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首页> 外文学位 >Synthesis of side chain-modified iodothyronines. Synthesis and structure-activity relationships (SARS) of galanthamine derivatives. Total synthesis of (+)-valyldetoxinine. Synthesis and mechanism of cyclic acetal and ketal formation in pentono-1,4-lactones.
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Synthesis of side chain-modified iodothyronines. Synthesis and structure-activity relationships (SARS) of galanthamine derivatives. Total synthesis of (+)-valyldetoxinine. Synthesis and mechanism of cyclic acetal and ketal formation in pentono-1,4-lactones.

机译：侧链修饰的碘甲状腺素的合成。加兰他敏衍生物的合成及其构效关系（SARS）。 （+）-Valyldetoxinine的全合成。戊通-1,4-内酯中环状缩醛和缩酮的合成及其机理。

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摘要

New side chain-modified iodothyronines have been synthesized. They include: 1- (4-(4-hydroxyphenoxy)-3,5-diiodo-phenyl) -1,2-ethanediol(T{dollar}sb2 {dollar}EG); {dollar}alpha{dollar}-hydroxy-4-(4-hydroxyphenoxy)-3,5-diiodobenzeneacetic acid (T{dollar}sb2{dollar}HAA) and their 4-methylether derivatives (MT{dollar}sb2{dollar}EG, MT{dollar}sb2{dollar}HAA); 1- (4-(hydroxyphenoxy)-3,5-diiodo-phenyl) -2-aminoethanol (T{dollar}sb2{dollar}EA); 1- (4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl) -1,2-ethanediol (T{dollar}sb3{dollar}EG); 1- (4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl) -2-aminoethanol (T{dollar}sb3{dollar}EA); and {dollar}alpha{dollar}-hydroxy-4-(3-iodo-4-hydroxyphenoxy)-3,5-diiodobenzeneacetic acid (T{dollar}sb3{dollar}HAA).; The synthesis and structure-activity relationships (SARs) of galanthamine derivatives are examined. Structural studies of the alkaloid galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and its salt, galanthamine methiodide, were carried out both in solution and in the solid state, using spectroscopic methods. Structural and pharmacological studies of nineteen analogs of galanthamine were conducted. Systematic derivatization of galanthamine at the cyclohexene ring, tertiary amino, hydroxyl and methoxyl functions indicated that these structural features are essential for biological activity. One derivative, galanthamine n-butyl carbamate, had an LD{dollar}sb{lcub}50{rcub}{dollar} of over 100 mg/kg (i.p.) in mice. In a passive avoidance paradigm, this analog improved performance in a dose-dependent fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice. With the surprisingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's disease.; The total synthesis is described of (+)-valyldetoxinine, a member of the detoxin complex, metabolites produced by Streptomyces caespitosus var. detoxicus 7072 GC{dollar}sb1.{dollar} The detoxin complex is a selective antagonist of the antibiotic blasticidin S. The total syntheses of (+)-valyldetoxinine and (2R,3S,4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine hydrochloride, a very potent competitive inhibitor of an {dollar}alpha{dollar}-galactosidase and a moderate inhibitor of an {dollar}alpha{dollar}-mannosidase, were both completed. (Abstract shortened with permission of author.)
机译：已经合成了新的侧链修饰的碘甲状腺素。它们包括：1-（4-（4-羟基苯氧基）-3,5-二碘-苯基）-1,2-乙二醇（T {dollar} sb2 {dollar} EG）； {美元}α{美元}-羟基-4-（4-羟基苯氧基）-3,5-二碘苯乙酸（T {dollar} sb2 {dollar} HAA）及其4-甲基醚衍生物（MT {dollar} sb2 {dollar} EG，MT {dollar} sb2 {dollar} HAA）； 1-（4-（羟基苯氧基）-3,5-二碘-苯基）-2-氨基乙醇（T {dollar} sb2 {dollar} EA）; 1-（4-（4-羟基-3-碘苯氧基）-3,5-二碘苯基）-1,2-乙二醇（T {dollar} sb3 {dollar} EG）; 1-（4-（4-羟基-3-碘苯氧基）-3,5-二碘苯基）-2-氨基乙醇（T {dollar} sb3 {dollar} EA）;和{美元}α{美元}-羟基-4-（3-碘-4-羟基苯氧基）-3，5-二碘苯乙酸（T {dollar} sb3 {dollar} HAA）。检查了加兰他敏衍生物的合成和构效关系（SAR）。使用光谱方法，在溶液和固态下都对生物碱加兰他敏（一种皮质乙酰胆碱酯酶（AChE）抑制剂）及其盐加兰他敏甲硫脲进行了结构研究。进行了十九种加兰他敏类似物的结构和药理研究。加兰他敏在环己烯环，叔氨基，羟基和甲氧基官能团上的系统衍生表明，这些结构特征对于生物学活性至关重要。一种衍生物，氨基甲酸加兰他敏氨基甲酸正丁酯，在小鼠中的LD {dollar} sb {lcub} 50 {rcub} {dollar}超过100 mg / kg（i.p.）。在被动回避范例中，该类似物以剂量依赖的方式改善了性能，在对照组中为0.1 mg / kg，在基础前脑病变小鼠中为0.5 mg / kg的峰值效应。以令人惊讶的高治疗率，该化合物可用于治疗中枢神经系统的胆碱能缺陷，例如阿尔茨海默氏病。总的合成描述了（+）-缬氨酰去毒素，它是一种由Caespitosus var链霉菌产生的代谢产物。 detoxicus 7072 GC {dollar} sb1。{dollar}排毒复合物是抗生素杀稻瘟素S的选择性拮抗剂。（+）-戊基排毒素和（2R，3S，4R）-2-羟甲基-3,4-的总合成都完成了二羟基吡咯烷盐酸盐盐酸盐，这是一种非常有效的{美元}α{美元}-半乳糖苷酶的竞争性抑制剂和一个适度的{美元}α{美元}-甘露糖苷酶的抑制剂。 （摘要经作者许可缩短。）

著录项

  • 作者

    Han, So-Yeop.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Chemistry Organic.; Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 1992
  • 页码 789 p.
  • 总页数 789
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 有机化学;药物化学;
  • 关键词

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