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.

A range of N-H alkynylaziridines were prepared from amphoteric unprotected aziridine aldehydes without protecting-group manipulation. Unprotected alpha -amino allenes can be obtained from these strained propargyl amines via a 9-BBN mediated hydride transfer. Further transformation of alpha -amino allenes to 2,4,6-trisubstituted pyridines was realized. We also developed another class of amphoteric molecules – alpha-boryl aldehydes, equipped with the tetrahedral MIDA boryl group. A wide range of boryl-substituted building blocks or functionalized boronic acid derivatives have been accessed from these bench-stable alpha-borylcarbonyl compounds. Further chemoselective transformations of these alpha-boryl aldehyde derived building blocks have been conducted, where alph-boryl isocyanates, alpha-aminoboronic acids, acylboronates, and borylated heterocycles were achieved through the decarboxylative functionalization of alpha-borylcarboxylic acids.

A range of N-H alkynylaziridines were prepared from amphoteric unprotected aziridine aldehydes without protecting-group manipulation. Unprotected alpha -amino allenes can be obtained from these strained propargyl amines via a 9-BBN mediated hydride transfer. Further transformation of alpha -amino allenes to 2,4,6-trisubstituted pyridines was realized. We also developed another class of amphoteric molecules – alpha-boryl aldehydes, equipped with the tetrahedral MIDA boryl group. A wide range of boryl-substituted building blocks or functionalized boronic acid derivatives have been accessed from these bench-stable alpha-borylcarbonyl compounds. Further chemoselective transformations of these alpha-boryl aldehyde derived building blocks have been conducted, where alph-boryl isocyanates, alpha-aminoboronic acids, acylboronates, and borylated heterocycles were achieved through the decarboxylative functionalization of alpha-borylcarboxylic acids.

No description available.

The research objective of this thesis research was to develop new methods for the asymmetric synthesis of amine derivatives using p-toluenesulfinimines. Enantiopure sulfinimines are versatile chiral building blocks for the asymmetric synthesis of alkaloids. Sulfinimines were prepared by the condensation of (S)- or (R)-p-toluenesulfinamide with aldehydes and ketones in good to excellent yields, which were prepared from the commercially available Anderson reagent. The first research project was the development of a new method for the preparation of enantiopure anti-anti- α-lkyl β-amino ketones and was accomplished by the stereoselective α-alkylation of enolates of sulfinimine derived β-amino esters. The anti- α-lkyl β-amino esters were transformed to their corresponding Weinreb amides by reacting with lithium dimethyl hydroxyl amine without epimerization. Reactions of the Weinreb amides with Grignard and organolithium reagents afforded the corresponding anti- α-lkyl β-amino ketones in modest yields and high optical purity. The modest yields are the results of competition between addition and reduction of the Weinreb amide. anti- α-lkyl β-amino ketones are important chiral building blocks for the asymmetric synthesis of nitrogen-containing biologically active molecules, such as pyrrolidines, piperidines and other alkaloids. To further illustrate the utility of sulfinimine -derived enantiopure N-sulfinyl anti- α-lkyl β-amino ketones, they was applied to the asymmetric synthesis of the unknown anti-C5, C6 derivative of 2,3,4,6-tetrasubsituted indolizidine 221-T. The key step in the synthesis was the stereoselective construction of the piperidine ring of the 5,6,8-tri-substituted indolizidine and was realized via the use of an acid-catalyzed intramolecular Mannich cyclization. The indolizidine was readily transformed in to the key intermediate 7-hydroxyl-2,3,4,6-tetrasubsituted indolizidine in high stereoselectivity and yield. Changing the sequence of chemical operation steps avoided the production of the side product β-pyrrole ketone. Reduction of the intermediate piperdinone, followed by ring-closing metathesis and reductive catalytic hydrogenation afford the bicyclic indolizidine with overall 76% yield of 3 steps. The C-2 branched cocaine analogs are thought to have varied bioactivities and potent therapeutical uses compared to other positions of substituted cocaine analogs. However, reports on the synthesis of such analogs are few. The first example of preparation of a cocaine analog having a dimethylphosphonate group at the C-2 position was reported. The key step in forming the required isoxazolidine intermediate, which controls the required cis stereochemistry at C-2 and C-3, was a novel microwave induce stereoselective [3+2] intramolecular cycloaddition of an α,β-unsaturated pyrrolidine nitrone. The use of the microwave irradiation techniques significantly reduce the time required for isoxazolidine formation from 96 hours to five hours. / Chemistry

No description available.

