Дисертації з теми "Benzylic derivatives"

This thesis describes stereospecific fluorination reactions, and addresses the synthesis of fluorosugars. In Chapter 1, the influence of fluorine on the physical properties of organic molecules, as well as its stereoelectronic effects, are introduced. Furthermore, an overview of nucleophilic and electrophilic fluorination reactions is given. Chapter 2 describes the dehydroxyfluorination of allylic alcohol diastereoisomers 155a and 155b, which can proceed either by direct or allylic fluorination. The regio- and stereo- selectivities were also assessed. Chapter 3 outlines the synthesis of the novel trifluoro D-glucose analogue 193 and trifluoro D-altrose analogue 216. The transport of these hexose analogues across the red blood cell membranes was then explored, to investigate the influence of polarity versus hydrogen bonding ability in carbohydrate-protein interactions. Chapter 4 describes the development and optimisation of Bio’s methodology, to promote stereospecific dehydroxyfluorination of benzylic alcohols (R)-213 and (R)-227 by addition of TMS-amine additives 226 and 229. And finally Chapter 5 reports the experimental procedures as well as the characterisation and the crystallographic data of the molecules prepared in this thesis.

Cette thèse présente un développement de la réaction de fonctionnalisation à distance par réarrangement métallotropique sur des dérivés benzyliques. Le travail repose sur l’utilisation d’un unique réactif métallique, un triorganozincate de lithium, lequel permet la formation de deux liaisons C(sp3)-C(sp2) et C(sp3)-C(sp3) sur des sites distants de 5 atomes en une seule opération. Le premier chapitre se focalise sur les dérivés benzyliques iodés en position 4 du cycle aromatique. Des conditions réactionnelles inédites basées sur l’utilisation d’un solvant biosourcé sont proposées. Elles permettent d’atteindre une portée synthétique sans précédent pour une telle réaction à partir de ces substrats. L’influence du solvant est discutée. Le deuxième chapitre est consacré à l’étude mécanistique par DFT de chacune des étapes composant la séquence réactionnelle étudiée précédemment. Ainsi, l’échange halogène/métal, la migration-1,2 de ligand ou encore le réarrangement métallotropique sont investigués avec prise en compte minutieuse du solvant de prédilection de la réaction. Un apport expérimental vient compléter cette étude. Enfin, l’extension de cette transformation aux dérivés hétéroaromatiques benzyliques, en particulier les thiophènes, est l’objet de l’ultime chapitre de cette thèse. Les travaux rapportés définissent une approche de fonctionnalisation à distance où une même boîte à outils, composée d’une plateforme unique (thiophène halogéné porteur d’un phosphate benzylique) et d’un réactif organométallique de même nature (organozincate de lithium), offre plusieurs opportunités synthétiques selon les désirs de l’expérimentateur
This thesis presents a development of the remote functionalization reaction by metallotropic rearrangement on benzyl derivatives. The work is based on the use of a single metal reagent, a lithium triorganozincate, which allows the formation of two bonds C(sp3)-C(sp2) and C(sp3)-C(sp3) on sites 5 atoms apart in a single operation. The first chapter focuses on benzyl derivatives with an iodine in position 4 of the aromatic ring. Novel reaction conditions based on the use of a bio-based solvent are proposed. They allow to reach an unprecedented synthetic scope for such a reaction from these substrates. The influence of the solvent is also discussed. The second chapter is devoted to the mechanistic study by DFT of each step composing the reaction sequence studied previously. Thus, the halogen/metal exchange, the 1,2-migration of ligand or the metallotropic rearrangement are investigated with careful consideration of the solvent of the reaction. An experimental contribution completes this study. Finally, the extension of this transformation to benzylic heteroaromatic derivatives, in particular thiophenes, is the subject of the last chapter of this thesis. The reported work defines an approach of remote functionalization where a same toolbox, composed of a unique platform (halogenated thiophene bearing a benzyl phosphate) and an organometallic reagent of the same nature (lithium organozincate), offers several synthetic opportunities according to the experimenter's desires

