Synthesis of Phosphonate Analogues of the Antibiotic Moenomycin A12

SUMMARY The moenomycin-type compounds are known to inhibit selectively the enzyme penicillin binding protein 1b (PBP 1b) that catalyses the transglycosylation reaction in the biosynthesis of bacterial cell wall peptidoglycan. The moenomycins (see moenomycin A12) have been shown to interfere with this biosynthetic step interacting with the enzyme(s). The moenomycins do not induce resistance readily. A weak point in this respect may, however, be the phosphate bond to unit F. Its cleavage by a yet poorly characterized enzyme is the only enzymatic degradation reaction of the moenomycins that is known to-date. With this in mind we started a programme aimed at synthesizing trisaccharide analogues of moenomycin A12 in which the phosphate oxygen at C-1 of unit F is replaced by a CH2 group. It seemed important to retain all other functional groups in ring F as present in moenomycin since they are known to be of major importance as far as antibiotic activity is concerned. It appeared that the commercially available and cheap b-D-galactose-pentaacetate 30 would be an interesting starting material for this synthesis. In this work, the synthesis began with the introduction of the C-glycoside appendage at position 1 according to Giannis et al., thus forming the allyl C-galactopyranoside 34, a substance that represents the first C-glycosyl backbone for the synthesis of the glycosyl acceptors. The total synthesis of the glycosyl acceptors is shown in Scheme 6.1. We wanted to convert the C-allyl glycoside 34 into its propenyl analogue. Attempts to achieve this with singlet oxygen and palladium-mediated reaction proved fruitless. On the other hand, ene reaction of 34 with 4-phenyltriazolin-3,5-dione in CH2Cl2 provided 56 in 83 % yield. Ozonolysis of this alkene (-70 °C, MeOH-CH2Cl2) and subsequent quenching with dimethyl sulfide, followed by reduction of the crude aldehyde with sodium acetoxyborohydride (prepared from NaBH4 and AcOH in THF) furnished the primary alcohol 35 (85 %). This alcohol was converted into the mesylate 60 (60 %), and this in turn into the bromide 61 (80 %) by heating it at 80 °C with tetrabutylammonium bromide in toluene. The acetate groups were hydrolysed using Zemplén conditions to furnish 62 quantitatively. The primary hydroxyl group in 62 was protected as a tBuPh2Si ether 63 (85 %) on reaction with TBDPSCl in DMF at 0 °C, and as a tBuMe2Si ether 94 (87 %) on reaction with TBDMSCl in DMF at 0 °C in the presence of imidazole. PTScatalysed isopropylidenation of the 3,4-diols 63 and 94 with 2,2-dimethoxypropane in dry acetone gave the 3,4-O-acetonide derivatives 53 (88 %) and 95 (90 %), respectively. On the other hand, the glycosyl acceptor 53 was converted into the glycosyl acceptor 92. The free hydroxyl group in compound 53 was protected as an acetate group on reaction with acetic anhydride in pyridine in the presence of DMAP giving 89 (88 %). The silyl ether in 89 was cleaved with a molar solution of TBAF in THF affording compound 90 in 87 % yield. The free hydroxyl group in 90 was then subjected to an oxidation using the TEMPO method affording the aldehyde which was in turn oxidised with sodium chlorite to the corresponding acid. The acid was converted to the amide 91, making use of Staab''s method, in which the acid was activated with CDI in dichloromethane to give the imidazolide, which upon reaction with ammonia furnished the amide 91 in an overall yield of 95 %. The required glycosyl acceptor 92 was obtained in quantitative yield by cleavage of the ester bond at position 5 under Zemplén conditions. Disaccharide formation was achieved employing the Jacquinet and Blatter method, which involves the use of glycosyl donor 67 and TMSOTf. No reaction was observed between this donor and acceptor 92, which may reflect the low nucleophilicity of