No description available.

No description available.

No description available.

No description available.

Nitrogen-containing bisphophonates (N-BPs) are a blockbuster class of drugs for the treatment of common metabolic bone diseases.  Recently, N-BPs have been shown to inhibit FPP synthase and/or isopentenyl diphosphate (IPP) isomerase (both enzymes in the mevalonate pathway), thereby preventing the synthesis of the isoprenoid lipids farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which are vital substrates for protein prenylation.  By preventing the synthesis of FPP and GGPP, N-BPs prevent the prenylation of small GTPases and inhibit osteoclast function. This study demonstrates conclusively that the major pharmacological target of N-BPs is FPP synthase.  Furthermore, minor structural modifications to the N-BPs that govern <i>n vivo </i>potency have a marked effect on potency for inhibition of FPP synthase <i>in vitro.  </i>Non-N-BPs, such as clodronate and etidronate, did not inhibit FPP synthase, consistent with other studies suggesting that the non-N-BPs and N-BPs act by different molecular mechanisms. Clinically, N-BPs have been shown to exhibit marked differences in efficacy between patients and may lie resident in the skeleton for many years.  J774 macrophage-like cells resistant to the effects of N-BP (J774-RES) were generated to study the possible cellular mechanisms underlying clinical resistance to treatment.  The J774-RES cells accumulated N-BP to a lesser extent than parental cells and also exhibited increased expression of the MCSF receptor, although further studies are required to clarify the exact mechanism of the resistance of J774-RES cells. Finally, N-BPs have been shown to induce the proliferation of the major subset (V<span style='font-family:Symbol'>g9V<span style='font-family:Symbol'>d2) of <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-T cells in humans, attributed to an agnostic effect on the <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-T cell receptor (TCR).  The findings of this study indicate that the N-BPs act indirectly, by inhibiting FPP synthase and causing the accumulation of IPP, a known agonist of the <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-TCR.  Furthermore, this proliferative effect of N-BPs could be abrogated by statins, possibly indicating a means of preventing the acute-phase response, the major side effect to intravenously-administrated N-BPs.

Nitrogen-containing heteroaromatics are ubiquitous in nature. In addition, 75% of FDA-approved drugs currently on the market are based on these compounds, establishing them and their analogues as a primary source of therapeutic agents in the pharmaceutical industry. The structural complexity exhibited by these nitrogen-based moieties necessitates the development of innovative strategies that demand mastery beyond routine and traditional organic chemistry that most synthetic chemists typically cultivate. The second chapter of this thesis describes the use of novel delayed radical precursors in Mn (OAc)3·2H2O mediated oxidative radical cyclization-fragmentation-dimerization processes from Banilides. The first part presents a sequential oxidative radical cyclization-decarboxylative-dimerization process from β-oxoacids, forming three bonds in a one-pot manner. This approach was successful with a diverse range of 3,3′-bisoxindoles substrates obtained in up to 96% yield. The second part of chapter two details a complementary and closely related sequential one-pot oxidative radical cyclization-deformation-dimerization process from β-oxoanilides, this motion was also applicable to a wide array of 3,3′-bisoxindoles with up to 98% yield. There are no clear-cut distinctions between the decarboxylative and deformylation approaches as they appear to be highly complementary to each other. The chapter concludes with a further demonstration of the utility of this methodology, in the formal synthesis of the calycanthaceae alkaloid, (±)-folicanthine via to the best of our knowledge the shortest linear route. The third chapter of this thesis describes a general extension of the second chapter, which involves an atom-efficient silver-catalysed double decarboxylative strategy for the one-step synthesis of quinolin2-ones. This is achieved via an oxidative radical addition–cyclisation–elimination cascade sequence of oxamic acids to acrylic acids, mediated either thermally or photochemically. The reaction proved to be successful with a wide range of 32 quinolin-2-ones synthesized in of up to 84% yield. The method features an elegant double-disconnection approach, which constructed the quinolin-2-one core through the formal and direct addition of a C(sp2)–H/C(sp2)–H olefin moiety to a phenyl formamide precursor. The theme of the thesis is centred around the synthesis of nitrogen-containing heteroaromatics using facile and efficient protocols that offer catalyst, atom and energy efficiency, while also providing substantial economic advantages. Additionally, the thesis presents systematic and in-depth mechanistic studies on both developed protocols to support and offer compelling evidence for the proposed mechanistic cycles. These studies provide insights into the reaction pathways and help establish a more comprehensive understanding of the radical synthetic pathways.

