Plant-derived natural products continue to be a valuable source of useful therapies for cancer as well as other diseases. As part of a continuing mission to obtain anticancer agents from natural sources, researchers at the National Cancer Institute (NCI) established the 60 human tumor cell line anticancer screen. The schweinfurthins are one family of unique natural products discovered through this screening process. Most of these natural compounds exhibit potent and differential activity in the 60-cell screen. Importantly, the pattern of activity displayed by the schweinfurthins shows no correlation to any clinically used anticancer drug, indicating that this family of natural products probably acts via a novel mechanism or at a novel target. Our group has conducted extensive structure-activity relationship studies in an effort to illuminate the mechanism of action of the schweinfurthins. In this thesis, the preparation and biological activity of a number of new schweinfurthin F analogues possessing variations in the D-ring alkyl chain and stilbene moiety will be discussed. These studies have clarified the importance of the D-ring to the schweinfurthins' pharmacophore. Based on the results obtained from the exploration of the structural requirements of these natural products, it was determi-ned that the right-half of the schweinfurthins would be an appropriate site for attachment of a molecular probe to be used in affinity experiments. The synthesis of these biotinylated probes will be examined in detail, and their use in pull-down assays will be summarized. The preparation of key schweinfurthin intermediates has involved the extensive use of Lewis acid-mediated cationic cascade cyclizations terminated by MOM-protected phenols. Those successes have inspired investigations of additional applications of these cyclizations. In particular, a variant of these cyclizations using "MOM-protected" enol ethers as reasonable substitutes for β-keto ester terminating moieties has been studied. These interrelated studies involving the synthesis of schweinfurthin analogues and the exploration of cascade cyclizations will be discussed in detail.

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Part¢¹¡GStudies of Electroorganic Reactions toward the Syntheses of Isoquinoline Alkaloids, and its possible mechanism. Part ¢º: Application of Radical Cyclization Reactions toward the Syntheses of Alkaloids, and other derivatives.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18097号 / 理博第3975号 / 新制||理||1573(附属図書館) / 30955 / 京都大学大学院理学研究科化学専攻 / (主査)准教授 依光 英樹, 教授 丸岡 啓二, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Lyconadin A is a pentacyclic Lycopodium alkaloid isolated from the club moss Lycopodium complanatum with antitumor properties. We have developed a novel 7-exo/6-exo acyl radical cascade cyclization as a method of making the bicyclo[5.4.0]undecane ring system of lyconadin A. The model products are trans-fused ring systems, while a cis-fused ring system is needed in lyconadin A. We have discovered a method to convert the trans-fused model cascade cyclization product into the desired cis isomer. Based on Donohoe's pyridone synthesis, we developed a method for the construction of 5-alkyl and 3,5-dialkyl-6-carbomethoxy-2-pyridones, the former of which is a subunit of lyconadin A. An intramolecular Reformatsky reaction is a key step in this process. We have proceeded with our total synthesis, in which we generated an epoxide by Shi asymmetric epoxidation and regioselectively opened epoxide rings. We have prepared carboxylic acid 197.

<p> Aryl radical ring closures onto the azo functional group were investigated. A series of ortho-substituted aryl radicals (83a-f) have been generated by bromine abstraction from the corresponding 1-(orthobromophenyl)-1-methoxy-azoethanes (82a-f) by tributyltin radicals. The radicals generated underwent cyclization in the 5-endo sense, to ultimately afford the substituted indazoles (86a-f). There was also some evidence for cyclization to the other azo nitrogen (closure in the 4-exo sense) to form a 4-membered ring. The aryl radical also underwent hydrogen atom abstraction from tributyltin hydride in competition with cyclization. Since the rate constant for hydrogen atom abstraction from tributyltin hydride by aryl radicals is known, this makes it possible to estimate the rate constants for cyclization throughout the series.</p> / Thesis / Master of Science (MSc)

<p> The reaction of lead tetra-acetate with ketone carbohydrazones and 4-substituted semicarbazones gave a series of 2-(substituted imino)-△^3-1,3,4-oxadiazolines. Spectroscopic and chemical evidence is presented to establish the proposed structure, and the scope of the reaction is described. The thermolysis of the 5,5-diaryl-2-phenylimino-△^3-1,3,4-oxadiazolines was studied in chlorobenzene solution. The results of kinetic experiments (gas evolution and infra-red) are reported, and the mechanism of the decomposition is discussed. A survey of the literature pertaining to related lead tetra-acetate oxidations, and to decomposition of cyclic azo compounds is presented.</p> / Thesis / Doctor of Philosophy (PhD)

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No description available.

The first part of this work describes the synthesis of a new histone deacetylase (HDAC) inhibitor (HDI). HDAC enzymes modify core histones, influence nucleosome structure and change gene transcription by removing the acetyl groups from lysine residues on proteins. HDIs are showing exciting potential as a new class of drugs for cancer and a variety of other diseases. A new HDAC inhibitor based on the hydroxamic acid motif has been synthesized. Two characteristic structural features were incorporated into the design of the novel inhibitor. A cyclic peptide mimetic of known structure was fused to a hydroxamic acid moiety through an aliphatic chain. The HDAC inhibitor provided significant inhibitory activity against HDACs with an IC50 value of 46 ± 15 nM, and against HDAC8 with an IC50 value of 208 ± 20 nM. The potent HDAC inhibitory activity of the HDAC inhibitor demonstrates the importance of the rim recognition region in the design of HDIs. The hydrophobic cyclic turn mimic allows the formation of a tight complex between HDI and HDAC enzymes. The second part of this work is to synthesize secondary structure mimics and incorporate them into the helix-turn-helix (HTH) motif. One of the important methods to study the conformation of the biologically active peptides is to incorporate the rigid peptidomimetics into the relevant peptides. Important information can be obtained from the study of conformationally constrained peptides. HTH proteins are well characterized and found in many organisms from prokaryotes to eukaryotes. The relatively small size, simple structure, and significance in stabilizing tertiary structures make the HTH peptide an attractive target to mimic. Both a Gly HTH turn mimic and a Ser HTH turn mimic were synthesized using stereoselective hydrogenation and macrocyclization starting from unnatural amino acids in a yield of 33% and 14%, respectively. The synthesis of Fmoc protected HTH turn mimics allowed incorporation into HTH peptides using Fmoc chemistry on solid phase. The incorporation of the HTH turn mimics into the peptides proved to be challenging, either by sequential elongation or by segment condensation. Alternative peptide synthesis strategies were employed in attempts to solve the problems. / Ph. D.