Le thiosemicarbazide et le 4-méthylthiosemicarbazide réagissent par condensation avec des dérivés benzaldéhyde pour donner des produits de type thiosemicarbazone pouvant jouer le rôle de ligands.Ces derniers peuvent conduire en milieu éthanolique à la formation de divers complexes en réagissant avec des sels métalliques comme les chlorures et/ou bromures de cuivre(II), de nickel(II), de zinc(II), de cobalt(II) et de cadmium(II). La structure de ces ligands et de leurs complexes a été déterminée par spectroscopie infrarouge, par des analyses élémentaires et par cristallographie. Les ligands se présentent tous sous forme thione à l’état solide tandis que les complexes obtenus peuvent revêtir différents états : soit monodentés, mononucléaire ou polynucléaire à deux atomes de soufre provenant du groupement thiosemicarbazone, comme l’étude cristallographique a pu le démontrer, soit bidentés avec des sites decoordination dont l’azote provenant du groupement imine et le soufre du groupement thiol. Les propriétés antifongiques de ces divers composés ont été testées vis-à-vis de champignons pathogènes de l’homme comme Aspergillus fumigatus, Candida albicans, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis et Exophiala dermatitidis. Seuls les complexes avec le cadmium ont montré des activités antifongiques significatives et le ligand de pdiméthylaminobenzaldéhyde thiosemicarbazone a inhibé presque totalement la croissance d’E. dermatitidis
Thiosemicarbazide and 4-methylthiosemicarbazide react with benzaldehyde derivatives by condensation to give different thiosemicarbazone ligands. The latter conduct in ethanolic medium to various complexes by reacting with chlorides and / or bromidesof copper (II), nickel (II), zinc (II), cobalt (II) and cadmium (II). The structures of the ligands and their complexes have been determined mainly by crystallography and by infrared spectroscopy, as well as by elementary analyzes. The ligands are in thion form in solid form.The complexes obtained are either monodentate, mononuclear or polynuclear complexes with two sulfur atoms of the thiosemicarbazone group, such as the determination of the crystal structure has shown either bidentate complexes with coordination sites, imine nitrogen and sulfur of the thio group. Their antifungal properties have been tested against human pathogenic strains: Aspergillus fumigatus, Candida albicans, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis and Exophiala dermatitidis. Only thecomplexes with cadmium exhibited significant activities against the fungal species studied and the thiosemicarbazone of p-dimethylaminobenzaldehyde ligand almost completely inhibited the growth of E. dermatitidis

Thesis (Ph. D.)--Georgia State University, 2008.
Title from file title page. Thomas L. Netzel, Dabney W. Dixon, committee co-chairs; David Boykin, Jerry Smith, committee members. Electronic text (250 p. : ill. (some col.)) : digital, PDF file. Description based on contents viewed Nov. 20, 2008. Includes bibliographical references.

碩士
國立陽明大學
生物藥學研究所
99
JAK (Janus kinase) is a cytokine-induced kinase that activates STAT (Signal Transducer and Activator of Transcription) on many kinds of physiological effect such as cell proliferation, differentiation, and angiogenesis. Literature has been shown that over-activated JAK2/STAT3 pathway leads to highly transcription of oncogenes in various cancers, including solid tumor (e.g., liver, breast) as well as hematological malignancies. A series of JAK2 inhibitors have been developed and some of the inhibitors have been tested in clinical trial. Therefore, development of small molecule inhibitors for JAK2 is a promising strategy in cancer therapy. In this thesis, we applied the caffeate scaffold and X-ray structure of JAK2 to design and synthesize caffeate analogues. The inhibitory effect IC50 of these compounds was examined in HCC cell line. The MTT result shows that 6-bromopyridine in R2 position and hydrophobic ring (e.g., naphthalene) in R1 position enhances potency in cell cyto-toxicity. The structure-activity relationship provides the hints to develop new potent inhibitors.