the acceptor. On the contrary, glycosylation with acceptor 53 gave 68 (79 %). Deprotection of the silyl group in the disaccharide 68 was easily accomplished on treatment with a molar solution of TBAF in THF at RT affording 71 (89 %). Synthesis of the uronamide 72 was achieved after three major steps, in an overall yield of 98 %. Oxidation of the primary hydroxyl group in unit F to the corresponding aldehyde was accomplished with sodium hypochlorite and TEMPO. Oxidation of the crude aldehyde to the carboxylic acid with sodium chlorite followed by amide formation according to Staab gave 72. Removal of the isopropylidene group from 72 with trifluoroacetic acid (TFA) at RT furnished the diol 73 (89 %). Introduction of the carbamoyl group at C-4F position was achieved in two steps. Conversion of the diol 73 into the cyclic carbonate 76 with CDI in CH2Cl2 (84 %) and subsequent ring opening of this carbonate by bubbling a stream of gaseous ammonia into the CH2Cl2 solution at 0 °C gave 74 (62 %) as well as its isomer 77 (21 %). Dehalogenation of the N-trichloroacetyl group was intensively studied, but interactions of other functional groups in the studied substances could not be avoided. The base-labile carbonate in 76 and the carbamoyl group in urethane 74 were cleaved under the reaction conditions. Hydrolysis of 76 with 0.5 M LiOH in MeOH-THF (1:1) followed by acetylation gave 80 (73 %), while its reduction with NaBH4 in ethanol followed by acetylation gave 82 (60 °C, 85 %; RT, 83 %). On the other hand, reduction of 74 with NaBH4 in ethanol at 60 °C followed by acetylation gave 82 (78 %), while performing the reduction step at 5 °C (THF-MeOH 4:1) or at RT (ethanol or isopropanol) gave 80 in an average yield of 65 %. In a non reproducible reaction (NaBH4, EtOH, RT, then Ac2O, pyridine, RT), the desired compound 83 (42 %) was obtained accompanied by 82 (46 %) The reaction between the N-trichloroacetyl group and NaBH3CN was also fruitless. The phosphonate grouping was installed making use of Arbuzov reaction furnishing 85 (70 %). Trisaccharides could not be obtained from the oxazoline donor 42 (prepared from chitobiose octaacetate 86) through its reaction with acceptor 53. There was also no coupling product between the recently synthesized donor 88 and the acceptor 92. However, in this work, trisaccharide formation was achieved through the glycosylation reaction of donor 88 and acceptor 95 in 50 % yield (-30 °C, 1,2-dichloroethane, 3 Å, TMSOTf-TEA). Selective deprotection of the TBDMS group in compound 96 was accomplished at -10 °C with 1 eq of a molar solution of TBAF in THF. The free hydroxyl group of 97 was subjected to an oxidation using the TEMPO method affording the aldehyde. After oxidation of the aldehyde with sodium chlorite, the resulting carboxylic acid was converted according to Staab''s method into the amide 93 in an overall yield of 95 % (based on 96). There were difficulties in converting the N-phthalimido group in 93 to the N-acetyl group which is necessary for biological activity of moenomycin-type compounds, since the reactions were accompanied by elimination of HBr. In conclusion, the synthetic methods employed in this work allow to prepare the di- and trisaccharides C-phosphonate analogues of moenomycin A12.Synthese von Phosphonat-Analoga des Antibiotikums Moenomycin A12 Universität Leipzig, Dissertation Diese Arbeit enthält 130 Seiten, 73 Abbildungen, 1 Tabelle, 156 Literaturangaben Referat: Im Rahmen der vorliegenden Arbeit wurden C-Glycosid-Di- und Trisaccharid-Bausteine des Antibiotikums Moenomycin A12 ausgehend von b-D-Galactose-pentaacetat hergestellt. Das Ausgangmaterial wurde in D-Galactoheptonamid übergeführt. Die Einheit F des Disaccharidbausteins hat alle Substituenten, die die Einheit F des Moenomycins A12 hat. Der ausgearbeitete Syntheseweg sollte zur Synthese anderer Analoga geeignet sein

