Spectral and inhibitory interactions of (±)−3, 4-methylenedioxyamphetamine (MDA) and (±)−3, 4-methylenedioxymethampetamine (MDMA) with rat hepatic microsomes

Incubation of racemic methylenedioxyamphetamine (MDA) or methylenedioxymethamphetamine (MDMA) with rat hepatic microsomes, in the presence of NADPH, generated a spectrally observed inhibitory complex with cytochrome P-450. The complex inhibited product formation from MDA and MDMA as well as other P-450 dependent reactions such as benzphetamine demethylation and CO binding. In the absence of NADPH, MDMA and MDA generated type I and type IIa difference spectra, respectively, suggesting differences in their binding to the enzyme active site. The N-demethylation of MDMA was partially inhibited by methimazole suggesting involvement of the hepatic flavin-containing monooxygenase.     

Synthesis of (±)-4′-Ethynyl and 4′-Cyano Carbocyclic Analogues of Stavudine (d4T)

The synthesis of (±)-4′-ethynyl (8) and 4′-cyano (9) carbocyclic analogues of the anti-HIV agent stavudine (5, d4T) is reported. The carbocyclic unit (16) was constructed from readily available β-keto ester 10. The ethynyl or cyano group of 8 and 9 were prepared, after the introduction of thymine base to 16, by manipulation of the ester function. Evaluation of the anti-HIV activity of 8 and 9 was also carried out.     

Synthesis,reactivity and biological activity of N(4)-boronated derivatives of 2′-deoxycytidine

By seeking new stable boron-containing nucleoside derivatives, potential BNCT boron delivery agents, a novel synthetic approach was tested, aimed at a boron attachment via a single bond to an aliphatic carbon of sp³ hybridization. The latter allowed successful modification of deoxycytidine in the reaction with 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of the deoxynucleoside amino group. For new compounds, detailed NMR, LDI HRMS (Laser Desorption/Ionization High-Resolution Mass Spectrometry) analyses along with in vivo phosphorylation studies, toxicity assays and DFT modelling are presented.     

Synthesis,structure and properties of syn-bis(μ-N-methylpiperidine-4-thiolate tricarbonyl iron)

The reaction of Fe₃(CO)₁₂ with N-methyl-4- mercaptopiperidine gives the title compound. Crystals are monoclinic, space group P2₁/c with a = 12.922(2), b = 14.784(5), c = 13.607(2) Å, β = 112.41(1)°. With Z = 4 the calculated density is 1.49 g cm⁻³. Solution of the structure by direct methods led to a final weighted R factor of 0.029 for 2270 independent reflections. The FeFe bond length is 2.534(1) Å and the S···S distance of 2.940(1) suggests bonding interactions. By heating upon reflux in toluene during 10 h, the IR spectrum of the chromatographed solution indicates the syn isomer formation. The reaction with CH₃I and HClO₄ produces the methylation and protonation, respectively, of the nitrogen atoms of the piporidine rings giving rise to the formation of the [Fe(μ-(CH₃)₂NC₅H₉S)(CO)₃]₂I₂·2H₂O and [Fe(μ-HCH₃NC₅H₉S)(CO)₃]₂·H₂O·CH₃OH compounds.     

Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl,and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters

Early studies led to the identification of 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid methyl ester (5) with high affinity at the DAT (IC₅₀ = 6.5 nM) and 5-HTT (K_i = 4.3 nM), while having much less affinity at the NET (K_i = 1110 nM). In the present study, we replaced the 4′-methoxy group of the 3β-phenyl ring with a bioisosteric 4′-methylthio group to give 7a. We also synthesized a number of 3β-(4-alkylthiophenyl)tropanes 7b–e, 3β-(4-methylsulfinylphenyl) and 3β-(4-methylsulfonylphenyl)tropane analogues 7f–h as well as the 3β-(4-alkylthiophenyl)nortropane derivatives 8–11 to further characterize the structure–activity relationship of this type of compound for binding at monoamine transporters. With exception of the 4′-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affinities at the 5-HTT. The K_i values ranged from 0.19 nM to 49 nM. The 3β-(4-methylthiophenyl)tropane 7a and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for the 5-HTT over the NET (NET/5-HTT = 314–364) in the series. However, none of the compounds showed selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR information for rational design of potent and selective monoamine transporter inhibitors.     

Total synthesis of (±)-elegansidiol, (±)-farnesiferol B,and (±)-farnesiferol D

The racemic total synthesis of elegansidiol, farnesiferol B, and farnesiferol D has been obtained following a Diels–Alder approach. Gillman addition, cross metathesis reaction are the other key steps involved in the target synthesis.     