碩士
中國醫藥學院
藥物化學研究所
89
Abstract Synthesized 1-benzyl carbazole-4-carboxaldehyde derivatives ( LCY ) examined for their growth inhibition effects in human leukemia cell lines. HL60, U937, and K562 cells were treated with these compounds for 24 hours and their proliferation was determined by the propidium iodide DNA staining method. A dose-dependent decrease in the cell proliferation rate was observed for all compounds. LCY-12 had the highest growth inhibitory, and its IC50 were 2.58, 0.77, and 19.49 μM for HL60, U937, and K562 cells, respectively. DAPI-stained cells revealed evident characteristics of apoptosis, which include cell shrinking, chromatin condensation, fragmentation of nuclei, and formation of apoptotic bodies. DNA from treated HL60 and U937 cells displayed a characteristic inter-nucleosomal ladder of DNA fragments. Furthermore, down-regulation of Bcl-2, up-regulation of Bax, activation of caspase 3, 8, and 9, and cleavage of PARP were detected by Western blotting method in LCY-12-treated HL60 cells. Caspase inhibitors significantly reduced LCY-12-induced caspase activity and cell death. In addition, LCY-12 and LCY-16 induced G2/M arrest in HL60 cells, and S arrest in U937 cells. The induction of cell cycle arrest occurred before the onset of apoptosis. Western blotting analysis of cyclins and CKIs revealed that LCY-12 induced the expression of cyclin B, cdc25c and p21 proteins. These results indicated that the ability of LCY-12 to inhibit cell proliferation may be mediated by the induction of apoptosis and cell cycle arrest.

碩士
中國醫藥大學
藥物化學研究所碩士班
94
The dissertation is based on the structure of 4-hydroxy- quinolin-2-(1H)-ones. In order to synthesize a series of derivatives of 1-benzyl-4-hydroxy-3-phenylquinolin-2(1H)-one (26a-g, 27a-g, 28, 29), Using the Bheemashankar′s solution-phase combinatorial synthetic method. The starting material is methyl anthranilate (16) that is condensated with 4-substituted-benzaldehydes 17a-h to obtain the 19a-h. On the other hand, 4-cyanophenyl acetic acids 20a-d were acylated with thionyl chloride to afford acid chlorides 21a-d. Then, 21a-d and 19a-h are combined by Schotten-Baumann reaction to give 22a-h, 23a-h, 24 and 25, respectively. The last, intermediate 22a-h, 23a-h, 24, 25 are cyclizated by amberlyst A-26 resin (OH- form) and then acidified with trifluroacetic acid to obtain 26a-g, 27a-g, 28 and 29, respectively. Moreover, it is important to evaluate the biological activity from the derivatives, anticipating obtaining leading compounds to establish the structure-activity relationships.

碩士
淡江大學
化學學系碩士班
93
The naturally occurring five- and six-membered azasugars are considered as glycosidase inhibitors. Most recently, the seven-membered azasugars(poly-hydroxyazepanes) were reported to have potential in treatment of diabetes, cancers and AIDS. These heterocycles are more flexible in conformation than the corresponding six- and five-membered counterparts and may bind in the minor groove of DNA. Little attention has been given to trihydroxyazepanes. We wish to describe herein a new approach to the synthesis of diastereomeric azasugars (3,4,6-trihydroxyazepanes) in ten steps each from the commercially available D-(-)-quinic acid. The biological test of this series of 3,4,6-trihydroxyazepanes and their derivatives allows us to compare with their corresponding tetrahydroazepanes. Especially, we can further learn the structure relationship regarding to the stereochemistry of hydroxy groups.

