Synthesis of 4,6-(and 5,7-)dimethoxy-3,3-dimethyl-1-indanones

Grignard reaction of ethyl 3-(3,5-dimethoxyphenyl)-propionate (4) followed by cyclodehydration of the carbinol (5) with conc H2SO4 gave 4,6-dimethoxy-3,3-dimethylindane (6). Oxidation of the indane (6) with CrO3-pyridine complex in methylene chloride gave 4,6-dimethoxy-3,3-dimethylindan-1- one (1) in high yield. Conjugate addition of methyl magnesium iodide to methyl α-cyano-β-methyl-3,5-dimethoxycinnamate (11), prepared from 3,5-dimethoxyacetophenone (10) by Knoevenagel condensation, resulted in methyl 2-cyano-3-(3,5-dimethoxyphenyl)-3,3-dimethylpropionate (12). Refluxing the ester (12) with aq DMSO containing sodium chloride gave the corresponding nitrile (15) which underwent Höesch reaction to yield 5,7-dimethoxy-3,3-dimethylindan-1-one (2).

Studies on the synthesis of cytochrome P-450 and cytochrome P-448 in rat liver

The synthesis of cytochrome P-450 (phenobarbital inducible) and cytochrome P-448 (3-methylcholanthrene inducible) have been studied in rat liver in vivo and in the wheat germ cell-free system using anti- cytochrome P-450 and anti-cytochrome P-448 antibodies. The major mature forms synthesized in vivo correspond to a molecular weight of 47,000 for cytochrome P-450 and 53,000 for cytochrome P-448. Translation of poly(A)-containing RNA from phenobarbital-treated rats in the wheat germ cell-free system reveals that the cell-free product immunoprecipitated with anti-cytochrome P-450 antibody has a molecular weight close to 47,000. In the case of 3-methylcholanthrene, the cell- free product immunoprecipitated with anti-cytochrome P-448 antibody shows a molecular weight around 59,000. Significant conversion of the 59,000 species to the 53,000 species can be demonstrated when the translation is carried out in the presence of microsomal membranes isolated from rat liver. Phenobarbital and 3-methylcholanthrene enhance the translatable messenger.

Enzyme molecular choreography : studies on soluble inorganic pyrophosphatases

Inorganic pyrophosphatases (PPases, EC 3.6.1.1) hydrolyse pyrophosphate in a reaction that provides the thermodynamic 'push' for many reactions in the cell, including DNA and protein synthesis. Soluble PPases can be classified into two families that differ completely in both sequence and structure. While Family I PPases are found in all kingdoms, family II PPases occur only in certain prokaryotes. The enzyme from baker's yeast (Saccharomyces cerevisiae) is very well characterised both kinetically and structurally, but the exact mechanism has remained elusive. The enzyme uses divalent cations as cofactors; in vivo the metal is magnesium. Two metals are permanently bound to the enzyme, while two come with the substrate. The reaction cycle involves the activation of the nucleophilic oxygen and allows different pathways for product release. In this thesis I have solved the crystal structures of wild type yeast PPase and seven active site variants in the presence of the native cofactor magnesium. These structures explain the effects of the mutations and have allowed me to describe each intermediate along the catalytic pathway with a structure. Although establishing the ʻchoreographyʼ of the heavy atoms is an important step in understanding the mechanism, hydrogen atoms are crucial for the mechanism. The most unambiguous method to determine the positions of these hydrogen atoms is neutron crystallography. In order to determine the neutron structure of yeast PPase I perdeuterated the enzyme and grew large crystals of it. Since the crystals were not stable at ambient temperature, a cooling device was developed to allow neutron data collection. In order to investigate the structural changes during the reaction in real time by time-resolved crystallography a photolysable substrate precursor is needed. I synthesised a candidate molecule and characterised its photolysis kinetics, but unfortunately it is hydrolysed by both yeast and Thermotoga maritima PPases. The mechanism of Family II PPases is subtly different from Family I. The native metal cofactor is manganese instead of magnesium, but the metal activation is more complex because the metal ions that arrive with the substrate are magnesium different from those permanently bound to the enzyme. I determined the crystal structures of wild type Bacillus subtilis PPase with the inhibitor imidodiphosphate and an inactive H98Q variant with the substrate pyrophosphate. These structures revealed a new trimetal site that activates the nucleophile. I also determined that the metal ion sites were partially occupied by manganese and iron using anomalous X- ray scattering.

