Hydroxyl Derivatives Research Articles

Biological metabolic transformation of polybrominateddiphenyl ethers

As widely used flame retardants polybrominateddiphenyl ethers(PBDEs)and their hydroxyl and methoxyl derivatives(OH-PBDEs and MeO-PBDEs)have been detected from various kinds of environmental media, different organisms and human bodies. The sources of low brominated PBDEs, OH-PBDEs, and MeO-PBDEs detected in organisms are not clearly elucidated, which may either be uptaken from the surrounding environment or formed via biotransformation in vivo . Since the biotransformation mechanism and transformation products of PBDEs in organism are closely related with their toxicities, it has been the focus of many literatures. Based on the analysis of distributions and sources of PBDEs and their metabolic derivatives in organism, the research progresses of reductive debromination and oxidation metabolism of PBDEs in organisms have been reviewed. The metabolism, pathways, and key enzymes involved in the biotransformation of PBDEs both in vivo and in vitro are explored. Directions for further studies on the bioaccumulation and biotransformation of PBDEs are proposed.

Methemoglobin incites primaquine toxicity through single-electron oxidation and modification

Primaquine (Pq) metabolic products are responsible for drug-associated hemotoxicity and limit primaquine usage. Methemoglobin (MetHb)-Pq molecular modeling was used to identify the Pq binding pocket. UPLC, mass spectrometry, and other indirect analytical methods were used to predict the metabolite. MetHb generation, development of oxidative stress, inhibition of antioxidant enzymes, and scanning electron microscope (SEM) were used to characterize the hemotoxic potentials of oxidized Pq (Pqox). MetHb binded Pq at the heme site with KD =6.4 μM as evidenced by a difference spectroscopy study. MetHb oxidized Pq through a single e-transfer mechanism to form Pqox. The analysis of Pq from MetHb-H2O2 peroxidase reaction mixture gave peaks at m/z 300.53 and m/z 243.42, corresponding to the hydroxyl and desamino derivative of Pq, respectively. Similar peaks were absent in Pq or Pq incubated with H2O2 in the same buffer system. A robust increase in MetHb formation, reactive oxygen species generation, and inhibition of antioxidant enzymes were found in red blood cells (RBCs) exposed to Pqox compared with a parent drug molecule. The RBC membrane exhibited visible damages to plasma membrane (holes) as evidenced by SEM analysis of Pqox-exposed RBCs. The MetHb-H2O2 system transforms quiescent parent drug molecule to a highly reactive oxidative form to exhibit severe hemolysis. MetHb-H2O2-mediated Pq hemolytic potentiation that is sensitive to spin trap indicates the role of Pq* radical or other single e-species in the process. The result suggests that MetHb incites the molecular property of the Pq and peroxidase inhibitors can be explored to control drug-associated toxicity.

Synthesis, reactions and antineoplastic activity of 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromene derivatives

Abstract The key 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromen-5-yl acetates 3 were synthesized in high yields by cyclocondensation of 4-oxo-4H-chromen-3-carbaldehydes 1 with coumarin-3-acetic acids 2 under mild conditions. The reaction pathway involves aldol condensation and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton 3. Further treatment of acetates 3 with alcohols, water or nitrogen containing compounds led to 5-alkoxy-, 5-hydroxy- or 5-acylamino-2H,5H-pyrano[3,2-c]chromen-2-ones 4-6 via nucleophilic substitution of acetyloxy group at C-5. Acetates and hydroxyl derivatives 3 and 5 undergo facile rearrangement in an acid medium yielding 5-hydroxypyrano[2,3-b]chromen-2(10aH)-ones 7. Twelve prepared compounds were evaluated on their antineoplastic activities on 60 human tumour cell line panels in NCI USA. The obtained biological results confirmed that 3-(2-oxo-2H-chromen-3-yl)-2H,5H-pyrano[3,2-c]chromen-2-one represents a new leading skeleton suitable for further antitumour activity study.

