This paper deals with the preparation of pyridinium derivatives of naphthoquinone. The starting material was 2,3-dichloro-1,4-naphthoquinone, and it was reacted with pyridine and 4-n-alkyl-pyridine derivatives.

The purpose of this paper is to derive certain of the fundamental properties of the Dini derivatives of an arbitrary real function. To this end it will be necessary to investigate the properties of the limits superior and inferior of real functions and to prove the Vitali Covering Theorem as well as a fundamental theorem on the metric density of arbitrary point sets.

Philosophiae Doctor - PhD / The abnormal death of neurons in the central nervous system of individuals suffering from neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, takes place by an intrinsic cell suicide programme known as apoptosis. This process is triggered by several stimuli, and consists of numerous pathways and cascades which lead to the death of neuronal cells. It is this multifactorial nature of neurodegenerative diseases that has over the years seen many researchers develop compounds that may serve as multi-target directed ligands (MTDLs) which could potentially confer neuroprotection by acting simultaneously on different receptors and target sites implicated in neurodegeneration. This study was aimed at developing MTDLs that may serve as neuroprotective agents by simultaneously (a) inhibiting N-methyl D-aspartate receptors (NMDAR) and blocking L-type voltage gated calcium channels (VGCC) thus regulating the Ca2+ influx mediated excitotoxic process; (b) inhibiting the monoamine oxidase enzymes A and -B (MAO-A/B) thus allowing increase in dopamine levels in the central nervous system and reducing the levels of the highly oxidative products produced by the activity of these enzymes; (c) possessing anti-apoptotic activity to halt the neuronal cell death process. In designing the compounds we focused on the structures of rasagiline and selegiline, two well-known MAO-B inhibitors and proposed neuroprotective agents, and of NGP1-01, a known VGCC blocker and NMDAR antagonist. The first series of compounds (reported in research article 1, Chapter 3), comprised polycyclic propargylamine and acetylene derivatives. Compounds 12, 15 and 16 from this series showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18 % to 59 % in micromolar concentrations, and compared favourably to the reference compounds. In the MAO-B assay, compound 10 exhibited weak MAO-B inhibition of 73.32 % at 300 μM. The rest of the series showed little to no activity on these target sites, despite showing significant anti-apoptotic activity. This suggested the compounds in this series to be exhibiting their neuroprotective action through some other mechanism(s) unexplored in this study.

Student Number : 0416598H - MSc research report - School of Public Health - Faculty of Health Sciences / Background Evidence shows that the efficacy of intravenous quinine, which is the mainstay for treating severe malaria in children, is decreasing. Artemisinin derivatives are the potential replacement for quinine. Their efficacy compared to quinine in treating severe malaria in children is not well known. Objective To assess the efficacy of parenteral artemisinin derivatives versus parenteral quinine in treating severe malaria in children. Search strategy The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2005), MEDLINE (1966 to October 2005), EMBASE (1980 to October 2005), and LILACS (1982 to October 2005) were searched. Malaria researchers and a pharmaceutical company were contacted. In addition, conference proceedings were also searched. Selection criteria Randomised controlled studies comparing parenteral artemisinin derivatives with parenteral quinine in treating severe malaria in children. All trials had to report mortality as an outcome. Data collection After data were extracted, two individuals independently assessed the trial quality. In addition, information on adverse effects from the studies was also collected. Main results Eleven trials were selected (1455 subjects), nine of them from Africa and the rest from Asia. Allocation concealment was adequate in seven trials (1238 subjects). Overall there was no difference in mortality between artemisinin derivatives and quinine (Risk Ratio= 0.89, 95% confidence interval 0.71 to 1.1). There was no difference in mortality between adequately concealed and inadequately concealed /unconcealed trials (Risk Ratio = 0.93, 95% confidence interval 0.74 to 1.16 and Risk Ratio=0.66, 95% confidence interval 0.36 to 1.22). In Parasite Clearance Time (PCT), though there was no statistical difference between the two groups there was a tendency towards favouring the artemisinin derivatives (weighted mean difference among studies which reported PCT as mean was -4.76 with 95% confidence interval -9.68 to 0.17 and all three studies which reported PCT as median showed that artemisinin derivatives cleared parasites faster than quinine, each had p<0.001). However; when only trials with adequate concealment were considered this potential advantage disappeared. In exploring heterogeneity for PCT, it was shown that study settings (Asia versus Africa) might have been a cause for heterogeneity. The artemisinin derivatives resolved coma faster than quinine (weighted mean difference=-5.32, 95%CI: -8.06 to -2.59), but when only trials with adequate concealment were considered this difference disappeared. Other secondary outcomes i.e. Fever clearance time, Incidence of neurological sequelae, and 28th day cure rate showed no significant difference between artemisinin derivatives and quinine. There was no enough data to make meaningful comparison of adverse effects between the two groups. Conclusions The available evidence suggests that parenteral artemisinin derivatives are as efficacious as quinine in preventing mortality from severe malaria in children.

