Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro

Quinazolinone derivatives I and their methyl esters were synthesized and evaluated as nonclassical lipophilic inhibitors of thymidylate synthase. Compounds Ib and Ic containing OH and CO2H as R substituents, respectively, were most effective, indicating that hydrogen bonding may contribute to the increased inhibitory activity. These compounds further showed high cytotoxic activity against tumor cells in culture.     

Synthesis and anticonvulsant properties of triazolo- and imidazopyridazinyl carboxamides and carboxylic acids

Analogues of 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine PC25 containing amide or carboxylic acid function were synthesized and tested for anticonvulsant activity. The compounds having the imidazole ring substituted with an amide group have been found to be generally more active against maximal electroshock-induced seizures in mice (15.2 < or = ED50 < or = 37.5 mg kg(-1) orally). Furthermore, maximum activity was generally associated with a 2,6-dichlorobenzyl substitution pattern. 3-Amido-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine 4b was also protective in the pentylenetetrazole-induced seizures test (ED50 = 91.1 mg kg(-1) orally) and blocked strychnine-induced tonic extensor seizures (ED50 = 62.9 mg kg(-1) orally). Moreover, calculated electrostatic isopotential maps of the whole active compounds were quite similar and, consequently, could be associated to optimum anticonvulsant activity.     

Probing the mechanism of bioactivation of MPTP type analogs by monoamine oxidase B: structure-activity studies on substituted 4-phenoxy-, 4-phenyl-, and 4-thiophenoxy-1-cyclopropyl-1,2,3,6-tetrahydropyridines

Previous studies have shown that 4-benzyl-1-cyclopropyl-1,2,3,6-tetrahydropyridine is an excellent monoamine oxidase B (MAO-B) substrate (kappa cat/KM = 1538 min-1 mM-1) although the corresponding 4-phenyl analog displays MAO-B inactivating properties only. This behavior led us to speculate that the pathway for the MAO-B catalyzed oxidation of these tetrahydropyridines may not necessarily proceed via an initial single electron transfer step as proposed by others but rather through an initial alpha-carbon hydrogen atom abstraction step. In the present studies we have examined the interactions of various 4-phenoxy-, 4-phenyl-, and 4-thiophenoxy-1-cyclopropyl-1,2,3,6-tetrahydropyridine derivatives, some of which bear substituents on the phenyl ring. The 4-thiophenoxy- and all of the 4-phenoxytetrahydropyridine derivatives proved to be substrates but not inactivators of MAO-B, while several of the 4-phenyltetrahydropyridine derivatives were inactivators but not substrates. A case of particular interest was 1-cyclopropyl-4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine, which displayed only substrate properties. The results are discussed in terms of two catalytic pathways, one of which involves partitioning of the proposed cyclopropylaminyl radical cation intermediate between cyclopropyl ring opening and proton loss while the second involves partitioning of the parent amine between an initial single electron transfer step, leading to cyclopropylaminyl radical cation formation and enzyme inactivation, and an initial alpha-carbon hydrogen atom abstraction step, leading to an allylic radical and dihydropyridinium product formation.     

Synthesis of N-aryl-N'-heteroaryl-substituted urea and thiourea derivatives and evaluation of their anticonvulsant activity

Starting from amino(di)azines and 2-chloro-6-methyliso(thio)cyanate a series of aryl-substituted urea and thiourea derivatives was prepared and screened as potential antiepileptics. Among the new derivatives tested, only 2b and 3c exhibited adequate anticonvulsant effects, whereas 3d and 4d were found to be convulsants per se.     

Regional distribution and production rate of 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO4) in rat brain

The levels of noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO4) in 15 brain regions showed a parallel distribution in male Wistar rats. The differences in regional distribution of MHPG-SO4 were similar to those in the rate of NA turnover reported by other investigators. The accumulation rates of MHPG-SO4 during 45 and 90 min after probenecid injection significantly correlated to the steady state levels of MHPG-SO4 in nine regions studied. With the results, the regional levels of MHPG-SO4 either in untreated or in probenecid-treated rats, are considered to be a useful index of NA turnover.     

Physico-chemical properties of 3-methoxy-2-nitrobenzoates of some rare earth elements（Ⅲ）

The complexes of 3-methoxy-2-nitrobenzoates of Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Er(III) and Tm(III) with the formula: Ln(C8H6NO5)3·2H2O, where Ln=lanthanides(III), were synthesized and characterized by elemental analysis, Forier transform irtrared (FTIR) spectroscopy, magnetic and thermogravimetric studies and also by X-ray diffraction (XRD) measurements. The complexes had col- ours typical for Ln(III) ions. The carboxylate groups bound as bidentate chelating. On heating to 1173 K in air they decomposed in the same way, at first, dehydrated in one step to anhydrous salts, and then decomposed to the oxides of respective metals with intermediate formation of the oxycarbonates. The enthalpy values of the dehydration process changed from 133.72 to 44.50 kJ/mol. Their solubility in water at 293 K was of the order of 10-4 mol/dm3. The magnetic moments of analysed complexes were determined by Gouy’s method in the range of 76-303 K.     