Modification of phospholipid bilayers induced by sulfurated naphthoquinones.

New thionaphthoquinones and their hydroxyl derivatives, bearing alkyl side chains that match the phospholipids POPC and POPE, were synthesized in order to investigate their interactions with lipids. It was observed that, in general, these additives destabilize the lipid bilayer and induce less organized structures with higher curvature, in particular the induction of an hexagonal phase on aqueous POPC mixtures. Moreover, cubic phases, not normally observed in the pure lipids when fully hydrated, were detected. Coexistence of lamellar phases was interpreted as a consequence of microsegregation of the components in the mixtures. These results are in line with previous observations on the effect of structurally similar (hydro)quinones in phase behavior of these lipids.

Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists for the human α4β2 and α7 nicotinic acetylcholine receptors

This work presents the synthesis and the pharmacological characterization of a series of novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodide derivatives at the human (h) α7 and α4β2 nicotinic acetylcholine receptors (nAChRs). The inhibitory activity of the compounds was determined by Ca2+ influx assays on cells expressing either the hα7 or hα4β2 nAChR subtype. To determine whether the observed inhibitory activity is mediated by a competitive or non-competitive mechanism, additional radioligand binding assays were performed using [3H]methyllycaconitine, [3H]cytisine, and [3H]imipramine. The results established that the compounds inhibit the nAChRs by a competitive mechanism and that the potencies are higher for the hα7 nAChR compared to that for the hα4β2 nAChR. Substitutions with oxygenated functional groups on the benzene ring increase the receptor selectivity. In particular, the hydroxyl derivatives 4b and 4c present the highest selectivity for the hα7 nAChR subtype. Molecular docking results indicate that the hydroxyl group forms a hydrogen bond with the carbonyl group at α7-Gln116, but not at β2-Phe115, supporting the observed receptor selectivity at the molecular level.

Metabolism and Quantification of [18F]DPA-714, a New TSPO Positron Emission Tomography Radioligand

[(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2[(18)F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide] is a new radioligand currently used for imaging the 18-kDa translocator protein in animal models of neuroinflammation and recently in humans. The biodistribution by positron emission tomography (PET) in baboons and the in vitro and in vivo metabolism of [(18)F]DPA-714 were investigated in rats, baboons, and humans. Whole-body PET experiments showed a high uptake of radioactivity in the kidneys, heart, liver, and gallbladder. The liver was a major route of elimination of [(18)F]DPA-714, and urine was a route of excretion for radiometabolites. In rat and baboon plasma, high-performance liquid chromatography (HPLC) metabolic profiles showed three major radiometabolites accounting for 85% and 89% of total radioactivity at 120 minutes after injection, respectively. Rat microsomal incubations and analyses by liquid chromatography-mass spectrometry (LC-MS) identified seven metabolites, characterized as O-deethyl, hydroxyl, and N-deethyl derivatives of nonradioactive DPA-714, two of them having the same retention times than those detected in rat and baboon plasma. The third plasma radiometabolite was suggested to be a carboxylic acid compound that accounted for 15% of the rat brain radioactivity. O-deethylation led to a nonradioactive compound and [(18)F]fluoroacetic acid. Human CYP3A4 and CYP2D6 were shown to be involved in the oxidation of the radioligand. Finally an easy, rapid, and accurate method--indispensable for PET quantitative clinical studies--for quantifying [(18)F]DPA-714 by solid-phase extraction was developed. In vivo, an extensive metabolism of [(18)F]DPA-714 was observed in rats and baboons, identified as [(18)F]deethyl, [(18)F]hydroxyl, and [(18)F]carboxylic acid derivatives of [(18)F]DPA-714. The main route of excretion of the unchanged radioligand in baboons was hepatobiliary while that of radiometabolites was the urinary system.

