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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Ligands synthesis and conformational studies for the investigation of opiate and protease receptor sites

Villeneuve, Gérald Blaise January 1994 (has links)
A topochemical model has been derived to account for the diverse selectivity of cyclic opioid peptides related to enkephalins and for narcotic alkaloids towards the $ mu$ and $ delta$ opiate subclasses. Efforts toward demonstrating its validity have later been accomplished. The model is based on a computer molecular modeling study using the opiate pharmacophore as a minimum prerequisite to align the molecules and benefit also of informations obtained from spectroscopic study in solution concerning the macrocycles conformation. The conformational properties of N$ sp alpha$Cbz-c((D)A$ sb2$Bu-Gly-Phe-Leu) were studied by nuclear Overhauser effect which provided semi-quantitative internuclear distances. One of the important elements that the model brings out is that the eventual presence of an aromatic ring on the beta carbon of Cys of the opioid peptide HTyr-(D)Pen-Gly-Phe-Cys-NH$ sb2$ should induce an increase in selectivity toward the 6 opiate subclass. Consequently, we engaged in preparing the special amino acid, P-phenylcysteine, using a method based on the addition of mercaptan to unsaturated azlactone. The diastereoisomers obtained were separated, and their relative configurations assigned by X-ray crystallography. The pure enantiomers were obtained by resolution with the enzyme carboxypeptidase A. Several difficulties were encountered during this preparation, the main concern being the S protecting group. This protecting group should be chosen with the property that it can be quantitatively removed when desired and compatible with the conditions of peptides synthesis. Moreover, the size of the protecting group should be minimized in order to be able to realize the resolution with the enzyme. We explored, by the same token, the size of the hydrophobic pocket of the exopeptidase. Using the structural information obtained from the X-Ray diffraction study of several of the $ beta$-phenycysteine, we have determined with the help of computer molecular modeling, the
2

Preparation of iodine SWNTs and iodine US-tubes: Synthesis and spectroscopic characterization of iodine-loaded SWNTs for computed-tomography molecular imaging

Kissell, Kyle Ryan January 2006 (has links)
This research presents the synthesis and spectroscopic characterization of I2-filled single-walled carbon nanotubes (I2 SWNTs) and I2-filled ultra-short carbon nanotubes (I2 US-tubes). These I2-internally-loaded SWNTs and US-tubes have applications both as a model system for the filling of SWNTs with other medically-interesting materials, such as alpha-radiotherapeutic radionuclides like At-211, and as synthons for a new class of computed-tomography (CT) X-ray contrast agents (CAs). Existing CT technology lacks the ability to diagnose critical diseases such as coronary artery vulnerable plaque, recently discovered as the cause of 70% of heart attacks, because current CAs circulate in the bloodstream rather than being targeted to specific cell-types. SWNT-based CAs offer several advantages over commercially-available CT CAs, such as the ability to sequester toxic ion and molecule imaging agents within the SWNT, to be targeted to specific cell types, and to translocate into targeted cells for intracellular molecular imaging. The synthesis of I2-SWNTs and I2-US-tubes is achieved via sublimation of molecular iodine (I2), a method proven to produce high yields for other filling materials. X-ray photoelectron spectroscopy (XPS) along with inductively-coupled plasma analysis (ICP-AE) and Raman spectroscopy have been used to define the location and quantify the amount of I2 in I2-SWNT and I2-US-tube samples. The exterior-adsorbed I2 can be removed (as I-) from I2-SWNTs by reduction with Na0/THF or by heating the I2-SWNTs to 300°C (without reduction), leaving I2 contained only within the interior of the SWNTs (I2 SWNTs). These I2 SWNTs contain ∼25 weight % of I2 and are stable without the loss of I2 even after exposure to additional reduction with Na 0/THF or upon heating to ca. 500°C. Micro CT experiments confirm that I2 SWNTs, with a radiodensity of 28,400 HU, are functional CT contrast agents. In contrast to I2-SWNTs, the internal I 2 in I2-US-tubes is unstable and is removed by either Na 0/THF reduction or temperatures of 300°C. To date, this instability has resulted in the inability to synthesize PEG-I2 US-tubes, a biocompatible water-soluble derivative of I2-US-tubes. However, initial experiments toward the synthesis of serinol-aide-I2 US-tubes have shown promising results, indicating a water-soluble derivative of I 2 US-tubes will be synthesized in the very near future. The I2 SWNTs and I2 US-tubes prepared in this research represent the first medical applications of filled SWNTs for CT imaging. I 2 SWNTs can now be used as a model system for the filling of SWNTs with other materials such as 211AtX (x = any halogen) for targeted alpha-radioimmunotherapy. They also signify the first step toward revolutionary intracellular CT imaging for the diagnosis of many diseases including coronary artery vulnerable plaque and cancer.
3