Synthesis, Reactivity and Biological Activity of 17β-HSD1 Inhibitors Based on a Thieno[2,3-d]pryrimidin-4(3H)-one Core

Breast cancer is the most common cancer in women in Western countries. In the early stages of development most breast cancers are hormone-dependent, and estrogens, especially estradiol, have a pivotal role in their development and progression. One approach to the treatment of hormone-dependent breast cancers is to block the formation of the active estrogens by inhibiting the action of the steroid metabolising enzymes. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of estradiol, the most potent female sex hormone. The 17beta-HSD1 enzyme catalyses the final step and converts estrone into the biologically active estradiol. Blocking 17beta-HSD1 activity with a specific enzyme inhibitor could provide a means to reduce circulating and tumour estradiol levels and thus promote tumour regression. In recent years 17beta-HSD1 has been recognised as an important drug target. Some inhibitors of 17beta-HSD1 have been reported, however, there are no inhibitors on the market nor have clinical trials been announced. The majority of known 17beta-HSD1 inhibitors are based on steroidal structures, while relatively little has been reported on non-steroidal inhibitors. As compared with 17beta-HSD1 inhibitors based on steroidal structures, non-steroidal compounds could have advantages of synthetic accessibility, drug-likeness, selectivity and non-estrogenicity. This study describes the synthesis of large group of novel 17beta-HSD1 inhibitors based on a non-steroidal thieno[2,3-d]pyrimidin-4(3H)-one core. An efficient synthesis route was developed for the lead compound and subsequently employed in the synthesis of thieno[2,3-d]pyrimidin-4(3H)-one based molecule library. The biological activities and binding of these inhibitors to 17beta-HSD1 and, finally, the quantitative structure activity relationship (QSAR) model are also reported. In this study, several potent and selective 17beta-HSD1 inhibitors without estrogenic activity were identified. This establishment of a novel class of inhibitors is a progressive achievement in 17beta-HSD1 inhibitor development. Furthermore, the 3D-QSAR model, constructed on the basis of this study, offers a powerful tool for future 17beta-HSD1 inhibitor development. As part of the fundamental science underpinning this research, the chemical reactivity of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones with electrophilic reagents, i.e. Vilsmeier reagent and dimethylformamide dimethylacetal, was investigated. These findings resulted in a revision of the reaction mechanism of Vilsmeier haloformylation and further contributed to understanding the chemical reactivity of this compound class. This study revealed that the reactivity is dependent upon a stereoelectronic effect arising from different ring conformations.

Solvothermal Synthesis of InP Quantum Dots

We report an efficient and fast solvothermal route to prepare highly crystalline monodispersed InP quantum dots. This solvothermal route, not only ensures inert atmosphere, which is strictly required for the synthesis of phase pure InP quantum dots but also allows a reaction temperature as high as 430 degrees C, which is otherwise impossible to achieve using a typical solution chemistry; the higher reaction temperature makes the reaction more facile. This method also has a judicious control over the size of the quantum dots and thus in tuning the bandgap.

Novel Biginelli dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study

Novel Biginelli dihydropyrimidines of biological interest were prepared using p-toluene sulphonic acid as an efficient catalyst. All the thirty-two synthesised dihydropyrimidines were evaluated for their in vitro antioxidant activity using DPPH method. Only, compounds 28 and 29 exhibited reasonably good antioxidant activity. Furthermore, the synthesised Biginelli compounds were subjected for their in vitro anticancer activity against MCF-7 human breast cancer cells. The title compounds were tested at the concentration of 10 μg. Compounds exhibited activity ranging from weak to moderate and, from moderate to high in terms of percentage cytotoxicity. Among them, compounds 10 and 11 exhibited significant anticancer activity. In order to elucidate the three-dimensional structure–activity relationships (3D QSAR) towards their anticancer activity, we subjected them for comparative molecular similarity indices analysis (CoMSIA). Illustration regarding their synthesis, analysis, antioxidant activity, anticancer activity and 3D QSAR study is described.

Synthesis and applications of carbon nanomaterials for energy generation and storage

The world is facing an energy crisis due to exponential population growth and limited availability of fossil fuels. Over the last 20 years, carbon, one of the most abundant materials found on earth, and its allotrope forms such as fullerenes, carbon nanotubes and graphene have been proposed as sources of energy generation and storage because of their extraordinary properties and ease of production. Various approaches for the synthesis and incorporation of carbon nanomaterials in organic photovoltaics and supercapacitors have been reviewed and discussed in this work, highlighting their benefits as compared to other materials commonly used in these devices. The use of fullerenes, carbon nanotubes and graphene in organic photovoltaics and supercapacitors is described in detail, explaining how their remarkable properties can enhance the efficiency of solar cells and energy storage in supercapacitors. Fullerenes, carbon nanotubes and graphene have all been included in solar cells with interesting results, although a number of problems are still to be overcome in order to achieve high efficiency and stability. However, the flexibility and the low cost of these materials provide the opportunity for many applications such as wearable and disposable electronics or mobile charging. The application of carbon nanotubes and graphene to supercapacitors is also discussed and reviewed in this work. Carbon nanotubes, in combination with graphene, can create a more porous film with extraordinary capacitive performance, paving the way to many practical applications from mobile phones to electric cars. In conclusion, we show that carbon nanomaterials, developed by inexpensive synthesis and process methods such as printing and roll-to-roll techniques, are ideal for the development of flexible devices for energy generation and storage – the key to the portable electronics of the future.