Simultaneous determination of phenolic compounds and triterpenic acids in oregano growing wild in Greece by 31P NMR spectroscopy

(31)P nuclear magnetic resonance (NMR) spectroscopy was used to detect and quantify simultaneously a large number of phenolic compounds and the two triterpenic acids, ursolic acid and oleanolic acid, extracted from two oregano species Origanum onites and Origanum vulgare ssp. Hirtum using two different organic solvents ethanol and ethyl acetate. This analytical method is based on the derivatization of the hydroxyl and carboxyl groups of these compounds with the phosphorous reagent 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxa phospholane and the identification of the phosphitylated compounds on the basis of the (31)P chemical shifts. Unambiguous assignment of the (31)P NMR chemical shifts of the dihydroxy- and polyhydroxy-phenols in oregano species as well as those of the triterpenic acids was achieved upon comparison with the chemical shifts of model compounds assigned by using two-dimensional NMR techniques. Furthermore, the integration of the appropriate signals of the hydroxyl derivatives in the corresponding (31)P NMR spectra and the use of the phosphitylated cyclohexanol as an internal standard allowed the quantification of these compounds. The validity of this technique for quantitative measurements was thoroughly examined.

Derivatization chemistry of the double-decker dicobalt sandwich ion targeted to design biologically active substances

A synthesis of the first double-decker sandwich ion [(1',2'-C2B9H11)-3,3'-Co-(1,2-C2B8H10)-6,3"-Co-(1",2"-C2B9H11)]2– (DD 2–) derivatives is described, having been developed in connection with our search for biologically active substances. A series of B-substituted hydroxyl derivatives was prepared by direct hydroxylation of the ion using aqueous sulfuric acid. Two isomers of monohydroxy derivatives were isolated. The main product was substituted at the central “canastide” ion fragment, whereas the substitution site for the minor isomer corresponded to a B(8) atom of one of the terminal 11-vertex dicarbollide parts. Similarly, the disubstitution occurred slightly more preferentially on the “canastide” fragment providing the main isomeric derivative with a symmetric structure. The cesium salt of this ion was characterized by X-ray diffraction. Two other isomeric species have one substituent sitting on the “canastide” ion and the second present on the dicarbollide ligand in apart or syn-geometric arrangement. A new zwitterion anion [(1',2'-C2B9H11)-3',3-Co-(8-(CH2)4O-1,2-C2B8H9)-6,3"-Co-(1",2"-C2B9H11)-]1– was prepared by the reaction of the parent ion with tetrahydrofuran (THF), activated by BF3·OEt2. This new compound serves as a versatile building block for constructing organic derivatives, as exemplified by the ring cleavage by various amines or phenolate ions and the synthesis of a basic series of compounds of general formulation [(1',2'-C2B9H11)-3',3-Co-(8-X-(CH2)4O-1,2-C2B8H9)-6,3"-Co-(1",2"-C2B9H11)] n– where the organic end-groups X adjacent to the “canastide” moiety via a B-oxatetramethylene spacer corresponds to C4H9NH2, NC5H5, N(C2H5)3, (C6H5)3P (n = 1), or (4-t-Bu-C6H4-1-O)– and (2-CH3O-C6H4O)– (n = 2). We show that dicluster compounds with two identical DD 2– anion units or asymmetric molecules containing two different clusters, the cobalt bis(dicarbollide) and the DD 2– anion, are accessible using this building block. All compounds were characterized by high-resolution NMR (1H, 13C, and 11B) and mass spectrometry. Some of the compounds were tested by in vitro assay for their ability to inhibit the HIV-protease (HIV-PR) enzyme. The majority of the tested species proved substantially high activity toward the HIV-PR, exhibiting on the other hand a noncompetitive mechanism of the inhibition.

New Tricks for an Old Natural Product: Discovery of Highly Potent Evodiamine Derivatives as Novel Antitumor Agents by Systemic Structure–Activity Relationship Analysis and Biological Evaluations

Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus . Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.