INVESTIGATIONS OF THE BIOSYNTHESIS OF ANTIBIOTICS

BUU, HANHPHUOC V. January 1984 (has links)
The biosynthesis of three natural products, L-2-amino-4-pentynoic acid (propargylglycine) (1), 3-(3-isocyanocyclopent-2-enylidene) propionic acid (2), and (+)-(alpha)-(S)-amino-(2,5-dihydro-5(S)-methyl)-furan-2(R)-acetic acid (3) (furanomycin), produced by an unidentified Streptomyces, Trichoderma hamatum, and Streptomyces threomyceticus respectively, have been investigated. Although two prospective labeled precursors of the amino acid (1), {1-('14)C}-norvaline and {1-('14)C}-allylglycine were synthesized, and procedures for the isolation, detection and degradation of (1) devised, the elucidation of the biogenesis of (1) was hampered due to lack of production of (1) by the microorganism. The isonitrile acid (2) has been shown by using ('14)C- and ('3)H-labeled precursor incorporation experiments to be derived from the amino acid tyrosine which undergoes an oxidative cleavage of the aromatic ring followed by recyclization. In addition to specific incorporation studies with {('14)C}- and {('3)H}-labeled precursors, experiments using {('2)H}, {('18)O}, and {('13)C}-labeled precursors in conjunction with ('2)H-NMR and ('13)C-NMR have been undertaken to investigate the biosynthetic origin of the amino acid (3). The evidence indicates that (3) arises from one unit of propionic acid and two units of acetic acid.
4

Bioreactor design for scaleup of Catharanthus roseus hairy root cultures for production of indole alkaloids

Vani, Sundeep N. January 1996 (has links)
C. roseus is the source of the important anticancer indole alkaloids, vincristine and vinblastine. Hairy root cultures are an attractive alternative for the production of plant derived secondary metabolites. C. roseus hairy root cultures were established in our laboratory by A. rhizogenes mediated transformation of C. roseus seedlings prior to the beginning of this project. The objectives of this project were twofold: (i) Alkaloid analysis of C. roseus hairy root cultures, (ii) Scaleup of hairy root cultures from shake flasks to bioreactors. An extraction method was adapted for the rapid quantification of C. roseus hairy root extracts, and was used for quantifying alkaloid yields from five different root clones. Optimum analytical wavelengths were chosen for quantification after analyzing chromatograms at five different wavelengths using PDA detection. Extracts were analyzed using different analytical techniques--GC/MS, MS, HPLC-PDA and TLC--and several alkaloids were identified. The presence of ajmalicine, akuammine, apparicine, catharanthine, hoerhammericine, lochnericine, serpentine and tabersonine was confirmed. The presence of vindoline--an important precursor of vinblastine and vincristine--could not be confirmed although GC/MS indicated the presence of vindoline fragment ions. A novel method based on non-linear regression analysis was developed for online measurement of oxygen uptake rates. Thus, mass transfer rates could be adjusted in bioreactor cultures to provide sufficient oxygen. Three different bioreactor configurations--two recirculation reactors (60 mL, 1L) and a 500 mL spinner flask--were designed for scaleup studies. Growth, nutrient utilization and alkaloid productivities were measured. This is the first study where several biochemical parameters have been measured in multiple bioreactor configurations and found to be comparable--without exception--to shake flask cultures. Cultures were cultivated in different gas phase environments--'air' and '2.5% CO$\sb2$'--in each bioreactor configuration. This is the first study of the effect of CO$\sb2$ on hairy roots cultivated in liquid culture. A beneficial effect ($>$98% confidence) of CO$\sb2$ was observed on biomass accumulation. Possible metabolic importance of CO$\sb2$ on heterotrophic plant cultures is discussed.
5