As a first generation of compounds, the nucleosides adenosine 8, cytidine 11, guanosine 9, inosine 116 and uridine 12, as well as the sugar ᴅ-(-)-ribose 100, were transformed into the corresponding 5’-O-(tert-butyldiphenylsilyl)- and 5’-O-(4,4’-dimethoxytrityl)-derivatives. These were subsequently protected as acetyl, benzoyl and allyl derivatives at various positions on the molecules, to give a range of twenty five unique compounds for biological testing. The nucleoside and corresponding ᴅ-(-)-ribose derivatives were evaluated for their antibacterial activity against two Gram-positive (Staphylococcus aureus ATCC 25923 and Bacillus cereus DL5) and two Gram-negative bacteria (Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922), for their anti-HIV activity against strain HLTVIIIB as well as for their anticancer properties, by evaluating inhibition of cell proliferation in two adherent (HT-29 and Caco-2) and three suspension (HL-60, Jurkat and K-562) cell lines. From these screens, and based on the 2,3,5-triphenyltetrazolium chloride (TTC) assay, it was found that 5’-O-(tert-butyldiphenylsilyl)uridine 107, 5’-O-(tert-butyldiphenylsilyl)-1'-O-methoxy-ᴅ-(-)-ribose 102 and tert-butyldiphenylsilyl alcohol 145 exhibited antimicrobial activity towards only the Gram-positive bacteria when compared to the ciprofloxacin 153 control. None of the compounds tested showed any antiviral activity when assayed against HIV; however, all compounds indicated some form of toxicity to the uninfected cells. Subsequent cell proliferation studies indicated pronounced activity against both the adherent and suspension cancer cell lines for 5’-O-(tert-butyldiphenylsilyl)uridine 107, 5’-O-(tert-butyldiphenylsilyl)cytidine 134, tert-butyldiphenylsilyl alcohol 145, 5’-O-(4,4’-dimethoxytrityl)uridine 126 and 4,4’-dimethoxytrityl alcohol 147. Our initial screen indicated that ᴅ-(-)-ribose derivatives do not show any significant general biological activity; whereas (tert-butyldiphenylsilyl)-protected nucleoside derivatives and the corresponding tert-butyldiphenylsilyl alcohol control are intrinsically more bio-active. From the data reported for the anti-bacterial and the cell proliferation studies, we concluded that the nucleoside showing the most promising results was uridine 12 and our mini structure- activity study on the uridine derivatives found that the best position for performing modifications to the nucleoside was at the 5'-OH position on the sugar ring. As such, this would become the initial focus for the synthesis of the second generation compounds. The second generation compounds included a series of ten uridine 12 and five 5-methyluridine 233 derivatives which were protected on the primary alcohol with a range of different silicon-containing protecting groups. At the same time, we used a general procedure to synthesize a series of fourteen silanols for use as control compounds. The uridine 12, 5-methyluridine 233 and corresponding silanol derivatives were screened for their antibacterial activity against the same two Gram-positive and two Gram-negative bacteria as above, as well as for their anticancer properties, by evaluating inhibition of cell proliferation in a series of six adherent cell lines (five human: Hs683, MCF-7, PC-3, SKMEL-28, U373, and one murine: B16F10) cell lines. The data obtained for our TTC assay showed that converting the base in 1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,-2,4]trioxadisilocin-8-yl]-pyrimidine-2,4(1H,-3H)dione 234 to the 5-methyl derivative 254 caused a corresponding loss in antibacterial activity for the compound, whereas oxidising the secondary alcohol on the 2'-position of the sugar ring to give compound 239 caused a corresponding increase in antibacterial activity. As such, we concluded that 1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,-2,4]trioxadisilo-cin-8-yl]pyrimidine-2,4(1H,3H)dione 239 was the compound with the best antibacterial activity out all of the first and second generations of nucleoside derivatives assayed. The results obtained in the TTC assay, were supported by our scanning electron (SEM) and confocal scanning electron (CSLM) microscopy studies. Interestingly, the CSLM study suggests that the synthetic compound 239 is bacteriocidal and is inactivating cells, not simply inhibiting their growth. From the inhibition of cell proliferation assay performed on the fifty combined first and second generation derivatives and their corresponding controls, we found that the six most active compounds (5'-O-(tert-butyldiphenylsilyl)adenosine 142, 5'-O-(tert-butyldiphenyl-silyl)cytidine 134, 5'-O-(tert-butyldiphenylsilyl)uridine 107, 2',3'-O-diacetyl-5'-O-(tert-butyl-diphenylsilyl)uridine 123, 2',3'-O-diacetyl-5'-O-(4,4'-dimethoxytrityl)uridine 127 and 3-benzoyl-1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,-5,2,4]trioxa-disilocin-8-yl]pyrimidine-2,4(1H,3H)-dione 235) had mean IC50 values of approximately 24-28 μM.