Conjugation of Glutathione to Oxidized Tyrosine Residues in Peptides and Proteins

Tyrosine residues are sensitive to oxidation and can be converted to hydroperoxides either by superoxide reacting with the Tyr radical or by singlet oxygen. These hydroperoxides rearrange to bicyclic derivatives that are readily reduced to more stable hydroxides. The aromatic character of tyrosine is lost, but the product contains an α-β unsaturated carbonyl group and is, therefore, an electrophile. We have generated hydroxide derivatives of several Tyr-containing peptides and shown using liquid chromatography/mass spectrometry that they undergo Michael addition with GSH. For Tyr-Gly, rate constants of 9.2 and 11.8 m(-1)min(-1) were measured for the two chromatographically distinct isomers. Unusual for GSH addition to an electrophile, the reaction is reversible, with a half-life of many hours for the reverse reaction. These kinetics indicate that with a typical cellular concentration of 5 mm GSH, >95% Tyr-Gly hydroxide would become conjugated with a half-life of ∼15 min. Sperm whale myoglobin forms a hydroperoxide on Tyr-151 in a hydrogen peroxide/superoxide-dependent reaction. We show that its hydroxide derivative reacts with GSH to form a conjugate. Detection of the conjugate required stabilization by reduction; otherwise, the reverse reaction occurred during tryptic digestion and analysis. Our findings represent a novel mechanism for peptide or protein glutathionylation involving a carbon-sulfur cross-link between oxidized Tyr and Cys. As with other electrophiles, the oxidized Tyr should undergo a similar reaction with Cys residues in proteins to give intramolecular or intermolecular protein cross-links. This mechanism could give rise to protein cross-linking in conditions of oxidative stress.

Study of sphingolipids oxidation by ESI tandem MS

AbstractSphingolipids are a class of lipids that play important cellular roles both as structural components of membranes and as signaling molecules. They have also an active participation in apoptosis and inflammation processes which are associated with oxidative stress conditions. However, no studies so far accomplished the oxidative modification of sphingolipids under oxidative stress conditions. In the present study, different sphingolipids, ((d18:1/16:0) sphingomyelin (N‐palmitoyl‐D‐erythro‐sphingosylphosphorylcholine, SM), (d18:1) sphingosylphosphorylcholine (a lysosphingolipid, SPC), and (d18:1/18:0) ceramide (Cer)) were oxidized by the hydroxyl radical, generated under Fenton reaction conditions, and the oxidation reaction was monitored by ESI‐MS in positive mode. No oxidation products were identified for Cer under the oxidative conditions used, while ESI‐MS spectra of SPC and SM after oxidation show some oxidation products that were analyzed by ESI‐MS/MS. This approach allowed identifying hydroxyl and keto derivatives of SPC and acetaldehydephosphorylcholine derivative (m/z 226). SM oxidation occurs exclusively in sphingosine backbone with formation of SPC, hydroxyl, and keto derivatives of SPC and the oxidation product at m/z 226. This study may give new insight and could help to understanding the behavior and biological roles of the sphingolipids under oxidative stress conditions.

Mono- and dihydroxyl glycerol dibiphytanyl glycerol tetraethers in marine sediments: Identification of both core and intact polar lipid forms