Synthesis of certain derivatives of 5-methoxy-3-[(benzazole-2-yl) thioacetylamino]-2,3-dihydrobenzofuran and research on their antihypertensive activities

In this study, some 5-methoxy-3-[(benzazole-2-yl)thioacetylamino]-2, 3-dihydrobenzofuran derivatives were synthesized and their structures were elucidated by IR, NMR and microanalyses. The antihypertensive activities of the compounds obtained were investigated.     

Synthesis and luminescence properties of white-light-emitting phosphor Sr3GdNa(PO4)3F:Dy3+

Novel Sr3Gd(1–x)DyxNa(PO4)3F(SGNP:x Dy3+, x=0.01, 0.03, 0.05, 0.07, 0.09, 0.11) phosphors were synthesized by a conventional solid-state reaction method at different compositions. The X-ray diffraction results confirmed that the as-prepared samples were pure phase. The phosphor had two intense emission bands centering at 481 and 574 nm which could be attributed to the 4F9/2→6H15/2 transition and the 4F9/2→6H13/2 transition, respectively. The chromaticity coordinates(x, y) of this phosphor were calculated to be(0.3054, 0.3354) located on the region of white light region when excited at 350 nm. The concentration quenching mechanism of Dy3+ was ascribed to the dipole-dipole interaction. The current research suggested that the phosphors might be potential application in the w-LEDs.     

Anti-AIDS agents. 31. Synthesis and anti-HIV activity of 4-substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) thiolactone analogs

Four DCK-thiolactone analogs (3-6) were synthesized asymmetrically and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. Based on the functionality on the thiolactonecoumarin nucleus, activity was in the order: methyl > H > propyl > benzyl. 4-Methyl-3',4'-di-O-(-)-camphanoyl-(+)-cis-khelthiolactone (4) exhibited extremely potent anti-HIV activity with EC50 and therapeutic index values of 0.00718 microM and > 21,300, respectively.     

Monoamine oxidase inhibitory properties of some methoxylated and alkylthio amphetamine derivatives: structure-activity relationships

The monoamine oxidase (MAO) inhibitory properties of a series of amphetamine derivatives with different substituents at or around the para position of the aromatic ring were evaluated. In in vitro studies in which a crude rat brain mitochondrial suspension was used as the source of MAO, several compounds showed a strong (IC50 in the submicromolar range), selective, reversible, time-independent, and concentration-related inhibition of MAO-A. After i.p. injection, the compounds induced an increase of serotonin and a decrease of 5-hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confirming the in vitro results. The analysis of structure-activity relationships indicates that: molecules with amphetamine-like structure and different substitutions on the aromatic ring are potentially MAO-A inhibitors; substituents at different positions of the aromatic ring modify the potency but have little influence on the selectivity; substituents at the para position such as amino, alkoxyl, halogens, or alkylthio produce a significant increase in the activity; the para-substituent must be an electron donor; bulky groups next to the para substituent lead to a decrease in the activity; substituents located at positions more distant on the aromatic ring have less influence and, even when the substituent is a halogen (Cl, Br), an increase in the activity of the compound is obtained. Finally, the MAO-A inhibitory properties of some of the compounds evaluated are discussed in relation to: (a) potential antidepressant activity, and (b) their reported hallucinogenic, neurotoxic, or anxiolytic effects.     

Synthesis of carboxymethylpullulan-peptide-doxorubicin conjugates and their properties

The amino group of doxorubicin (DXR) was found to be bound to the carboxyl group of carboxymethylpullulan (CMPul) either directly or through tetrapeptide spacers, including Gly-Gly-Phe-Gly, Gly-Phe-Gly-Gly and Gly-Gly-Gly-Gly. These conjugates had DXR contents of 6.1-7.1%, with the degree of substitution of carboxymethyl groups being 0.6 per sugar moiety. These conjugates associate in phosphate-buffered saline (PBS) (pH 7.4), forming micelles with hydrophobic DXR inside and hydrophilic CMPul on the outside. The amounts of DXR released from the conjugates in the presence of rat liver lysosomal enzymes were determined by HPLC. The rate of the drug release differed among the conjugates tested. CMPul-DXR conjugate bound through Gly-Gly-Phe-Gly released 35% of its DXR over 24 h. On the other hand, CMPul-DXR conjugate without spacer released no free DXR. The antitumor effect of each conjugate in rats bearing Walker 256 was studied by monitoring the tumor weights after a single intravenous injection. Compared with DXR, CMPul-DXR conjugates bound through Gly-Gly-Phe-Gly and Gly-Phe-Gly-Gly spacers significantly suppressed the tumor growth, while CMPul-DXR conjugate bound through Gly-Gly-Gly-Gly showed less antitumor effect than DXR. CMPul-DXR conjugate bound through Gly-Gly-Gly-Gly showed less antitumor effect than DXR. CMPul-DXR conjugate without spacer showed no in vivo antitumor effect even at a dose equivalent to as much as 20 mg/kg of DXR.     