Trypanosomiasis and Leishmaniasis are tropical diseases caused by the parasites Trypanosoma and Leishmania, that cause severe medical and economical problems for millions of people in the developing world. Trypanosomiasis can be divided into African and American trypanosomiasis, which are caused by Trypanosoma brucei and Trypanosoma cruzi respectively. There are more than 20 different species of Leishmania worldwide that cause Leishmaniasis, but the most severe infection, visceral leishmaniasis, is caused by Leishmania donovani. Both diseases are transmitted by blood sucking insects like the tsetse fly and the sand fly. The majority of existing drugs for trypanosomiasis and leishmaniasis are either too toxic or have low efficacy, and in some cases parasites have also developed resistance. There is therefore a pressing need to develop new chemotherapeutic agents, and in this context, the enzyme trypanothione reductase (TryR) has emerged as an attractive validated target for drug design. The natural product cadabicine, extracted from the plant Cadaba farinosa, is a diphenyl ether-containing macrocyclic spermidine alkaloid which has been identified as a potential inhibitor of TryR by virtual screening. In order to investigate the potential of cadabicine as a TryR inhibitor, an efficient synthetic route to the natural product was delivered. This work was focused on the preparation and combination of three key synthetic units, namely an orthogonally protected spermidine derivative and two functionalised cinnamic acid units. This approach lead to the formation of the macrocycle by an intramolecular nucleophilic aromatic substitution followed by a convenient conversion to the natural product. In the same manner cyclic and noncyclic analogues of cadabicine were prepared, in order to examine the structure-activity relationship of these alkaloids to TryR.

It was the aim of this investigation to prepare derivatives of 1,4-naphthoquinone substituted at the 2- and 3- positions with various amino groups. 2,3-Dichloro-1,4-naphthoquinone was selected as the starting material because of the possibility of replacing the chloro groups in direct substitution reactions with amines.