Hydroxylated glycerol dialkyl glycerol tetraethers (hydroxy-GDGTs) were detected in marine sediments of diverse depositional regimes and ages. Mass spectrometric evidence, complemented by information gleaned from two-dimensional (2D) 1H–13C nuclear magnetic resonance (NMR) spectroscopy on minute quantities of target analyte isolated from marine sediment, allowed us to identify one major compound as a monohydroxy-GDGT with acyclic biphytanyl moieties (OH-GDGT-0). NMR spectroscopic and mass spectrometric data indicate the presence of a tertiary hydroxyl group suggesting the compounds are the tetraether analogues of the widespread hydroxylated archaeol derivatives that have received great attention in geochemical studies of the last two decades. Three other related compounds were assigned as acyclic dihydroxy-GDGT (2OH-GDGT-0) and monohydroxy-GDGT with one (OH-GDGT-1) and two cyclopentane rings (OH-GDGT-2). Based on the identification of hydroxy-GDGT core lipids, a group of previously reported unknown intact polar lipids (IPLs), including the ubiquitously distributed H341-GDGT (Lipp J. S. and Hinrichs K. -U. (2009) Structural diversity and fate of intact polar lipids in marine sediments. Geochim. Cosmochim. Acta 73, 6816–6833), and its analogues were tentatively identified as glycosidic hydroxy-GDGTs. In addition to marine sediments, we also detected hydroxy-GDGTs in a culture of Methanothermococcus thermolithotrophicus. Given the previous finding of the putative polar precursor H341-GDGT in the planktonic marine crenarchaeon Nitrosopumilus maritimus, these compounds are synthesized by representatives of both cren- and euryarchaeota. The ubiquitous distribution and apparent substantial abundance of hydroxy-GDGT core lipids in marine sediments (up to 8% of total isoprenoid core GDGTs) point to their potential as proxies.

New Structure–Activity Relationships of A- and D-Ring Modified Steroidal Aromatase Inhibitors: Design, Synthesis, and Biochemical Evaluation

A- and D-ring androstenedione derivatives were synthesized and tested for their abilities to inhibit aromatase. In one series, C-3 hydroxyl derivatives were studied leading to a very active compound, when the C-3 hydroxyl group assumes 3β stereochemistry (1, IC(50) = 0.18 μM). In a second series, the influence of double bonds or epoxide functions in different positions along the A-ring was studied. Among epoxides, the 3,4-epoxide 15 showed the best activity (IC(50) = 0.145 μM) revealing the possibility of the 3,4-oxiran oxygen resembling the C-3 carbonyl group of androstenedione. Among olefins, the 4,5-olefin 12 (IC(50) = 0.135 μM) revealed the best activity, pointing out the importance of planarity in the A,B-ring junction near C-5. C-4 acetoxy and acetylsalicyloxy derivatives were also studied showing that bulky substituents in C-4 diminish the activity. In addition, IFD simulations helped to explain the recognition of the C-3 hydroxyl derivatives (1 and 2) as well as 15 within the enzyme.

Abstract 749: A Phase I, open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors

Abstract Background Cabazitaxel (Cbz) is a novel semi-synthetic taxane that promotes the assembly of tubulin and stabilizes microtubules. In preclinical studies, Cbz demonstrated efficacy in both docetaxel-sensitive and -resistant tumor models (Bissery et al. AACR 2000). Furthermore, the Phase III TROPIC trial demonstrated that, compared with mitoxantrone, Cbz improved overall survival in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen (hazard ratio 0.70; P < 0.0001). The human plasma pharmacokinetics of Cbz have been described previously (Mita et al. Clin Cancer Res 2009), but detailed analyses of the metabolism and excretion pathways of Cbz have not yet been published in the literature. Methods Four patients with advanced solid tumors (3 males; median age 52.5 years; performance status 0-1) received an IV infusion of 25 mg/m*2 [14C]-Cbz (50 µCi, 1.85 MBq) over 1 hour at cycle 1. Blood, plasma, urine, feces and expired air samples were collected at various times up to 14 days post-dosing. Radioactivity determination was performed by liquid scintillation counting, either directly (plasma, urine or CO2 traps) or after combustion (whole blood and feces). Analyses were carried out using liquid chromatography, with radioactivity and mass spectrometry detection for metabolite profiling, quantification and identification. Subsequent IV infusions were conducted every 3 weeks with non-radiolabeled drug until disease progression, intolerance or other study discontinuation criteria were reached. Results In plasma, Cbz was the main circulating compound, representing approximately 70% of the radioactivity AUC. Seven metabolites were detected, each accounting for ≤ 5% of the parent drug exposure; none of these, including the pharmacologically active docetaxel (di-O-demethyl-Cbz), were therefore considered relevant metabolites. In excreta, the majority of the radioactivity was recovered in feces (mean: 76.0% of administered dose within 2 weeks); 3.7% of the dose was excreted in urine within 1 week. No unchanged compound was excreted in feces and, on average, only 2.3% of the dose in urine, revealing an extensive hepatic metabolism of Cbz in humans. Approximately 20 metabolites were detected in excreta; the main metabolites corresponded to combined mono- or di-O-demethyl derivatives on the taxane ring, with hydroxyl or cyclized derivatives on the lateral chain. Docetaxel (di-O-demethyl-cabazitaxel) was only detected as traces in excreta. Conclusions Cbz is extensively metabolized in patients, but no relevant metabolites were observed in plasma, indicating that parent Cbz is the only entity responsible for the pharmacologic activity. Cbz metabolites are formed through 3 main metabolic pathways and are almost exclusively excreted in the feces. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 749. doi:1538-7445.AM2012-749