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Condensation of chromatin and alteration of chemical groups in the proteins around which the DNA is wrapped play major role in regulation of transcription. Histones are basic proteins rich in arginine and lysine residues which form the nucleosomal core. Histone modifications like acetylation, methylation, phosphorylation, etc. have broadened the horizon for researchers to study epigenetics more in detail. Histone methyl transferases and histone demethyl transferases are enzymes which add or remove methyl groups on histone lysine and arginine residues respectively. In this study a jumonji domain containing putative histone demethyltransferase has been shown to be responsible in controlling flowering phenotype in Arabidopsis thaliana. The knocked out mutants for this gene (JMJ14) showed an early flowering phenotype along with elevated levels of FT transcript (Flowering locus T, gene responsible for controlling the flowering time in Arabidopsis thaliana). We show that methylation was altered on H3K36 in the FT ene in the mutants using ChIP (chromatin immunoprecipitation experiments). The possible role of SDG8 gene, a histone methyl transferase in ABA signaling was also studied during the research. A SET domain containing Sdg8 (group 8 methyltransferase) mutant was found to be responsible for ABA signaled altered root growth in Arabidopsis thaliana. The cell number and cell size in roots decreased in both meristematic and elongation zones leading to decrease in root size in sdg8 mutants and number of root hairs increased when treated with Abscisic acid, a plant hormone. In this part of study, as part of an interaction between epigenetics and gene regulation, it was observed that a putative histone demethylase gene, JMJ14 was responsible for regulating the flowering time by controlling the expression of FT and SDG8 played a role in altered root growth in response to ABA in Arabidopsis thaliana. Further studies on these genes could lead to generation of commercial crops with phenotypes that would increase the plant productivity and be beneficial agronomically.

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WWOX is a tumor suppressor and the down-regulation of WWOX has been demonstrated in prostate, lung, breast, gastric cancers. However, the role of WWOX in renal cell carcinoma (RCC) remains unknown. It has been demonstrated that WWOX addressed in mitochondria, golgi apparatus, rough ER, lysosome, plasma membrane and nuclear. The Subcellular localization of WWOX has been controversial. There are two parts in this study: (I) The expression of WWOX in RCC and the probability of WWOX to be a diagnostic and a prognostic marker. (II) The regulation of WWOX by phosphorylation. For the study of WWOX expression in RCC, we prepared polyclonal WWOX antibody and characterized the specificity of the antibody. We applied this specific antibody to 33 NT paring RCC tissue specimen for immunoblotting study and 138 cases of paraffin-embedded specimens for IHC, respectively. Our results demonstrated that hWOX1 was specifically down-regulated in clear cell type RCC (p=0.018). The percentage of down-regulation in patient specimen is 60.7 % and 90.7 % in immunoblotting and IHC study, respectively. And in clear cell and clear-granular combined type RCC, down-regulation of WWOX was significantly correlated with the survival rate of patients (p=0.0482). Therefore, WWOX could be used as a diagnostic and a prognostic marker in clear cell type RCC. Besides, we performed bioinformatics to predict the phosphorylation site of WWOX and investigated the effect of phosphorylation on WWOX subcellular localization. Our results demonstrated that hWOX1 was phosphorylated by PKC at Thr49 and Thr102 and the phosphorylation regulated the subcellular localization of WWOX.