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摘要组蛋白乙酰转移酶(histone acetykransferase，HAT)和组蛋白去乙酰酶(histone deacetylase，HDAC)通过对组蛋白氮端氨基酸残基进行乙酰化或去乙酰化，调节组蛋白的乙酰化水平，调控基因表达，该过程与癌症的发生具有密切的关系。组蛋白去乙酰酶抑制剂通过增加细胞内组蛋白的乙酰化程度，提高p21等基因的表达水平等途径，抑制肿瘤细胞的增殖，诱导细胞分化和(或)凋亡。
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Largazole是选择性抑制I型HDAC的环肽类天然产物，且对肿瘤细胞和正常细胞具有显著的选择性。本论文基于Largazole和FK228的结构设计了一类新的环肽类HDAC抑制剂所需要的一个片段的合成.主要是一种新的手性辅基的合成及在不对称羟醛缩合反应中的应用.34424
手性化合物在医药和材料科学等领域中被广泛应用，其合成越来越受到重视。
在众多有机小分子催化剂中，恶唑烷酮类手性辅基是不对称合成中使用成功且应用最为广泛的一类手性辅基。然而，以手性噻唑啉为母体的手性辅基，还没有广泛的开发和利用。所以对手性噻唑啉化合物进行结构修饰和改造，开发一类新型手性催化剂具有重要意义。因此，本文首先以 L-苯甘氨酸为基础，围绕Largazole合成中所需要的辅基，通过引入不同的官能团，对其进行修饰与改造，合成了Evans噻唑硫酮类手性辅基。
L-苯甘氨酸经酯化高收率还原成L-苯甘氨醇,在KOH水溶液中与CS2环合生成2-硫酮-4-苯基噻唑,产率81%
2-硫酮-4-苯基噻唑经过酰化得到2-硫酮3-乙酰基-4-苯基噻唑
围绕Largazole合成中所需重要片段利用2-硫酮3-乙酰基-4-苯基噻唑进行不对称羟醛缩合反应得到手性目标片段
毕业论文关键词：Evans辅基；噻唑硫酮；手性合成；不对称羟醛缩合反应
ABSTRACT
Histone acetyltransferases (HAT) and histone deacetylases (HDACs) as the corresponding enzymes regulate the change of histones in two antagonist forms , acetylated or deacetylated. The histone deacetylases inhibitors (HDACIs) are potent inducers of growth arrest , differentiation and apoptosis of tumor cells , and have entered clinical trials for both solid and liquid tumors. However , the molecular basis for their anticancer selectivity remains largely unknown. An improved understanding of the structure and action mechanism of HDAC inhibitors will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment .
Largazole is a natural cyclic peptide which can selectively inhibit Class I histone deacetylase and show remarkable selectivity between transformed and nontransformed cells. In this paper,we Designed and synthesized a new class of synthetic cyclic peptide HDAC inhibitors need a clip. The main is a new synthesis of chiral auxiliary group, and in the asymmetric aldol reaction of applications.
Chiral compounds are widely used in medicine and materials science and other fields, Oxazolidinone, thiophene thione, oxazolidine thione and camphor derivatives, such as chiral auxiliary reagents are widely used in the induction of asymmetric aldol condensation reaction, to obtain good asymmetric induction effect. So chiral compounds thiazoline structural modification and transformation, the development of a novel class of chiral catalysts is important. Therefore, this paper first to L- phenylglycine based around Largazole synthesis cofactor required, by introducing different functional groups, its modification and transformation, thiazole synthesis Evans chiral auxiliary Thiones L- phenylglycine reduced to high yield via esterification L- Phenylglycine alcohol, in aqueous KOH solution and CS2 cyclization to produce 2-thione-4-phenyl-thiazole, 81% yield
2- thione-4-phenyl-thiazol-acylation to give 2-thione 3-acetyl-4-phenyl-thiazole
Around Largazole synthesis required the use of 2- thione important sequences 3-acetyl-4-phenyl-thiazole-asymmetric aldol reaction of chiral target fragment