Novel polycyclic ‘cage’-1,2-diamines as potential anti-tuberculosis agents

A series of polycyclic ‘cage’ derivatives of N-geranyl-1,2 diamines were synthesized and screened for their anti-mycobacterial activity against H37Rv, multidrug resistant (MDR) and extensively drug-resistant (XDR) strains of tuberculosis. By substituting the adamantyl skeleton of SQ109 with trishomocubanyl (9), oxa-pentacycloundecyl (14, 16), pentacycloundecyl, PCU, (10, 15) and azapentacycloundecyl (22, 23), the effect of other polycyclic “cage” skeletons could be investigated. Compound 9 (trishomocubanyl moiety) proved to be the most active (MICs: 0.5–2 μg/mL) while PCU hydroxyl derivatives (15 and 23), oxa-pentacycloundecyl and azapentacycloundecyl derivatives displayed similar activity to SQ109 (MICs: 0.5–4 μg/mL) against all three strains of TB used in this study.

Foaming and emulsifying properties of fatty acids neutralized by tetrabutylammonium hydroxide

Our paper aims at determining the interfacial, foaming and emulsifying properties of a series of dispersions made of long chain fatty acids (carboxylic acids) and hydroxyl derivatives neutralized by tetrabutylammonium hydroxide (TBAOH). Those fatty acids were myristic, palmitic and stearic acid as saturated fatty acids and juniperic and 12-hydroxystearic acid as the hydroxyl fatty acids. All these systems are already known to form micelles in water at room temperature. Here, we determined the critical micelle concentration (CMC) for all those systems using electrical conductivity. Foaming and emulsifying properties were then studied below and above the CMC. Relatively stable emulsions can be produced above but not below the CMC. There is a noticeable effect of the alkyl chain length and the presence of a hydroxyl group. The foamability is good but the foam stability is low in all cases above the CMC. Below the CMC, the foamability depends on the fatty acid and foams destabilize very quickly. Thus, the use of TBAOH to disperse fatty acids in water at room temperature allows using long chains fatty acids and hydroxylated derivatives for the production of emulsions and foams, the stability of which can be modulated.

Effect of N3 Modifications on the Affinity of Spin Label ç for Abasic Sites in Duplex DNA

Noncovalent site-directed spin labeling (NC-SDSL) of abasic sites in duplex DNAs with the spin label ç, a cytosine analogue, is a promising approach for spin-labeling nucleic acids for EPR spectroscopy. In an attempt to increase the affinity of ç for abasic sites, several N3 derivatives were prepared, and their binding affinities were determined by EPR spectroscopy. Most of the N3 substituents had a detrimental effect on binding. The triazole-linked polyethylene-glycol derivative (12 a) showed a 15-fold decrease in affinity, whereas the binding affinities of ethyl azido (8 b) and hydroxyl (8 c) derivatives were five- to sixfold lower. The spin-labeled nucleoside Ç showed only a twofold decrease, thus binding better than 8 c, even though it contains the larger 2'-deoxyribose substituent at N3 instead of a 2-hydroxyethyl group. N3 derivatives that contained the basic ethyl amino (9) or ethyl guanidino (10) substituents had both higher binding affinity and solubility, attributed to their cationic charge at neutral pH. Compounds 9 and 10 are promising candidates for NC-SDSL of nucleic acids, for distance measurements by pulsed EPR spectroscopy.

