C13-fragment including the ante-iso moiety. The optically active C13-fragment was synthesized asymmetrically by using the Wittig reaction from chiral synton for comparison with the natural fragment.
Three new diarylheptanoids, called alpinnanins A—C (1—3), together with two known chalcones, 2′,4′-dihydroxy-6′-methoxychalcone and 4′,6′-dimethylchalconaringenin, two known flavanones, alpinetin and naringenin 5-O-methyl ether, a known diarylheptanoid, (3S,5S)-trans-3,5-dihydroxy-1,7-diphenyl-1-heptene, stigmasterol and β-sitosterol as a mixture, and β-sitosterol 3-O-β-D-glucopyranoside were isolated from the rhizomes of Alpinia pinnanensis T. L. WU et SENJEN (Zingiberaceae). Their structures were elucidated by spectroscopic analyses.
Two new eremophilane-type sesquiterpenes, 3β-(2′-methylbutanoyloxy)-8βH-eremophil-7(11)-ene-12,8α-(14,6α)-diolide (1) and 8βH-eremophil-3,7(11)-diene-12,8α(14,6α)-diolide (2), and two new norursane-type triterpenes, 2α,3β,19α-trihydroxy-28-norurs-12-ene (7) and 2α,3α,19α-trihydroxy-28-norurs-12-ene (8), were isolated from the roots of Ligularia tongolensis, together with nine known compounds. The structures of the new compounds were elucidated by spectroscopic methods.
Four new iridoid glucosides, called genamesides A—D, have been isolated from the fruit of Genipa americana L. (Rubiaceae), along with four known iridoid glucosides, geniposidic acid, geniposide, gardenoside and genipin-gentiobioside. Their chemical structures were determined on the basis of spectroscopic data.
Three new acylated flavonol glycosides, cypellogins A (1), B (2) and C (3), along with eight known phenolic compounds, were isolated from the dried leaves of Eucalyptus cypellocarpa, and their structures were elucidated using spectroscopic methods, including 2D NMR experiments and chemical evidence.
In our investigation of in vitro anti-allergic screening of medicinal herbal extracts, the ethyl acetate extract of the root of Wikstroemia indica was observed to inhibit nitric oxide (NO) production in a lipopolysaccharide (LPS) and recombinant mouse interferon-γ (IFN-γ) activated murine macrophage-like cell line, RAW 264.7. Fractionation of the active extract led to the isolation of two new lignan dimer bis-5,5-nortrachelogenin (1) and bis-5,5′-nortrachelogenin (2), and three known lignans. Compound 1 and lirioresinol B (5) inhibited NO production with IC50 values at 48.6 and 53.5 μM, respectively. Compound 5 also showed free radical scavenging effect on 1,1-diphenyl-2-picrylhydrazil (DPPH) at IC50 values at 19.5 μM.
Biphenol was shown to bind dihydrogenphosphate (H2PO4−) selectively over various other anions (MeCO2−, Cl−, Br−, I−, NO3−, HSO4−). The highly selectivity of biphenol toward dihydrogenphosphate is explained in terms of the basicity and shape of the guest anion.
Two new monoterpene glucosides, demethylsecologanol and 3′′′-O-glucosylsenburiside II, were isolated from Ophiorrhiza liukiuensis (Rubiaceae) together with 23 known compounds, including camptothecins and β-carboline-type alkaloids. Their structures were determined by spectroscopic analysis.
Treatment of 1,2-cyclohexanedione with 1,2-diamines, e.g. ethylenediamine and cis-(and trans-)1,2-diaminocyclohexane, caused [4+2] cyclocondensation to give the corresponding dihydropyrazine derivatives (compounds 1—6). They exhibited stronger DNA strand-breakage activity than that of dihydropyrazines, which has already been reported in previous papers.
Three new C-seco limonoids (1—3) and one new tetracyclic limonoid (4) were isolated from a methanol extract of the ripe fruits of Melia azedarach collected in Curitiba, Brazil, and their structures were elucidated by spectroscopic data analysis and comparison of spectral data with those of the previously known compounds. Among the limonoids isolated in the present study, compounds 3 and 4 exhibited significant inhibitory activity against HeLa S3 cancer cells, whereas 1 and 2 showed weak cytotoxicity.
An efficient and reliable procedure for the preparation of dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL)4, a universally effective catalyst for a range of enantioselective carbene transformations, is described. The N-phthaloylation of (S)-tert-leucine by the method of Bose with essentially no racemization is a key to this process.
The scope of microwave-assisted coupling reaction of alkynylstibane and aryl iodides to form diarylalkynes is presented. Highly efficient reaction took place smoothly in dimethyl sulfoxide in the presence of cetyltrimethylammonium bromide with much shorter time (1 min) and lower catalyst loading (0.5 mol%) than the conventional method (heating for 24 h with 10 mol% catalyst).