No description available.

Farnesyl pyrophosphate synthase (FPPS) is a key branch point enzyme in the mevalonate pathway and the main molecular target of nitrogen-containing bisphosphonates (N-BPs), potent inhibitors of osteoclastic activity and the leading drug of choice for conditions characterized by excessive bone resorption. The main aim of this thesis is to investigate the interaction of N-BPs with FPPS in order to gain further insights into the mechanism of drug inhibition. Kinetic and crystallographic studies following site-directed mutagenesis of FPPS reveal key residues involved in stabilization of carbocation intermediate, substrate binding and formation of a tight enzyme-inhibitor complex. The aromatic ring of Tyr204 is involved in N-BP binding but not in the catalytic mechanism, where the hydroxyl moiety plays an important role. Lys200 is implicated in regulation of substrate binding, product specificity and enzyme isomerization which leads to a tight binding inhibition. Phe239 is considered important for the FPPS C-terminal switch which stabilizes substrate binding and promotes the inhibitor induced isomerized state. The highly conserved Arg112, Asp103 and Asp107 are pivotal for catalysis. Successful purification of the full length of Rab geranylgeranyl transferase (RGGT) complex downstream of the FPPS in the mevalonate pathway was achieved and may lead to co-crystallization with BP analogues and identification of the putative site of drug binding. Investigation of the in vitro effect of N-BPs on osteoclastogenesis suggest a correlation with FPPS inhibition kinetics for the most potent N-BPs but indicate an alternative mechanism of the disruption of bone resorption by alendronate. Together these results highlight the importance of the multiple interactions of N-BPs with side-chain residues of FPPS which dictate their strength of binding and advance the understanding of their pharmacophore effect.

Polycyclic aromatic hydrocarbons (PAHs) and nitrogen-containing polycyclic aromatic compound (N-PAC) are widespread toxic pollutants in environments. The fate of PAHs and N-PACs are of great concern because some of these compounds were identified as caricinogenic, mutagenic and teratogenic compounds. As described in literature, dissolved organic matter (DOM) is an important factor in control of their fate; however, the binding behaviors between these compounds and DOM are still not fully understood. The binding constants (KDOC) between humic substances and one selected N-PAC, benzo[h]quinoline, were measured at varying pH levels using fluorescence quenching (FQ) method. As fluorescence characteristics of benzo[h]quinoline change with pH, determination required two optimum sets of excitation and emission wavelength pairs. A simple mixing model was proposed and used to eliminate the inherent fluorescence interference between benzo[h]quinoline (BQ) and its protonated form, benzo[h]quinolinium (BQH+), and to deduce Kmix which represents the overall binding as the sum of that for the individual analogs. The characteristics of humic substances, especially their hydrophobicity and aromaticity, established by principal components analysis of structural and elemental compositions, were the main determinants of their binding affinity with both benzo[h]quinoline and benzo[h]quinolinium (KBQ and KBQH+) across a range of pH values. Hydrophobic interaction is likely to control the binding between humic substance and benzo[h]quinoline and benzo[h]quinolinium, in lower and higher pH ranges (pH<3, pH>6). In contrast, cation exchange seems to control on the binding affinity of benzo[h]quinolinium in the middle range of pH. Determination of PAH concentration is quite essential for investigating the fate of PAHs in environments. Microwave-assisted headspace solid-phase microextraction (MA-HS-SPME) with a polydimethylsiloxane/divinylbenzene (PDMS/DVB) fiber was applied as a single step prior to determination of PAH concentrations in water using GC-MS. To optimize the extraction efficiency of PAHs by MA-HS-SPME, the influence of various parameters, including temperature, duration of thermal desorption, microwave irradiation power and duration, and the temperature of the circulating cooling water system, was studied. The proposed method was demonstrated applicable to environmental water samples. In addition, DOM matrix effect did not influence the determination and extraction efficiency of PAHs. Although the proposed simple mixing model can eliminate the fluorescent interference of hydrophobic organic compounds with acid-base pair forms, it is still limited in using for correcting the KDOC measurement of more than two fluorescent compounds simultaneously. A new alternative protocol, complexation-flocculation combined with MA-HS-SPME/GC-MS method, was proposed to determine the binding constants of seleted PAHs to humic substances. The results obtained are comparable with KDOC data reported in literatures. CF-MA-HS-SPME/GC-MS provides some advantages over other methods, such as applicable not limited to fluorescent compounds, faster in determination and capable in measuring varieties of compounds simultaneously.