Synthesis and Antinociceptive Behaviors of New Methyl and Hydroxyl Derivatives of Phencyclidine

Phencyclidine (I) and its derivatives show such pharmacological behaviors as analgesic, anticonsulvant, anti-anxiety and antidepressant, while interacting with central nervous system. In this study, new methyl and hydroxyl derivatives of PCP were synthesized and their antinociceptive behaviors in animals were examined by measuring the number of writhing in a writhing test of visceral pain and the pain scores in Formalin test. Compared to control and PCP groups, findings in experimental groups indicated the new synthesized analogues (compounds II, III and V, 10 mg/kg) of PCP were able to produce more analgesic effects in formalin and writhing tests, especially for compound V. It was concluded that the new synthesized derivatives of PCP could substantially and respectively diminish acute and chronic pains.

Inverted binding due to a minor structural change in berberine enhances its phospholipase A2 inhibitory effect

Biotransformation of berberine by Rhizopus oryzae leads to its demethylation, producing hydroxyl derivatives, as revealed by Fourier Transform Infra Red spectroscopy, Nuclear Magnetic Resonance and Electro Spray Ionization–Mass Spectrometric analyses. Surface Plasmon Resonance and enzyme kinetic studies showed that biotransformed derivatives of berberine had a higher inhibitory potential than berberine towards phospholipase A2. X-ray crystal structures demonstrated that biotransformed berberine binds to PLA2 in an entirely different, inverted orientation with respect to the binding of berberine. This study brings out the significance of biotransformation in generation of better drug-lead compounds.

Production and Characteristics of a Heavy Metals Removing Bioflocculant Produced by Pseudomonas aeruginosa

TIhe flocculating activity ofa bioflocculant produced by Pseudomonas aeruginosa ATCC-10145 using kaolin clay was assayed. The influence of carbon, nitrogen sources, pH and culture temperature on bioflocculant production was investigated. The effects of cationic compounds, bioflocculant dosage, pH and temperature on flocculating activity were also determined. Of the cations tested, Ca2+, K+, Na+, Zn2+, Mg2+ and Cu2+ improved flocculating activity whereas Fe3+ and Al3+ caused its inhibition. The highest flocculating activity was observed at pH 7.0.The bioflocculant had a good flocculating activity of 80.50% for kaolin suspension with a dosage of only 1%. The bioflocculant was heat-stable and its activity was only decreased to 60.16% after heating at 100 degrees C for 60 min. Chemical analyses of the purified bioflocculant indicated that it was a sugar-protein derivative, composed of protein (27%, w/w) and carbohydrate (89%,w/w) including neutral sugar, uronic acid and amino sugar as the principal constituents in the relative weight proportions of 30.6%, 2.35% and 0.78%, respectively. The elemental analysis of the bioflocculant revealed the mass proportion of C, H and N was 19.06, 3.88 and 4.32 (%), correspondingly. Fourier transform infrared analysis showed that the exopolymers consisted of carboxyl, hydroxyl, amino and sugar derivative groups. The heavy metal adsorption by the bioflocculant of Pseudomonas aeruginosa was found to be influenced by the initial metal concentration, bioflocculant concentration and pH of the biosorption solution. This study demonstrates that microbial bioflocculant has potential to be used as an alternative bioremedial tool for industrial effluents and wastewater treatments which are co-contaminated with heavy metals.