Immunoconjugates of carbon nanostructures

Ashcroft, Jared Mark January 2006 (has links)
For the first time, carbon nanostructures have been designed and synthesized to form immunoconjugates with monoclonal antibodies (mAb) for use in cell-targeted cancer diagnosis and therapy. The immunoconjugates are derived from various nanoscale carbon-based building blocks, specifically fullerenes (C60 ), gadofullerenes (M C60) and ultra-short carbon nanotubes (US-tubes). The exterior of each nanostructure has been derivatized with water-solubilizing addends using Bingel-type (nucleophilic cyclopropanation) addition chemistry to facilitate biocompatibility. Initially, conjugation to the murine anti-gp240 melanoma antibody (ZME-018 mAb) was completed with two different water-soluble C60 derivatives, only one of which had the potential to covalently attach to the ZME-018 mAb. After conjugation, this covalently linked C 60-SPDP conjugate incorporated 15 C60 moieties per antibody, while retaining 80% of the antibody's target specificity. In a second experiment a non-covalently linked C60-Ser conjugate incorporated 38 fullerenes per antibody but retained only 4% of the antibody's target specificity. These findings suggest that covalent attachment of C60 derivatives to antibodies may not be essential for the development of fullerene immunotherapy (FIT), although the ratio of C60: antibody may need to be minimized so as not to inhibit antibody targeting. To study the cell internalization characteristics of the fullerene immunoconjugates, two water-soluble Gd C60 derivatives, which allowed for Gd 3+ monitoring by inductively-coupled plasma mass spectrometry (ICP-MS) at concentrations <10 ppb, have been utilized. These studies have provided evidence that the fullerene-based immunoconjugates retain the ability to effectively internalize into target cells, with approximately 20% of the available Gd 3+ internalizing into the A375m melanoma cells. These results suggest that immunoconjugates derived from C60-based chemotherapeutics may become new-targeted therapies against cancer. Of the carbon-based nanomaterials studied in this work, US-tubes are perhaps the most attractive candidates for nanomedicine platforms, due to the possibility of internally loading medically interesting materials, such as Gd3+ ions for magnetic imaging resonance (MRI) or iodine (I2) for computed tomography (CT). Toward this end, single-molecule US-tubes have been isolated by chemical reduction of the US-tubes, followed by immediate functionalization using Bingel chemistry to produce debundled and derivatized US-tube materials. Three different malonate addends have been attached to the US-tubes, including serinol, polyethylene glycol (PEG) and amide malonates. Each of the US-tube derivatives exhibited varying degrees of solubilities in water ranging from 0.25 mg/mL to 1.00 mg/mL. An n-octanol/water partition coefficient has also been determined for each derivative, with values ranging from 0.25 to 1.20, which suggest that these derivatized nanocapsules might readily internalize into cells. Loaded internally with medically-useful materials such as Gd3+ ions, I2 or radionuclides for imaging and therapeutic applications, these biocompatible carbon nanocapsules may be engineered into a universal platform for the containment and delivery of an array of medical agents in vivo.
6

Design, synthesis and evaluation of selective estrogen receptor modulator/histone deacetylase inhibitor merged bifunctional ligands