Metabolism of (2Z,4E)-γ-Ionylideneethanol and (2Z,4E)-γ-Ionylideneacetic Acid in Cercospora cruenta

[2–¹⁴C]-(2Z,4E)-γ-Ionylideneethanol and [2–¹⁴C]-(2Z,4E)-γ-ionylideneacetic acid were converted by Cercospora cruenta to [2–¹⁴C]-(2Z,4E)-1′,4′-dihydroxy-γ-ionylideneacetic acid and [2-¹⁴C]-(2Z,4E)-4′-hydroxy-γ-ionylideneacetic acid, which are intermediates of ABA biosynthesis in C. cruenta.     

Cytology and morphology of the amphiploid Hordeum chilense (4x) × Aegilops squarrosa (4x)

Summary The intergeneric amphiploid Hordeum chilense × Aegilops squarrosa has been synthesized. The amphiploid plants have the expected chromosome number of 28. The average meiotic chromosome pairing was 12.48 bivalents + 3.04 univalents. The morphology of the amphiploid resembles that of the Aegilops parent. Nucleoli from both H. chilense and A. squarrosa are expressed in the amphiploid. Neither chromosome instability nor homoeologous pairing was found. The amphiploid is fertile and vigorous.     

Kinetics of β-N-methylamino-L-alanine (BMAA) and 2, 4-diaminobutyric acid (DAB) production by diatoms: the effect of nitrogen

The neurotoxins β-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB) are produced by cyanobacteria, diatoms and dinoflagellates and have been detected in seafood worldwide. Our present knowledge of their metabolism or biosynthesis is limited. In this study, the production of BMAA and DAB as a function of time was monitored in five strains representing four species of diatoms, i.e. Phaeodactylum tricornutum, Thalassiosira weissflogii, Thalassiosira pseudonana and Navicula pelliculosa, previously identified as BMAA and DAB producers. Subsequently, three strains were selected and exposed to three nitrogen treatments – starvation, control (the standard concentration in f/2 medium) and enrichment, because BMAA metabolism has been suggested to be closely associated with cellular nitrogen metabolism in both cyanobacteria and diatoms. Chlorophyll a and total protein concentrations were also determined. Our results indicate that BMAA and DAB production in diatoms is species- and strain-specific. However, production might also be affected by stress, particularly as related to nitrogen starvation and cell density. Furthermore, this study shows a significant correlation between the production of the two neurotoxins which might further suggest common steps in the metabolic pathways.     

DFT study of (17)O, (1)H and (13)C NMR chemical shifts in two forms of native cellulose, I(α) and I(β)

This computational study is intended to shed light on the crystalline and molecular structure, together with the hydrogen bonding (H-bonding) differences between two forms of native cellulose. DFT calculations were carried out to characterize the ¹⁷O, ¹H and ¹³C nuclear magnetic resonance (NMR) parameters in cellulose I_α and I_β with the B3LYP functional employing the 6–311++G7 and 6–31+G1 basis sets. Geometry optimization revealed that the average HB length is shortened by 0.01–0.08 Å when the chains are aligned, whereas the average bond angle increases by about 4–8° exhibiting the enhancement of HB strength. For the isolated cellotetramer chains, the isotropic ¹⁷O–H chemical shifts were plotted as a function of HB length. Our results indicated that as the HB length in cellotetramer I_α increases, the ¹⁷O–H chemical shift isotropy increases, but this parameter changes in the opposite direction for the other structure. Moreover, B3LYP/6–311++G7 calculations reveal that there is an acceptable correlation between the calculated ¹³C chemical shifts of the two structures and their experimental values.     

Distribution of Copper, Iron, and Zinc in Biological Samples (Scalp Hair, Serum, Blood, and Urine) of Pakistani Viral Hepatitis (A–E) Patients and Controls

The aim of the present study was to compare the level of copper (Cu), iron (Fe) and zinc (Zn) in biological samples (serum, blood, urine, and scalp hair) of patients suffering from different viral hepatitis (A, B, C, D, and E; n?=?521) of both gender age ranged 31–45 years. For comparative study, 255 age-matched control subjects, of both genders residing in the same city were selected as referents. The elements in the biological samples were analyzed by flame atomic absorption spectrophotometry, prior to microwave-assisted acid digestion. The validity and accuracy of the methodology was checked by using certified reference materials (CRMs) and with those values obtained by conventional wet acid digestion method on same CRMs. The results of this study showed that the mean values of Cu and Fe were higher in blood, sera, and scalp hair samples of hepatitis patients, while Zn level was found to be lower than age-matched control subjects. The urinary levels of these elements were found to be higher in the hepatitis patients than in the age-matched healthy controls (p?<?0.05). These results are consistent with literature-reported data, confirming that the deficiency of zinc and hepatic iron and copper overload can directly cause lipid peroxidation and eventually hepatic damage.     

