by Tse Chung Ming. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1987. / Bibliography: leaves [148]-[173].

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Thesis (M.Sc.)--York University, 2004. Graduate Programme in Biology. / Typescript. Includes bibliographical references (leaves 46-56). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url%5Fver=Z39.88-2004&res%5Fdat=xri:pqdiss&rft%5Fval%5Ffmt=info:ofi/fmt:kev:mtx:dissertation&rft%5Fdat=xri:pqdiss:MQ99354

Two pyrrolo[2,3-d]pyrimidines and a nucleoside analogue have been prepared. The nucleobases were obtained by spontaneous cyclisation of 4-aminopyrimidyl-acetaldehydes as an acetal. The adenosine analogue has been made by glycosylation of a suitable sugar derivative with the corresponding heterocyclic base. This nucleoside can be converted into fluorescently-labeled chain-terminating substrates for DNA polymerase after subsequent triphosphorylation and coupling to through-bond energy transfer systems. Fluorescein-based donor components to be incorporated into through-bond energy transfer systems have been prepared. The synthesis of 5-ethynylfluorescein-(5-tert-butoxycarbonyl)-pentyl ester has been executed in five steps from 1,3-dihydroxybenzene and phthalic anhydride. The donor fluorescein carboxylate has been alkylated with the tert-butyl ester of 6-bromohexanoic acid to provide a handle for attachment to biomolecules. In the context of regioisomerically pure halofluoresceins, besides the synthesis of pure regioisomers of bromofluorescein derivatives, 5-iodosulfofluorescein and pure regioisomers of 5-nitrofluorescein diacetate, as an intermediate in the synthesis of 5-iodofluoresceins, have been synthesized. New rhodamine-based acceptor components with extended aromatic systems have been prepared from an affordable starting material, tetralin. The attempts to isolate them via repeated recrystallizations and flash chromatography have been unsuccessful. However, these pyrylium cations are expected to fluoresce at longer wavelengths.

Two pyrrolo[2,3-d]pyrimidines and a nucleoside analogue have been prepared. The nucleobases were obtained by spontaneous cyclisation of 4-aminopyrimidyl-acetaldehydes as an acetal. The adenosine analogue has been made by glycosylation of a suitable sugar derivative with the corresponding heterocyclic base. This nucleoside can be converted into fluorescently-labeled chain-terminating substrates for DNA polymerase after subsequent triphosphorylation and coupling to through-bond energy transfer systems. Fluorescein-based donor components to be incorporated into through-bond energy transfer systems have been prepared. The synthesis of 5-ethynylfluorescein-(5-tert-butoxycarbonyl)-pentyl ester has been executed in five steps from 1,3-dihydroxybenzene and phthalic anhydride. The donor fluorescein carboxylate has been alkylated with the tert-butyl ester of 6-bromohexanoic acid to provide a handle for attachment to biomolecules. In the context of regioisomerically pure halofluoresceins, besides the synthesis of pure regioisomers of bromofluorescein derivatives, 5-iodosulfofluorescein and pure regioisomers of 5-nitrofluorescein diacetate, as an intermediate in the synthesis of 5-iodofluoresceins, have been synthesized. New rhodamine-based acceptor components with extended aromatic systems have been prepared from an affordable starting material, tetralin. The attempts to isolate them via repeated recrystallizations and flash chromatography have been unsuccessful. However, these pyrylium cations are expected to fluoresce at longer wavelengths.

Thesis (M.Sc.)--York University, 2006. Graduate Programme in Biology. / Typescript. Includes bibliographical references (leaves 62-69). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR29595

Thesis (M.Sc.)--York University, 2008. Graduate Programme in Biology. / Typescript. Includes bibliographical references (leaves 66-86). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR38812

Nucleosides possess many physiological and pharmacological properties. Among nucleosides, adenosine is a particularly important as it regulates many physiological functions in cardiovascular system. For instance, adenosine possesses anti-inflammatory effect through its action on endothelial cells. The functions of adenosine are indirectly controlled by the human equilibrative nucleoside transporters (hENTs). These transporters mediate the uptake of adenosine, thereby reducing the amount of extracellular adenosine available for the adenosine receptors and hence reducing its vascular protective effects. Nucleoside analogs such as gemcitabine, are commonly used as anti-cancer drugs in chemotherapy. Most of the anti-cancer nucleoside drugs require human concentrative nucleoside transporters (hCNTs) for their transport into cancer cells. On the other hand, hENTs is supposed to be responsible for the efflux of anti-cancer nucleoside drugs out of the cancer cells. In theory, hENT inhibitors should reduce the removal of adenosine from extracellular compartment by endothelial cells and hence increase and prolong the cardioprotective effect of adenosine. hENT inhibitors should also inhibit the efflux of anti-cancer nucleoside drugs, that in turn increases the drug accumulation in the cancer cells, resulting in a higher efficacy. Some typical and clinically used hENT inhibitors have side effects which limit their uses. Emodin, an active ingredient in many herbs, has been proven to have cardioprotective and anti-tumor properties. However, the mechanisms are not fully understood. We hypothesized that these properties may relate to its interaction with nucleoside transporters. The aims of this study were to investigate the pharmacological effects of emodin on hENTs and its implications on vascular functions and anti-cancer therapy. Our result showed that emodin inhibited both hENT-1 and hENT-2 dose-dependently with no priority to any subtypes of hENTs. The inhibitory effect of emodin on hENTs was reversible and non-competitive, indicating that emodin may interact with the allosteric sites on hENTs. 1,8-dihdroxy-3-methyl anthraquinone, which is similar to emodin in terms of chemical structure but it lacks hydroxyl group at position 3,did not inhibit hENTs. It implied that the presence of 3-hydroxyl group was critical for the inhibitory effect of emodin. Our result also demonstrated that emodin reduced the lipopolysaccharide-induced expression of adhesion molecule in human umbilical vein endothelial cells, reflecting its anti-inflammatory effect. Emodin also enhanced the cytotoxic effect of gemcitabine in HepG2, a liver cancer cell line. Nevertheless, these effects may not be due to the inhibitory effect of emodin on hENTs and further investigation is required. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

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