Williams, Benjamin January 2014 (has links)
Breast cancer remains one of the most persistent threats to women's health in the Western world. The selective estrogen receptor modulator (SERM) tamoxifen is a front-line treatment for the disease, but suffers from a high rate of acquired resistance and an increased risk of endometrial cancer. As such, improved small molecule inhibitors with the ability to overcome antiestrogen resistance while limiting adverse side effects are valuable pharmaceutical targets. Histone deacetylase inhibitors (HDACi) have recently emerged as versatile anticancer agents with antiproliferative activity in breast cancer cells. Combination therapy of SERMs and HDACi has demonstrated enhanced cytotoxicity and the ability to restore tamoxifen sensitivity to antiestrogen-resistant cancer cell lines. This research project describes a novel approach to overcoming antiestrogen resistance by combining the anticancer properties and cooperative activity of SERMs and HDACi into compact, merged bifunctional ligands. Previous research by the Gleason laboratory indicated that HDACi functionality, in the form of zinc-chelating hydroxamic acids, could be integrated into the polar side chain of SERMs while maintaining antiestrogenicity at micromolar concentrations. Building from these preliminary results, a series of novel hybrid molecules was designed with zinc-binding groups incorporated into the aliphatic side chain or the triphenylethylene core structure of the active tamoxifen metabolite 4-hydroxytamoxifen (4-OHT). The resulting structures were investigated in silico using the molecular docking program FITTED. Twelve hybrid compounds were then synthesized by geminal Suzuki coupling and McMurry coupling procedures. Despite the propensity of the compounds to isomerize around the central double bond, the majority of the syntheses proceeded diastereoselectively and HPLC purification furnished the final products as a single isomer or in good diastereomeric excess. The HDAC inhibition and ER antagonism of the bifunctional molecules were evaluated in collaboration with the Mader laboratory of the Université de Montréal. Side chain-substituted hybrid compounds demonstrated good affinity for the ER binding pocket and nanomolar ER inhibitory activity. In addition, long-chain chimeric ligands possessing amide linkers exhibited significant HDAC 6 inhibition, with one compound displaying inhibitory activity at sub-micromolar concentrations. However, these side-chain substituted hybrids also exhibited substantial ER agonism in the absence of estradiol, which limited their effectiveness as antiestrogens. Conversely, a compound containing a phenyl hydroxamic acid in the aromatic core of 4-OHT acted as a full antagonist at micromolar concentrations and displayed no estrogenic behaviour. The core-substituted hybrid also exhibited modest HDAC inhibition, though it lacked the strong activity of its side chain counterparts. The synthesized SERM/HDACi molecules therefore displayed encouraging results and provided important structural insight into the future creation of bifunctional ligands.A brief side project is also described as a contribution towards the total synthesis of (R)-puraquinonic acid. The enantioselective synthesis of this natural product was previously accomplished by the Gleason group using a novel lactam auxiliary alkylation sequence to set the molecule's sole stereocenter. However, the specific rotation of the final product was opposite that expected and contradicted previous stereochemical assignments of the alkylation sequence. To address this inconsistency, a convergent stereochemical proof was completed which allowed direct comparison of alkylation products to auxiliary-based Mannich addition products that could be characterized by X-ray diffraction. The absolute stereochemistry of the sequence was thereby unambiguously assigned and strongly supported the conclusion that our group had successfully synthesized (R)-puraquinonic acid. / Le modulateur sélectif des récepteurs des œstrogènes (SERM) tamoxifène est le traitement principal pour le cancer du sein, mais souffre d'un taux élevé de résistance acquise et augmente le risque de developer un cancer de l'endomètre. Par conséquence, de nouvelles molécules antiestrogénique avec la capacité de surmonter la résistance aux antioestrogènes et de limiter les effets secondaires indésirables sont nécessaires. Les inhibiteurs d'histones déacétylase (HDACi) ont récemment emergés comme des agents possédant une activité antiproliférative contre les cellules du sein cancéreuse. La thérapie combinatoire des SERMs et HDACi démontre non seulement une cytotoxicité améliorée, mais aussi la capacité de restaurer la sensibilité envers tamoxifène dans les lignées cellulaires de cancer résistantes aux antioestrogènes. Ce projet décrit une nouvelle stratégie pour combattre la résistance antioestrogène en combinant l'activité des SERMs et des HDACi par la fusion des pharmacophores pour produire des ligands bifonctionnels.Les recherches précédentes par le laboratoire du Dr. Gleason ont indiqué que la fonctionnalité HDACi - sous la forme d'acides hydroxamiques - peut être intégrée dans la chaîne polaire des SERMs tout en conservant une antiestrogenicité modérée. Basé sur ces résultats préliminaires, une série de nouvelles molécules hybrides a été conçue avec des groupes se liant au zinc incorporés soit dans la chaîne latérale ou dans la structure centrale triphényléthylène du métabolite actif de tamoxifène, 4-hydroxytamoxifène (4 -OHT). Ces molécules ont été étudiés in silico à l'aide de FITTED, un programme de modélisation moléculaire. Douze molécules hybrides ont été synthétisées par des reactions de Suzuki et des réactions de McMurry. La majorité des synthèses ont pu être accomplies d'une manière diastéréosélective et la purification par CLHP a fourni les produits finaux sous forme d'isomère pure ou dans de bons excès diastéréoisomèriques.Les molecules bifonctionnelles ont été évaluées pour l'inhibition des HDACs et l'antagonisme envers le recepteur d'oestrogens (ER) en collaboration avec le laboratoire du Dr. Mader à l'Université de Montréal. Les hybrides possédant une acide hydroxamique sur la chaîne laterale ont démontré une bonne affinité pour ER de l'ordre nanomolaire. De plus, les ligands chimériques à longue chaîne possédant un amide ont démontré une inhibition importante envers HDAC 6 à une concentration micromolaire. Cependant, ces hybrides ont également démontré une activité agoniste substantielle de ER, qui limité leur efficacité comme antioestrogènes. Par contre, un hybride contenant un acide hydroxamique dans la structure centrale aromatique de 4-OHT a agi comme une antagoniste à des concentrations micromolaires, sans comportement oestrogénique. Les molécules ciblant SERM/HDACi offrent donc des résultats initiaux encourageants et des leçons importantes pour la création de nouveaux ligands bifonctionnels.Un bref projet contribuant à la synthèse totale de l'acide (R)-puraquinonique est aussi décrit. La synthèse énantiosélective de ce produit naturel a été accompli par le groupe Gleason avec l'aide d'une séquence d'alkylation utilisant un auxiliaire chirale bicyclique pour établir l'unique stéréocentre de la molécule. Toutefois, le pouvoir rotatoire spécifique du produit final était l'inverse de ce qui était attendu, et en contradiction avec la stéréochimie précédente de la séquence d'alkylation. Pour prouver la stéréochimie de notre processus d'alkylation, une voie de synthèse convergente a été accomplie qui a permis une comparaison directe des produits d'alkylation avec des produits d'addition de Mannich dont on était capable de caractériser par diffraction aux rayons X. La stéréochimie absolue de la séquence a été ainsi assignée sans ambiguïté et procure une confirmation que notre groupe avait réussi à synthétiser l'acide (R)-puraquinonique.
7