Synthesis and properties of Tb~(3 ) isomultiligand complexes

Synthesis and properties of Tb~(3 ) isomultiligand complexes     

A new method of preparing and some properties of high molecular weight monoamine oxidase from swine liver mitochondria

Isolation of highly purified and highly molecular monoamine oxidase (MAO) from pig liver mitochondria have been worked out. Specific activity of isolated preparation is 2700 times higher than of original mitochondria homogenate. Enzyme solubilization by digitonin, affinity chromatography purification and ultrafiltration underlie this method. MAO catalytic properties changing during the process of purification by different methods have been investigated. Substrate specificity was studied; kinetic parameters of enzymatic desemination were calculated.     

Pyrazole-related nucleosides. 4. Synthesis and antitumor activity of some 1-tetrahydropyranyl-4-substituted pyrazoles

Continuing our studies on the structure-activity relationships of some pyrazole nucleosides (1a-h) structurally related to ribavirin, tiazofurin and selenazofurin, we describe here the synthesis and antitumor/antiviral/antimicrobial activity of a new series of 1-tetrahydropyranyl-4-substituted pyrazoles. In this study, the tetrahydropyranyl moiety (THP), designed as a mimic of the glycosidic portion of the parent compounds 1a-h, has led to a few derivatives with moderate cytotoxic activity against leukemia/lymphoma and solid tumor-derived cell lines (IC50 14-100 microM). The compounds obtained through substitution of the ribofuranosyl moiety by the THP moiety were still active, the free heterocyclic bases were devoid of any activity.     

Synthesis and antimycobacterial activity of some new 3-heterocyclic substituted chromones

The aldol synthesis of benzimidazole, benzothiazole and benzothiazolium salt derivatives of chromones is described. The structures of the compounds have been proved by elemental analysis and 1H NMR spectra. The antimycobacterial activity of some of the prepared compounds have been tested in vitro against Mycobacterium tuberculosis (H37Rv) and Mycobacterium fortuitum (1021).     

Synthesis and optical properties of LiNd(PO_3)_4 nanocrystals dispersion in DMSO/TBE

Lanthanide doped nanocrystals with strong fluorescence, long lifetime at high doping concentrations have great potential application in bio-imaging and liquid gain medium. LiNd(PO_3)_4(LNP) crystal was reported to be one of the most excellent laser crystals with high Nd3+ concentration, and their nanocrystals synthesized via improved combustion method for the first time had strong emission intensity and long fluorescence lifetime of 122 μs. Besides,LiNd(PO_3)_4 nanocrystals can be dispersed in mixed solvents of DMSO/TBE(CHBr2 CHBr2) to form a transparent colloidal dispersion, and Judd-Ofelt theory was used to evaluate their optical parameters. In summary, LiNd(PO_3)_4 nanocrystals possess long lifetime(116 μs), low solvents quenching rate(4.9%), large emission cross section(7.63 × 10~(-20) cm~2) and high quantum yield(35.2%) under high Nd3+ ions concentration(1×10~(20) cm~(-3)), which would be the most competitive colloidal gain medium of optical amplification and laser with LD pump and potential biomaterial with low particles concentration.     

Synthesis and luminescence properties of BaWO4：Pr^3＋ microcrystal

BaWO4:Pr3+ (hereafter BWO:Pr) microcrystals were prepared via a hydrothermal route, and characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), photoluminescence excitation and emission spectra. The as-prepared products with different morphologies of egg-shape rod, olive-like, and quasi-sphere were obtained by the addition of the surfactants and chelating agents. The emis-sion spectra of BWO:Pr microcrystals showed the strong red emission (642 nm) assigned to the Pr3+ ions of 3P0→3F2 transition with blue ex-citation (484.6 nm, 3H4→3P0).     

Synthesis and luminescent properties of polycrystalline Gd2(MoO4)3:Dy3+ for white light-emitting diodes

Polycrystalline Gd₂(MoO₄)₃:Dy³⁺ phosphors have been synthesized by high temperature solid-state reaction method. The phosphors were characterized with X-ray diffractometer, thermogravimetric analysis and different scanning calorimeter, scanning electron microscopy, and photoluminescence spectrofluorimeter. Several peaks at 351, 389, 425, 452, and 472 nm appeared in photoluminescence excitation spectrum, which matched well with the emission of the ultraviolet (UV) and blue-light emitting diode (LED) chips. Upon excitation at 389 nm UV light, intense emissions centered at 484, 575 and 668 nm were attributed to the transitions of ⁴F_9/2→⁶H_15/2, ⁴F_9/2→⁶H_13/2 and ⁴F_9/2→⁶H_11/2 of Dy³⁺, respectively. The chromaticity coordinates and correlative color temperatures have been calculated and presented in the Commission International de I'Eclairage (CIE) diagrams. The results indicated that Gd_1.9(MoO₄)₃:Dy_0.1³⁺ with CIE coordinates of (x=0.38, y=0.41) and the correlative color temperature of 4134 K is a potential candidate for white LEDs.