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by William, Wai-lun Lam. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1993. / Includes bibliographical references (leaves 85-95). / Chapter I. --- Introduction --- p.1 / Chapter II. --- Our Approach --- p.9 / Chapter III. --- Results and Discussion - Synthetic Strategy --- p.29 / Chapter IV. --- Results and Discussion - Pharmacological Activity --- p.44 / Chapter V. --- Conclusion --- p.49 / Chapter VI. --- Further Development --- p.53 / Chapter VII. --- Experimental Section --- p.55 / Chapter VIII. --- References --- p.85 / Chapter IX. --- Supplementary Materials --- p.96

by Li Tin Yau. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 56-60). / Acknowledgment --- p.i / Table of Contents --- p.ii / Abstract --- p.iii / Abbreviation --- p.iv / Chapter I --- Introduction --- p.1 / Chapter I-1 --- General Background --- p.1 / Chapter I-2 --- Mechanistic Aspect of Glycosidase Inhibition --- p.4 / Chapter I-3 --- Previous Syntheses of Valienamine and its Diastereomers --- p.7 / Chapter II --- Results and Discussion --- p.16 / Chapter II-1 --- General Strategy --- p.16 / Chapter II-2 --- Synthesis of Tribenzyl ether69 --- p.18 / Chapter II-3 --- Synthesis of Diol67 --- p.20 / Chapter II-4 --- "Synthesis of N,O,O, O, O-Pentaacetylvalienamine30 and its 2-Epimer62" --- p.22 / Chapter II-5 --- Synthesis of Diacetate66 --- p.26 / Chapter II-6 --- Synthesis of the Valienamine Derivatives 63 and64 --- p.30 / Chapter III --- Conclusion --- p.34 / Chapter IV --- Experimental --- p.36 / Chapter V --- Reference --- p.56