Antioxidative long chain alkylresorcinols. Synthesis and deuterium labelling of bioactive compounds present in whole grains

The first synthesis of long chain 5-n-alkylresorcinols (C15-C25) in whole grains and whole grain products by a novel modification of Wittig reaction is described. 5-n-Alkylresorcinols are phenolic lipids that have various effects on biological systems, such as antioxidant activity and interaction with biological membranes. These compounds are considered as biomarkers of whole grain intake, which is connected with reduced risk of cardiovascular diseases and certain cancers. Novel hapten derivatives of 5-n-alkylresorcinols, potential compounds for immunoanalytical techniques, are prepared by the same procedure utilizing microwave catalysed aqueous Wittig reaction as the key step. The synthesised analogues are required by various analytical, metabolism and bioactivity investigations. Four alternative strategies for producing deuterium polylabelled 5-n-alkylresorcinols are explored. Ring-labelled D3-alkylresorcinols were synthesized by acidic H/D exchange. Side chain -labelled D4-derivative was prepared by a total synthesis approach utilizing D2 deuterogenation of a D2-alkene derivative, and deuterogenation of alkynes was investigated in another total synthesis approach. An -D3-labelled alkylresorcinol is isotopically pure and completely stable under all relevant conditions encountered during analytical work. The labelling of another phenolic component of whole grains was explored. The preparation of D3-ferulic acid and related compounds by way of selective methylation of the precursors is described. The deuterated compounds are useful as standards in the quantification of these natural products in various substances, such as food and human fluids. The pure 5-n-alkylresorcinol analogues prepared were used in in vitro experiments on alkylresorcinol antioxidant activity and antigenotoxicity. The in vitro experiments show that alkylresorcinols act as antioxidants, especially when incorporated into biological systems, but possess lower activity in chemical tests (FRAP and DPPH assay). Whole grain alkylresorcinols are shown for the first time to have a protective effect against copper induced oxidation of LDL, and H2O2 or genotoxic faecal water induced damage on HT29 cells.

Titanium Complexes for the Polymerisation of Ethene and Caprolactone

The literature part of the thesis mainly reviews the results of the use of titanium catalysts for ethene and caprolactone polymerisation. The behaviour of titanium catalysts bearing phenoxy-imino ligands has been the focus of more detailed investigations in ethene polymerisation. Reasons for the production of multimodal polyethene for a range of catalysts are also given. The experimental part of the thesis is divided into two sections based on the monomers used in the polymerisations: Part A (ethene) and part B (caprolactone). Part A: Titanium(IV) complexes bearing phenoxy-imino ligands are known to possess high ethene polymerisation activities after MAO activation. Depending on the ligand, the activities of the catalysts in polymerisation can vary between 1 and 44000 kgPE/(mol*cat*h*bar). Depending on the polymerisation temperature and the electronic and steric properties of the catalyst ligands, low to high molar mass values and uni- and multimodal polydispersity values can been observed. In order to discover the reasons for these differences, 22 titanium(IV) complexes containing differently substituted phenoxy-imino derivatives as di- and tetradentate ligands were synthesised with high yields and used as homogeneous catalysts in ethene polymerisations. Computational methods were used to predict the geometry of the synthesised complexes and their configuration after activation. Based on the results obtained, the geometry of the catalyst together with the ligand substituents seem to play a major role in defining the catalytic activity. Novel titanium(IV) complexes bearing malonate ligands were also synthesised. Malonates are considered to be suitable ligand pre-cursors since they can be produced by the simple reaction of any primary or secondary alcohol with malonylchloride, and thus they are easily modifiable. After treatment with MAO these complexes had polymerisation activities between 10 and 50 kgPE/(mol*cat*h*bar) and surprisingly low polydispersity values when compared with similar types of catalysts bearing the O?O chelate ligand. Part B: One of the synthesis routes in the preparation of the above mentioned phenoxy-imino titanium dichloride complexes involved the use of Ti(NMe2)4 with a range of salicylaldimine type compounds. On reaction, these two compounds formed an intermediate product selectively and quantitatively which was active in the ring-opening polymerisation of caprolactone. Several mono-anionic alcoholates were also combined with Ti(NMe2)4 in different molar ratios and used as catalysts. Full conversion of the monomer was achieved within 15 minutes with catalysts having a co-ordination number of 4 while after 22 hours full conversion was achieved with catalysts having a co-ordination number of 6.