Conformationally rigidified inhibitors of human farnesyl pyrophosphate synthase

Gritzalis, Demetrios January 2014 (has links)
The mevalonate pathway is important in all eukaryotic cells. One of the key enzymes in this pathway is the human farnesyl pyrophosphate synthase (hFPPS), which has a pivotal role in cell prenylation. Nitrogen containing bisphosphonates (N-BPs) are a class of drugs that have been shown to effectively inhibit hFPPS and improve the survival of patients with various cancers, including multiple myeloma. However, the current drugs on the market (Risedronate and Zoledronate) interact with the active site of hFPPS sub-optimally and suffer from poor oral bioavailability and soft tissue exposure. A new series of inhibitors have been designed that can potentially interact with both the GPP and IPP sub-pockets of hFPPS. Based on a computational model, substituted benzimidazole- and indole-based inhibitors were designed to bind in both sub-pockets of the active site cavity of hFPPS. The benzimidazole-based inhibitors were found to be chemically unstable due to a reversible Michael reaction. Thus all efforts were subsequently turned towards the synthesis of indole-based inhibitors. These compounds were chemically stable when the bisphosphonate moiety was placed at C-3. The compounds were tested by DSF and in an inhibition enzymatic assay. The 2-substituted indoles were found to be active and provide a new structural class of hFPPS inhibitors. / La voie du mévalonate est importante pour toutes les cellules de type eucaryote. La farnésyle pyrophosphate synthase humaine (FPPSh) est une des enzymes clés pour cette voie qui possède un rôle pivot dans la prénylation cellulaire. Les molécules azotées contenant des biphosphonates (N- BPS) appartiennent à une classe de médicaments pouvant inhiber efficacement FPPSh et améliorer le taux de survie de patients atteints de plusieurs types de cancers, incluant notamment le myélome. Cependant, les médicaments en circulation sur le marché pharmaceutique (Risedronate et Zoledronate) interagissent inefficacement avec le site actif de FPPSh et offrent à la fois une mauvaise biodisponibilité orale et une exposition des tissus mous. Une nouvelle série d'inhibiteurs a donc été proposée pouvant potentiellement interagir avec les sous cavités GPP et IPP de FPPSh. Les inhibiteurs dont la structure est basée sur le motif benzimidazole substituée en position 2 et indole présentent ce critère et ont donc été désignés pour ce projet. Bien que les inhibiteurs possédant le motif benzimidazole aient été synthétisés, il a malheureusement été impossible d'isoler les produits de réactions du fait de la réversibilité de la réaction de Michael. Nos efforts se sont alors tournés vers la synthèse d'inhibiteurs possédant le motif indole. Ces composés sont bien plus stables lorsque le groupement biphosphonate est placé au C-3. Ces molécules ont été évaluées par DSF et des essais enzymatiques. A notre plus grand plaisir, les indoles substituées en positions 2 se sont révélées être des molécules meneuses pour une nouvelle classe d'inhibiteurs de FPPSh.
8