At the end of this thesis, the 1H and 13C{ 1H} NMR spectra for all the new compounds and the crystallographic data are given as an Appendix. / Chapter 1 presents an overview of phthalocyanines and subphthalocyanines, including their general synthesis, properties, photosensitizing applications, and supramolecular chemistry. / Chapter 2 describes the synthesis and spectroscopic characterization of a series of subphthalocyanines axially substituted with an oligoethylene glycol chain [SPcB(OCH2CH2)nOH] (n = 3, 4) or a p-phenoxy oligoethylene glycol methyl ether chain [SPcBOC 6H4(OCH2CH2)nOCH3] (n = 2, 3). Their in vitro photodynamic activities toward HT29 human colorectal adenocarcinoma and HepG2 human hepatocarcinoma cells have also been investigated. In general, these compounds are essentially non-aggregated, resulting in a strong fluorescence emission and high efficiency to generate singlet oxygen. Being formulated with Cremophor EL, these subphthalocyanines function as efficient photosensitizers and exhibit a high photocytotoxicity. The phenoxy analogues show a relatively high photostability and are particularly potent toward these cell lines. / Chapter 3 reports the synthesis, spectroscopic characterization, and in vitro photodynamic activities of a new series of water-soluble subphthalocyanines. The photodynamic activities of these compounds against HepG2 and HT29 cells have also been evaluated. They exhibit high singlet oxygen quantum yields, but different degree of photostability, which greatly affects their photocytotoxicity. The relatively high photostability of the carboxy subphthalocyanine and its salts renders them highly photocytotoxic. / Chapter 4 describes the axial coordination of two subphthalocyanines having an axial pyridyl group with several tetrapyrrole derivatives, including zinc(II) and ruthenium(II) porphyrins and phthalocyanines. By using various spectroscopic methods and X-ray diffraction analyses, the formation of 1:1 hetero-dyads has been confirmed. The binding constants between the pyridyl subphthalocyanines and these metallotetrapyrrole derivatives have also been determined by a fluorescence titration method. / Chapter 5 presents the synthesis and spectroscopic characterization of a covalently linked subphthalocyanine-cyclodextrin conjugate. The host-guest interactions between this compound and a tetra-sulfonated porphyrin in aqueous medium have been investigated by various spectroscopic methods. This supramolecular system exhibits an efficient photo-induced energy transfer process from the excited subphthalocyanine core to the porphyrin moiety. This host-guest approach provides a new strategy to construct mixed subphthalocyanine and porphyrin systems, which have not been explored so far. / Chapter 6 reports the use of a series of zinc(II) and silicon(IV) phthalocyanines as photocatalysts for the photooxidation of olefins and 1-naphthol. These compounds are efficient photosensitizers producing singlet oxygen to form the oxidized products in high yields. The only exceptions are two dendritic silicon(IV) phthalocyanines which have a relatively low efficiency to generate singlet oxygen. Three photosensitizers have also been examined for their recyclability in the photooxidation of alpha-terpinene and furan-2-carboxylic acid. All of them can be recycled at least four times without a significant loss of catalytic activity. / This thesis reports our investigation of two versatile classes of functional dyes, namely phthalocyanines and subphthalocyanines, focusing on their photosensitizing applications and supramolecular chemistry. / Xu, Hu. / Adviser: Dennis K. P. Ng. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3506. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

*Please refer to dissertation for diagrams. / In Chapter 2, the development of organocatalysis is briefly summarized. Also the development of asymmetric Morita-Baylis-Hillman (MBH) reaction and asymmetric Diels-Alder (DA) reaction and their strategies are presented. Some representative examples are delineated with in-depth discussion. / In Chapter 3, the idea of the design of organocatalysts from tetraphenylenes is illustrated. The syntheses of enantiopure (S,S)- and ( R,R)-1,8,9,16-tetrahydroxytetraphenylene (1) and racemic 1,4,5,8,9,16-hexahydroxytetraphenylene (2) are described. The functionalization of compounds 1 and 2 and the attempt to synthesize amino acid from compound 1 are discussed. The syntheses of racemic and chiral amine derivatives from compound 1 and their applications on the catalysis of MBH reaction and asymmetric DA reaction are presented and discussed. / In Chapter 4, the application of marcocyclic compounds on enantiomeric recognition is briefly reviewed. The strategies and syntheses of the two enantiomeric tetrameric form of 1,8,9,16-tetraalkoxytetraphenylene, which is a potential chiral recognition reagent, are discussed. / In Chapter 5, the background information of the chemistry of liquid crystals is briefly reviewed, and the syntheses of different alkoxy-derivatives from compound 1 are presented. Among these derivatives, three of them were found to have liquid crystal properties. The details on the characterization of their liquid crystal properties are discussed. / In Chapter 6, a short summary and conclusion of the results in the previous chapters are given. / In Chapter 7, experimental details are summarized.* / Tetraphenylenes are structurally exceptional molecules featuring a rigid conformation. As such, substituents of these compounds would demonstrate highly directional disposition. As a result, these molecules, in their optically pure forms, are potential candidates as organocatalysts in asymmetric synthesis. In this thesis, some essential background information and previous works about the development of the tetraphenylenes are first presented in Chapter 1. / The second part is about the potential applications of tetraalkoxytetraphenylene derivatives. / The thesis is divided into two parts. The first part is about the applications of amino-substituted tetraphenylene derivatives as organocatalysts. / pt. 1. Amino-substituted tetraphenylene derivatives as organocatalysts -- pt. 2. Potential applications of tetraalkoxytetraphenylenes. / Hau, Chun Kit. / Adviser: H. N. C. Wong. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 260-282). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Chi-Keung Lam. / "August 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 202-210). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.