| Summary: | 碩士 === 東海大學 === 化學系 === 88 === Abstract
I. Inhibition and Mechanistic Studies of 4-Hydroxyphenylpyruvate Dioxygenase
4-Hydroxyphenylpyruvate dioxygenase (4-HPPD) catalyzes the reaction of 4-hydroxyphenylpyruvate with molecular oxygen to homogentisate and carbon dioxide. In our continuous efforts to elucidate this intriguing enzyme catalyzed reaction, we have designed and chemically synthesized compound 21 as the substrate analogue. After incubation with enzyme 4-HPPD, compound 21 was found to be neither a substrate nor an inhibitor for 4-HPPD. Compound 23 and 24 were also prepared since they both possess the similar structure to the proposed arene oxide intermediate for this 4-HPPD catalyzed reaction. The inhibition results indicated that neither of them were potent 4-HPPD inhibitors, which suggested that 4-HPPD has higher steric demand for the substrate. Furthermore, the inhibition study of compounds 25~28 and 42~43 implied that keto-enol tautomerization of the triketone type inhibitors plays an important role in 4-HPPD inhibition.
II. Synthesis of the Potential Vitamin K-dependent γ-Glutamate Carboxylase Inhibitors
Vitamin K is an obligatory cofactor in the blood coagulation cascade. Vitamin K in its reduced hydroquinone form, vitamin KH2, effects carboxylation of the N-terminal glutamates leading toγ-carboxy-glutamate which allow chelation of calcium leading to blood coagulation. In an effort to develop a new type of anticoagugants, we have designed and synthesized compound 19 as a potential carboxylase inhibitor. Preparation of this compound was commenced with the reduction of 1,4-naphthoquinone to give the hydroquinone 32. After BF3Et2O-catalyzed alkylation and Ag2O-mediated oxidation, the compound 34 was further reacted with pyridinium salt in basic condition to give 35. The compound 35 was then reduced by LiAlH4 to afford the final target 19. Furthermore, compound 20 was designed and prepared in an effect to provide a new mechanistic evidence for this carboxylase catalyzed reaction. The first step of the synthesis involved the methylation of 1-naphthol by methyl iodide to give 37. Reaction of compound 37 with DMF in the presence of POCl3 afforded aldehyde 38. Compound 38 was then reacted with N-acetylglycine in acetic anhydride to furnish compound 39. The final ring opening of the azalactone 39 and acid-catalyzed hydrolysis of 40 in aqueous HCl solution gave the target 20.
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