8-Cyclopentyl-3-(3-(4-fluorosulfonylbenzoyl)oxy)propyl-propylxanthine (44, FSCPX) has been reported to exhibit potent and selective irreversible antagonism of the A1 adenosine receptor when using in vitro biological preparations. However, FSCPX (44) suffers from cleavage of the ester linkage separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine pharmacophore when used in in vivo biological preparations or preparations containing significant enzyme activity, presumably by esterases. Cleavage of the ester linkage renders FSCPX (44) inactive in terms of irreversible receptor binding. In order to obtain an irreversible A1 adenosine receptor antagonist with improved stability, and to further elucidate the effects of linker structure on pharmacological characteristics, several FSCPX (44) analogues incorporating the chemoreactive 4-(fluorosulfonyl)phenyl moiety were targeted, where the labile ester linkage has been replaced by more stable functionalites. In particular, ether, alkyl, amide and ketone linkers were targeted, where the length of the alkyl chain was varied from between one to five atoms. Synthesis of the target compounds was achieved via direct attachment of the N-3 substituent to the xanthine. These compounds were then tested for their biological activity at the A1 adenosine receptor via their ability to irreversibly antagonise the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX, ( 9) to the A1 adenosine receptor of DDT1 MF-2 cells. For comparison, the xanthines were also tested for their ability to inhibit the binding of [3H]-4-(2-[7-amino-2-{furyl} {1,2,4}- triazolo{2,3-a} {1,3,5}triazin-5-ylamino-ethyl)]phenol ([3H]ZM241385, 36) to the A2A adenosine receptor of PC-12 cells. The results suggest that the length and chemical composition of the linker separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine ring contribute to the potency and efficacy of the irreversible A1 adenosine receptor ligands. Like FSCPX (44, IC50 A1 = 11.8 nM), all derivatives possessed IC50 values in the low nM range under in vitro conditions. Compounds 94 (IC50 A1 = 165 nM), 95 (IC50 A1 = 112 nM) and 96 (IC50 A1 = 101 nM) possessing one, three and five methylene spacers within the linkage respectively, exhibited potent and selective binding to the A1 adenosine receptor versus the A2A adenosine receptor. Compound 94 did not exhibit any irreversible binding at A1 adenosine receptors, while 95 and 96 exhibit only weak irreversible binding at A1 adenosine receptors. Those compounds containing a benzylic carbonyl separating the 4-(fluorosulfonyl)phenyl moiety from the xanthine ring in the form of an amide (119, IC50 A1 = 24.9 nM, and 120, IC50 A1 = 21 nM) or ketone (151, IC50 A1 = 14 nM) proved to be the most potent, with compound 120 exhibiting the highest selectivity of 132-fold for the A receptor over the A2A receptor. compounds 119, 120 and 151 also strongly inhibited the binding of [3H]DPCPX irreversibly (82%, 83% and 78% loss of [3H]DPCPX binding at 100 nM respectively). compounds 120 and 151 are currently being evaluated for use in in vivo studies. Structure-activity studies suggest that altering the 8-cycloalkyl group of A1 selective xanthines for a 3-substituted or 2,3-disubstituted styryl, combined with N-7 methyl substitution will produce a compound with high affinity and selectivity for the A2A adenosine receptor over the A1 adenosine receptor. Compound 167 (IC50 A2A = 264 nM) possessing 8-(m-chloro)styryl substitution and the reactive 4-(fluorosulfonyl)phenyl moiety separated from the xanthine ring via an amide linker in the 3-position (as for 119 and 120), exhibited relatively potent binding to the A2A adenosine receptor of PC-12 cells, with a 16-fold selectivity for that receptor over the A1 adenosine receptor. However, compound 167 exhibited only very weak irreversible binding at A2A adenosine receptors. Overall, at this stage of biological testing, compound 120 appears to possess the most advantageous characteristics as an irreversible antagonist for the A1 adenosine receptor. This can be attributed to its high selectivity for the A1 adenosine receptor as compared to the A2A adenosine receptor. It also has relatively high potency for the A1 adenosine receptor, a concentration-dependent and selective inactivation of A1 adenosine receptors, and unbound ligand is easily removed (washed out) from biological membranes. These characteristics mean compound 151 has the potential to be a useful tool for the further study of the structure and function of the A1 adenosine receptor.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Pharmacology and Toxicology. Title from title-page of electronic thesis. Bibliography: leaves 266-287.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 84-100).

Thesis--M.D., University of Hong Kong, 1982.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Folate derivatives are required for nucleotide/DNA synthesis and DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylenctetrahydrofolate to 5-methyltetrahydrofolate, the folate derivative required for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine. Approximately 45%--50% of the general population is heterozygous for a common substitution (677C &rarr; T, A to V) in MTHFR. Due to loss of heterozygosity (LOH) in cancer cells, individuals who are heterozygous for MTHFR in their constitutional DNA may contain only one of the above alleles in their tumor DNA. / Loss of heterozygosity of MTHFR was observed in 40% of ovarian carcinoma tumor samples and in 16% of colon carcinoma samples suggesting that the chromosomal location to which the MTHFR gene maps (1p36.3) undergoes frequent LOH. Examination of cell viability of human fibroblasts and of human colon carcinoma cell lines in minimum essential media (MEM) lacking methionine found both cell types to be extremely sensitive to the methionine deficiency. Replacing methionine with homocysteine and vitamin B12 restored the growth of normal fibroblast lines to levels that approached those of replete MEM, but the transformed lines increased proliferation only slightly under these conditions. These results support earlier reports regarding the increased methionine dependence of transformed lines. Targeting specific MTHFR variants with the antisense oligonucleotide resulted in &sim;50% decreased survival of two carcinoma cell lines (V/V genotype), possibly due to MTHFR's involvement in methionine synthesis. Allele-specific targeting of MTHFR could therefore provide an effective approach for cancer therapy. Furthermore, cancer patients with the V/V genotype may require less aggressive anti-folate chemotherapy since V/V carcinoma lines were highly sensitive to drug treatment (IC50 < 25 nM) whereas the A/A lines were more variable in response.