Psychometric Characteristics of the Mathematical Fluency and Calculation Tests "MFaCTs" for Primary Stage Students in Jordan

The aim of this study was to extract psychometric properties of the mathematical fluency and calculation tests for students of the primary stage (level) in the Jordanian environment. To achieve this goal, the test instructions were translated, and the mathematical writing was modified to suit the target sample. The test consists of two basic tests, including the calculation of the calculation (50) item, and the test of mathematical fluency (100) items. The study sample consisted of 3160 students - ordinary students - from grades 2 to 5, who were selected according to the random sampling method of Jordanian schools. The results of the study showed that all the values of the consistency coefficients / item statistics for the MFACTs for all grades in the standardization sample, and for the overall test score were greater than or equal to 0.699. On the other hand, mathematical fluency test was greater than or equal to 0.890. The values of the reliability coefficients ranged within the internal consistency / item statistics using the Cronbach Alpha formula to test the calculation between 0.699 for the second grade, and 0.876 for the fifth grade. Similarly, the reliability coefficients ranged from 0.890 for the second grade and 0.901 for the fifth grade. The coefficient of repeatability (Test- Retest) of the test for the total sample was 0.87 in the calculation test and 0.90 in the mathematical fluency test. The results further implied that there were no statistically significant differences between the two groups in the performance of the test according to the gender. As for the performance of the test, the average performance of the study sample steadily increased in the different grades. The correlation between the MFACTs and the mathematics student average in the previous year was

Poverty, Growth and Income Distribution in Lebanon

This Country Study is based on a full national report that is the first to draw a profile of poverty in Lebanon based on money-metric poverty measurements of household expenditures. The report provides a comprehensive overview of the characteristics of the poor and estimates the extent of poverty and the degree of inequality in the country. It finds that nearly 28 per cent of the Lebanese population can be considered poor and eight per cent can be considered extremely poor. However, the most important finding of the report is that regional disparities are striking. For example, whereas poverty rates are insignificant in the capitol, Beirut, they are very high in the Northern city of Akkar. In general, the North governorate has been lagging behind the rest of the country and thus its poverty rate has become high. Levels of poverty are above-average in the South but are not as severe as expected. There are three other major results that have notable implications for a poverty-reduction programme in Lebanon. First, with few exceptions, measures of human deprivation, such as that provided by an Unsatisfied Basic Needs methodology, are generally commensurate with those for money-metric measures based on household expenditures. Second, the projected cost of halving extreme poverty is very modest, namely, a mere fraction of the cost of the country?s large external debt obligations. However, such a cost would rise dramatically if inequality were to worsen (i.e., if future growth were anti-poor). Also, the cost of reducing overall poverty would be substantially higher. Third, the poor are heavily concentrated among the unemployed and among unskilled workers, with the latter concentrated in sectors such as agriculture and construction. This places a priority on a broad-based, inclusive pattern of economic growth that could stimulate employment in such sectors. Based on such findings, the report concentrates on providing general policy recommendations on issues of directing public expenditures to poor households. One of its major recommendations is to concentrate on channelling resources to poor regions below the governorate level, such as to four ?strata? where two-thirds of the poor in Lebanon are concentrated. However, the report notes that macroeconomic policies, particularly fiscal policies, will have to be redesigned to mobilize the reources necessary to finance the increases in public expenditures on the social safety nets and public investment in social services that should be part of a major poverty-reduction programme.Poverty, Growth and Income Distribution in Lebanon

Metal Ion Effect on the Absorbance Response of Chlorpheniramine Maleate in Pharmaceutical Dosage Form: A Study on Correlation between Spectroscopic and Potentiometric Measurements

The interference between metal ions in human body and drug molecules is highly serious. A widely used drug by children and adults to treat throat pain and tonsillitis has been studied. The absorbance intensity of Chlorpheniramine Maleate drug in the presence of Fe3+, Co+2, Ca+2 and Mg+2 metal ions has been studied. The addition of Fe3+, Co+2, Ca+2 and Mg+2 metal ions to an aqueous solution of chlorpheniramine maleate increases the absorbance signal significantly and rapidly. These metals are chosen because they have high concentration in human body. Increasing the pH value of the aqueous solution of chlorpheniramine maleate has a contrary effect on the absorbance signal. Potentiometric measurements have been performed to correlate the spectrophotometric results and found to be consistent. Potentiometric and spectrophotometric measurements prove that there is a change in drug concentration at different pH value and to think carefully when using such drugs.   Keywords: Chlorpheniramine Maleate, spectrophotometric and Potentiometric measurements