碩士
國立暨南國際大學
應用化學系
107
I、Most of the natural amino acids are mainly L-amino acids, and the D-amino acids are the enantiomers of L-amino acids, which can be incorporated into the peptides to adjust their biological activities. In this laboratory, we used the camphor as the starting material for the Witting reaction, the oxidation reaction, the ring expansion reaction and the reduction reaction to obtain the organic catalyst based on camphor. On this basis, we used palladium metal as the catalyst after the hydrogenation expansion product. The hydrogenated product is obtained, and then pyridine is added as a solvent acetic anhydride, followed by reaction with Iodosobenzene diacetate and Potassium hydroxide to obtain a corresponding product, and then ring-opening reaction is carried out to successfuliy cyclopentanyl D-Amino Acid 57. II、Many structures in nature have a bicyclic structure. Due to the rare amount of such natural substances and antibacterial effects, such as: Pallidol, these two specific monomers have been found to have antibacterial functions, so we have used the laboratory to publish The basic basis for a series of compounds in one pot, it is desirable to shorten the steps and obtain novel phenylcarbonyl olefins without the use of a metal catalyst.

博士
中國醫藥大學
藥物化學研究所
96
In the previous study, ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) was identified as the first selective non-peptide protease-activated receptor 4 (PAR4) antagonist. In order to develop noel PAR4 antagonist, YD-3 was selected as lead compound. Two series of N1-substituted arylmethyl-3-(4-ethoxycarbonylphenyl)indazole derivatives (I) and N2-substituted arylmethyl-3-(4-ethoxycarbonylphenyl)indazole derivatives (II) were synthesized. The key intermediate, ethyl 4-(1H-indazol-3-yl)- benzoate (8) was prepared according to the know method. Then, compound 8 was subjected to alkylation with directly substitution or Mitsunobu reaction to yield corresponding N1-substituted arylmethyl derivatives (I) as major products. However, the microwave-assisted synthetic technique can be successfuly promote N2- substituted arylmethyl derivatives (II) as major products. The synthesized compounds were evaluated for their selective anti-protease- activated receptor 4 (anti-PAR4) activity. Through structure-activity relationships (SAR) study the functional groups contributing to anti-PAR4 activity was identified. Several new compounds with anti-PAR4 activity comparable to YD-3 were found. Among them, ethyl 4-[1-(3-chlorobenzyl)-1H-indazol-3-yl]benzoate (71) showed the most potent inhibitory effect on PAR4-mediated platelet aggregation. Compound 71 is worthy of further investigation. In addition, the synthesized compounds were examined for their anti- inflammatory, anti-allergic, cytotoxic, and