New virtual screening tools for molecular discovery

Corbeil, Christopher January 2009 (has links)
In the field of molecular discovery, virtually screening large libraries of compounds proved to be often more cost-efficient than the traditional experimental approaches. In fact, it has now become common practice thanks to the virtual screening tools available to chemists in the pharmaceutical industry, specifically docking. Most docking programs do not account for the dynamics associated with protein-ligand binding whether it is protein flexibility or the inclusion of displaceable water molecules. FITTED1.0 was developed to include these specific two features and has been validated on a testing set of 33 protein-ligand complexes. Further developments were needed to increase the speed of FITTED to enable its application as virtual screening tool. This enhanced version, FITTED1.5, has been applied to the screening of the Maybridge library onto the HCV polymerase and revealed FITTED’S ability to identify active substances. With this and other successful applications of FITTED, a comparative study was performed against other docking programs, with a specific interest in the effect of the ligand and protein input conformation and the inclusion of bridging water molecules on the accuracy of docking programs. All three had major effects on accuracy and led to suggestions on how to better conduct comparative studies. In parallel, we applied our expertise in the virtual screening area to the field of asymmetric catalyst development and led to the creation of ACE1.0. When creating a tool for predicting steroselectivities, one has to describe the transition state with great accuracy although within a reasonable amount of time. To tackle this problem, ACE creates the transition states from linear combinations of reactant and product interactions. A genetic algorithm is then exploited as a conformational search engine to optimize the TS structure. ACE has been applied to the Diels-Alder cycloaddition and the proline-catalysed aldol reactions and has showed good correlatio / Dans le domaine pharmaceutique, le criblage virtuel de large bibliothèques de molécules est une alternative moins couteuse et souvent au moins aussi efficace que le criblage à haut débit. D’ailleurs, le développement de tels outils –et plus particulierement de méthodes de "docking"– a permis au criblage virtuelle de devenir pratique courante dans l’industrie pharmaceutique. Cependant, la plupart des méthodes de docking ne prennent pas en compte la dynamique des complexes protéine/ligand et plus spécifiquement la flexibilité des protéines et la présence de molécules d’eau nécessaires à une liaison optimale. Dans cette optique, FITTED1.0 a été développé et validé sur un jeu de 33 complexes protéine/ligand. Ainsi, FITTED1.0 permet de modéliser des complexes ternaires protéine/ligand/eau entièrement flexibles. D’autres développements ont ensuite été nécessaires pour en accroître la rapidité et permettre son utilisation pour le criblage de larges bibliothèques. Cette version améliorée, FITTED1.5, a été appliquée au criblage de la bibliothèque Maybridge sur la polymérase du virus de l’hépatite C et a permis la découverte de deux nouveaux inhibiteurs. Après ces résultats très encourageants, une étude comparative a été entreprise visant spécifiquement à évaluer l’impact des données d’entrées sur le pouvoir prédictif des programmes de docking les plus couramment utilisés incluant FITTED2.6. Nous avons alors démontré que la présence d’eau, la conformation du ligand et de la protéine au départ du calcul ont un impact majeur. En parallèle, nous avons bénéficié de notre expertise pour développer un second outil de criblage virtuel ACE1.0 mais cette fois appliqué au criblage de catalyseurs asymétriques. Dans le domaine de la catalyse asymétrique, il nous fallait prédire la structure et l’énergie potentielle des états de transition et ce, dans un temps raisonnable. Pour ce faire, ACE cr
9