Scientific issues in the Holy Qur'an : the meaning and translation of verses relating to the creation of the universe

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Impact of MD5 Authentication in Secured and Non-Secured Traffic Routing for the Case of EIGRP, RIPv2 and OSPF Routing Protocols

Routing is the process of forwarding data across an inter-network from a designated source to a final destination. Along the way from source to destination, at least one intermediate node is considered. Due to the major role that routing protocols play in computer network infrastructures, special cares have been given to routing protocols with built-in security constraints. In this thesis, we evaluate the impact of MD5 Authentication on routing traffic for the case of EIGRP, RIPv2 and OSPF routing protocols in case of secured and non-secured routing traffic. A network model of four Cisco routers has been employed and a traffic generation and analysis tools have been developed and used to generate traffic data and measure delay time, jitter and overhead. The results show that the average delay time and jitter in the secured MD5 case can become significantly larger when compared to the unsecured case even in steady state conditions. Also, the EIGRP protocol shows the minimum overhead even when the system is extremely overloaded

LYAPUNOV FUNCTION-BASED STABILIZING CONTROL SCHEME FOR WIRELESS POWER TRANSFER SYSTEMS WITH LCC COMPENSATION NETWORK

A stabilizing control scheme based on a Lyapunov function is proposed for wireless power transfer (or WPT) systems. A state-space model of the WPT system is developed and the Lyapunov function is formulated based on an energy equation of the system involving state variables. The internal resistance of a battery varies during charge and discharge. Therefore, if a WPT system is used to charge a battery, its output load will vary. Furthermore, the coupling coefficient between the transmitter (primary) and receiver (secondary) coils decreases when they are misaligned. Comparative case studies are conducted to verify the efficacy of the proposed controller in maintaining stability of the WPT system under load variation and acute misalignment of transmitter and receiver coils

DEPOSITION OF YTTRIA-STABILIZED ZIRCONIA CERAMIC ON SS316L BY PULSED SOLID-STATE ND:YAG LASER

Austenitic stainless steel in general has a limited service temperature up to 600°C. Nevertheless, service temperature more than that temperature are one of the key feature of advanced nuclear reactors to gain higher thermal efficiency which is related to economic beneficial, and also to withstand from abnormal condition. However, austenitic stainless steel such as SS316 class is well-known structure material for nuclear power reactors and other power plants. Therefore, one of the key issue is to modify SS316 so that has capability to service higher temperature. One of the technique for that purpose is ceramic-coated SS316L. In this preliminary study, thin films of zirconia-based ceramic i.e. YSZ (Yttria-Stabilized Zirconia) have been deposited on a SS316L using Plasma-Pulsed Laser Deposition (PLD) at Center For Science and Technology of Advanced Materials laboratory – National Nuclear Energy Agency of Indonesia (BATAN). Thin film was deposited with the constant oxygen flow injection of 20 and 40 sccm (Standard Cubic Centimeters per Minute) that produce a chamber pressure of 60 and 200 mTorr for the numbers of laser shots of 7.2×104 and 14.4×104, respectively. The substrate temperature during deposition was of 850oC. Afterward, the samples were analyzed using Optical Microscope, Scanning Electron Microscope – Energy Dispersive X-ray Spectroscope (SEM-EDS) and Atomic Force Microscope (AFM). The results showed that the YSZ could homogeneously and sticky deposited on the surface of the SS316L surface.  The surfaces were very smoothly formed with the surface roughness in the nano-meter scale range of 20-90 nm

An approximation of a multivariative stochastic model for the analysis of longitudinal data

We propose to approximate a model for multivariate repeated measures that incorporated random effects, correlated stochastic process and measurements error. The model is generalization for univariate longitudinal data given by Taylor et al. (1994). The stochastic process used in this paper is the multivariate Integrated Omstein-Uhlenbeck (IOU) process. We consider a Bayesian approach which is motivated by the complexity of the model, thus, we propose to approximate the IOU stochastic process in a simple way that will mitigate the necessity to invert the stochastic process covariance matrix separately for each group at each iteration of the Markov Chain Monte Carlo (MCMC) sampler. The proposed method is illustrated by application to the melanoma data set