anti-bacterial activity. Among these tested compounds, methyl 4-(1H-indazol-3-yl)benzoate (6) and 4-(1-benzyl-1H-indazol-3- yl)-N-hydroxybenzamide (23) showed the better inhibitory effect of LPS induced TNF-α formation than positive control SB-203580 (IC50≒4.8?b2.4 and 2.1?b0.2 μM, respectively). Compounds 8, 4-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-N-hydroxy benzamide (117), 4-[1-(3-fluorobenzyl)-1H-indazol-3-yl]-N-hydroxybenzamide (118), 4-[1-(2-methoxybenzyl)-1H-indazol-3-yl]-N-hydroxybenzamide (120), 4-[1-(3- methoxybenzyl)-1H-indazol-3-yl]-N-hydroxybenzamide (121), and 4-[1-(4-methoxy benzyl)-1H-indazol-3-yl]-N-hydroxybenzamide (122) showed the better inhibitory effect of LPS induced TNF-α formation than positive control genistein (IC50≒1.7?b0.8, 2.4?b0.7, 1.7?b0.2, 3.5?b0.5, 3.5?b0.4, and 2.9?b1.3 μM, respectively). 4-[1-(3-Chlorobenzyl)-1H-indazol-3-yl]-N-hydroxybenzamide (115) showed the better inhibitory effect of fMLP/cytochalasin B induced neutrophil superoxide formation than positive control DPI (IC50≒1.2?b1.1, 0.8±0.2, 1.3±0.6, and 2.0±0.6 μM, respectively). 4-(1-Benzyl-1H-indazol-3-yl)benzamide (17) and 4-(1-benzyl-1H- indazol-3-yl)-N-hydroxybenzamide (23) showed the better inhibitory effect for β-glucuronidase expression of fMLP/cytochalasin B induced neutrophil degranulation than positive control genistein (IC50≒6.4?b1.1 and 1.6?b0.5 μM, respectively). Methyl 4-(4,5,6,7-tetrahydro-1H-indazol-3-yl)benzoate (5), 6, ethyl 4-(2-benzyl-2H-indazol- 3-yl)benzoate (11), 4-(1-benzyl-1H-indazol-3-yl)benzoic acid (12), 17, 23, 135, and methyl 4-(2-benzyl-2H-indazol-3-yl)benzoate (137) showed the better inhibitory effect for lysozyme expression of fMLP/cytochalasin B induced neutrophil degranulation than positive control genistein (IC50≒8.6?b0.6, 8.9?b0.6, 8.7?b1.4, 15.0?b0.6, 4.7?b1.2, 4.0?b0.4, 12.0?b1.3, 11.7?b1.2, 10.5?b2.1, and 9.1?b1.1 μM, respectively). Compounds 8, 117, and [4-(1-benzyl-6-methoxy-1H-indazol-3- yl)phenyl]methanol (134) showed the better inhibitory effect for β-glucuronidase expression of fMLP/cytochalasin B induced neutrophil degranulation than positive control TFP (IC50≒8.4?b2.6, 5.7?b1.4, and 9.4?b0.8 μM, respectively). Compounds 8, showed the better inhibitory effect for lysozyme expression of fMLP/cytochalasin B induced neutrophil degranulation than positive control TFP (IC50≒3.9?b2.3 μM). They were found to exhibit significant anti-inflammatory activity and were selected as new lead compounds. Besides, compounds 92, 4-[1-(3-chlorobenzyl)-1H-indazol- 3-yl]benzoic acid (93), 4-[1-(3-fluorobenzyl)-1H-indazol-3-yl]benzoic acid (96), 115, and 118 were found to exhibit significant anti-bacterial activity against Staphylococcus aureus ATCC 25923, Staphylococcus aureus 1, and Staphylococcus aureus 2.