Hydrolase catalyzed resolutions of enantiomers : a structural basis for the chiral preference of lipases : preparation of enantiomerically-pure phosphines, phospine oxides, sulfoxides and pipecolic acid

Serreqi, Alessio N. January 1994 (has links)
Enantiomerically-pure compounds are becoming increasingly important particularly to the pharmaceutical industry. Enzymes are useful tools in the synthesis of such compounds. To better understand how lipases discriminate between enantiomers of chiral secondary alcohols we obtained x-ray crystal structures of covalent complexes of Candida rugosa lipase with the transition-state analogs (1R)-menthyl hexylphosphonate and (1S)-menthyl hexylphosphonate. These compounds are transition-state analogs for the hydrolysis of menthyl esters. We observed that the transition-state analog of the unfavored (1S)-enantiomer of menthol disrupted the hydrogen bond between N$ varepsilon$2 of histidine 449 and the menthol oxygen. His 449 is part of the catalytic triad in CRL. This may account for the slower reaction of the (1S)-enantiomer of menthol. The crystal structures also identified binding site regions for secondary alcohols in CRL. These regions are common among many lipases and esterases and account for their common enantiopreference toward secondary alcohols. / Lipases and esterases can resolve compounds with phosphorus and sulfur stereocenters by hydrolysis of a pendant acetoxy group. Both CRL and cholesterol esterase have high selectivity for (2-acetoxy-1-naphthyl)methylphenylphosphine oxide. They resolved this substrate with and E of 81 and 32 respectively. A synthetic scale resolution of this substrate with subsequent recrystallization and chemical transformation followed by stereospecific reduction gave both enantiomers of (2-methoxy-1-naphthyl)methylphenyl-phosphine with 96-97% ee. This chiral phosphine is potentially useful in asymmetric syntheses. / CE is the most selective enzyme for the sulfur substrates tested but these enantioselectivities were moderate, E's ranged from 5 to 25. From the CE resolution of the phosphorus and sulfur compounds and others we propose an empirical model that predicts which enatiomer reacts faster. The model is based on the size of the substituents and their conformational preferences. / Crude Aspergillus niger resolves esters of pipecolic acid with an E of 20 $ pm$ 4. A simple partial purification of ANL by fractional precipitation with ammonium sulfate increased the enantioselectivity to $>$100. The partially purified ANL can be used in a synthetic scale resolution of ($ pm$)-n-octyl pipecolate to give (S)-($-$)-pipecolic acid (93% ee) and (R)-(+)-pipecolic acid (97% ee).
10

Liquid chromatographic separation of enantiomers and structurally-related compounds on b-cyclodextrin stationary phases

Li, Song, 1957- January 1992 (has links)
The retention behaviour of 16 phenothiazines and structurally-related drugs on a $ beta$-cyclodextrin-bonded phase column was studied with respect to pH, mobile phase composition and column temperature. Both isocratic and gradient-elution separations of these compounds were investigated. / The enantiomers of twelve racemic dinitrophenyl amino acid derivatives were separated on a $ beta$-cyclodextrin-bonded phase column. The effects of pH, methanol and triethylammonium acetate (TEAA) buffer concentrations on the retention and resolution were investigated. The chiral recognition mechanism was studied by means of UV-visible, circular dichroism and proton nuclear magnetic resonance spectroscopic methods. / A multiple-interaction type of chiral stationary phase was developed by bonding $ beta$-cyclodextrin to silica gel and modifying the cyclodextrin cavity by flexibly capping its primary hydroxyl or small side. These modified $ beta$ cyclodextrin stationary phases contain a hydrophobic cavity, capable of inclusion complexation; aromatic groups, capable of $ pi$-$ pi$ interaction; and polar hydrogen-bonding sites, capable of forming hydrogen-bonding with the polar functional groups of the solutes. These stationary phases exhibit a high stereoselectivity toward a wide variety of chiral compounds. The preparation and properties of these modified $ beta$-cyclodextrin stationary phases are described. The enantiomeric separation of amino acids and their derivatives, of carboxylic acids, of phenothiazine drugs, and of other chiral compounds are reported. The effects of mobile phase composition on the retention and resolution are discussed.

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