Revision of the lectotype ofFavreina salevensis (Paréjas) (Crustacea,Decapoda) and description of favreine form-species from the Jurassic and Cretaceous of Scotland,Portugal, Yougoslavia and Pakistan

The lectotype ofFavreina salevensis (Paréjas) is re-examined and illustrated and the following new favreine form-species proposed:Favreina guinchoensis from the Upper Jurassic of Portugal,Favreina njegosensis andFavreina dinarica from the Neocomian of the Dinarids, andFavreina eiggensis from the Bathonian of the Inner Hebrides, Scotland.Favreina murciensis Cuvillier, Bassoulet & Fourcade is recorded from the Jurassic of Pakistan.     

Inhibition of NADH oxidase activity and growth of HeLa cells by the antitumor sulfonylurea,N-(4-methylphenylsulfonyl)-N′-(4-chlorophenyl)urea (LY181984) and response to epidermal growth factor

Right side-out plasma membrane vesicles isolated from HeLa cells exhibited an NADH oxidase activity at their external surfaces that was inhibited by the antitumor sulfonylurea, N-(4-methylphenylsulfonyl)-N′-(4-chlorophenyl)urea (LY181984). Intact HeLa cells (fresh or frozen) also exhibited an NADH oxidase activity at the external cell surface. The inhibition of this activity by LY181984 was enhanced by the addition of epidermal growth factor (EGF). The order of addition was critical. It was necessary that the LY181984 be followed by the EGF. If the EGF was administered first, the response to LY181984 was unaffected by EGF. Binding of [³H]LY181984 to HeLa cells also was enhanced by EGF. Growth experiments with HeLa cells revealed a similar pattern of response to EGF. The EC₅₀ of growth inhibition of LY181984 was about 100 μM. However, if the LY181984 was followed by addition of 10 nM EGF, the EC₅₀ for LY181984 was reduced to about 30 nM which now approximated the previously determined K_d of [³H]LY181984 binding of 30 nM and the EC₅₀ of 30 nM for inhibition of NADH oxidase activity by LY181984 by isolated vesicles of plasma membranes. The tumor-inactive sulfonylurea N-(methylphenylsulfonyl-N′-(phenyl)urea (LY181985) was ineffective in the inhibition of NADH oxidation and of growth with HeLa cells either in the presence or absence of EGF.     

Isolation and characterization of dinoflagellate and chrysophyte cytochrome-f (553–4)

Cytochrome-f (553–4) was isolated from mass cultures of the six dinoflagellates, Amphidinium carterae (2 strains), Cachonina niei, Glenodinium sp., Peridinium foliaceum, Gonyaulax polyedra, and one chrysophyte, Cricospherae carterae. Sonication of whole cell suspensions released the water-soluble protein, which was then purified by vacuum dialysis, salt fractionation and column chromatography. Reduced forms of isolated cytochromes had absorption maxima at 270–6, 316–8, 415–6, 522–3 and 553–4 rim. The α-absorption peak was asymmetrical. MW's, as determined by SDS polyacrylamide gel electrophoresis, ranged from 10 700 to 13 500. Amino acid analysis of C. niei cytochrome-f revealed 102 residues, with a composite MW of 10836. Purified cytochromes had isoelectric points ranging from 3·45 to 4·25 and oxidation-reduction potentials ranging from +0·374 to +0·351 V.     

Synthesis, structure, spectroscopic properties, and electrochemical behavior of mixed ligand bis(β-ketoesterato)zirconium (IV) and -hafnium (IV) phthalocyaninates

The synthesis of new zirconium and hafnium mixed ligand phthalocyanine complexes PcM(β-ketoester)₂, where M-Zr (IV), Hf (IV); Pc - the dianion of phthalocyanine, and β-ketoester - the out planed ligand, is reported. The obtained complexes are characterized by ¹H NMR, IR, UV-Vis spectroscopy and cyclic voltammetry. ¹H NMR and elemental analysis confirm the substitution of two Cl atoms for two β-ketoester fragments to the central atom of the macrocycle. The data of ¹H NMR, UV-Vis spectroscopy have allowed us to conclude that two β-ketoester ligands are in the cis geometry to the phthalocyanine plane. X-ray crystallography for bis(isopropyl 3-oxobutanoato)hafnium(IV)phthalocyanine confirms this conclusion. The central macrocycle of the phthalocyanine ligand is not exactly planar (deviations from the least-square plane exceed 0.15 Å) and has the conformation of an essentially flattened crown. The Hf(1) atom is 1.349(3) above this least-square plane. Cyclic voltammetry investigation shows that the introduction of two β-ketoester ligands to the central atom of phthalocyanine complex leads to both chemical and electrochemical stabilization of the whole Pc system.