碩士
中國醫藥學院
藥物化學研究所
91
Abstract 1-Benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (YC-1) was first synthesized in our laboratory as a novel antiplatelet agent. Encouraged by the initial results, a series of 5-methoxy derivatives of YC-1 analogues were synthesized and examined for their biological activities. The starting material methyl 5-(3-methoxybenzoyl)-2-furoate (1) was treated with benzylhydrazine to yield a mixture of E- and Z-form isomers 2. The hydrazone was then treated with lead tetraacetate in dichloromethane at low temperature, then boron trifluoride etherate was added and the mixture heated to form the expected key intermediate ：methyl 5-(1-benzyl-5-methoxy-1H-indazol-3-yl)-2-furoate (4). Starting from methyl 5-(1-benzyl-5-methoxy-1H-indazol-3-yl) -2-furoate (4), various esters 8a—8d、amides 9a—9h and amino acid methyl esters 10a—10f were synthesized，biological evaluation of the synthesized compounds are currently under investigation.

Two types of monodisperse rod-like polymers, poly($\gamma$-benzyl $\alpha$,L-glutamate) (PBLG) and poly($\gamma$-4-(hexadecyloxy)benzyl $\alpha$,L-glutamate) with backbone sequences of have been prepared by chemical modification of monodisperse poly($\alpha$,L-glutamic acid) (PLGA) that was synthesized by recombinant DNA biosynthesis techniques. The monodisperse PLGA () was produced in Escherichia coli as a fusion to mouse dihydrofolate reductase and purified to homogeneity by metal affinity chromatography, CNBr digestion and ion-exchange chromatography.$$\rm GluAsp(Glu\sb{17}Asp)\sb{x}GluGlu\quad x = 3, 4, 5, 6\eqno {\bf1}$$ The monodisperse PBLG derived from showed smectic ordering both in solution and in films as characterized by polarized light optical microscopy and X-ray diffraction. The layer spacings of smectic order were nearly identical to the expected length of the rods, given the axial rise per residue of 1.5 A for the $\alpha$-helix. X-ray diffraction patterns of magnetically oriented films were consistent with the supramolecular structure in which helical rods are arranged in layers with their helical axes approximately perpendicular to the smectic layers. Transmission electron microscopy and electron diffraction on the PBLG films revealed a banded morphology with an approximately 120 nm period which provides strong evidence for helical rotation of the director field as in cholesteric order. Detailed examination of the relative orientation of the banding in the morphology image and the reflections in the electron diffraction pattern leads to the conclusion that the structure of the unoriented smectic PBLG is that of a smectic A*. The monodisperse poly($\gamma$-4-(hexadecyloxy)benzyl $\alpha$,L-glutamate)s exhibit strong melting transitions at around $40\sp\circ$C; however no ordered melt was observed due in part to the reduced aspect ratio brought about by the long alkyl side groups.

碩士
嘉南藥理科技大學
藥學系
101
5, 6-Dihydro-4H-benzo[de]quinolone camptothecin (BQC), a derivative of camptothecin, has been identified as a potential anti-tumor drug. Additionally, BQC could be conjugated with a methyl glucuronate to improve its tumor specificity and also its water solubility. Dr. Masamichi. firstly synthesized compound 6 from compound 1 through nitrification, oxidation and reduction. Compound 6 then was conjugated with compound 7 to give BQC. However, when the start material is compound 1, the nitrification step would produce a 6-nitro and 6, 8-dinitro byproduct, thus it requires purification of the 8-nitro main product. The yield of nitrification and oxidation is 13.0% and 77.4%, respectively, the total yield is just 10%. In our study, in order to increase the total yield, we modified the synthesis process. We obtained compound 5 by using the same starting material (compound 1) but with different orders, which are oxidation and nitrification. The yield of oxidation and nitrification is 42.7% and 69%, respectively. The total yield is 33%. It is 3-folds better than the original process. In order to improve the practicality of clinical applications by increased the tumor targeting, we were according to the strategy of prodrug. We have been designed and synthesized a BQCG -ester type compound.

Biosynthesis of monodisperse poly(α,L-aspartic acid) and optimization of poly(α,L-glutamic acid) production have been accomplished. Protein design having as ultimate goal the synthesis of monodisperse benzyl-ester derivatives of α-helical polypeptides by genetic engineering has been performed. This comprises design of a monomeric DNA cassette, cloning, multimerization, ligation into an expression vector, and expression of the target gene followed by purification of the resultant protein. Advantages of such techniques include control of molecular size, composition, sequence and stereochemistry of the synthesized polymers. 1H NMR (nuclear magnetic resonance), amino acid analysis, and MALDI-MS (matrix-assisted laser desorption mass spectrometry) analytical techniques were employed for characterization of monodisperse poly(α, L-amino acid)s. Modification of conventional purification and cyanogen bromide cleavage reactions are included as part of the strategy to obtain monodisperse poly(α, L-aspartic acid). Optimization of polymer production was achieved by means of utilization of a variety of Escherichia coli strains and plasmids, modification of large scale fermentation conditions, and alterations of purification procedures. Monodisperse poly(α,L-amino acid)s were benzylated by treating the acid forms of the polymers with phenyldiazomethane. Polarized light optical microscopy was used to observe textures from birefringent samples of poly(β-benzyl α,L-glutamate) and poly(β-benzyl α,L-aspartate). Small-angle X-ray diffraction data shows evidence of smectic ordering of monodisperse poly(β-benzyl α,L-glutamate) (DP = 76). poly(γ-4-(hexadecyloxy)benzyl α,L-glutamate) DP = 300, was synthesized by methods developed in our laboratories. Differential scanning calorimetry (DSC) and polarized light optical microscopy (POM) data is presented as evidence for thermotropic liquid crystal behavior.