新肉球菌素类似物的合成及手性叔醇的旋光研究
其他题名Synthesis of Neoengleromycin Analogues and Study of Chiral Tertiary Alcohol Optical Rotation
廖头根
学位类型博士
导师朱华结
2008-05-29
学位授予单位中国科学院昆明植物研究所
学位授予地点昆明植物研究所
学位专业植物学
关键词新肉球菌素 异羟肟酸 抗肿瘤 旋光计算 矩阵模型 叔醇
摘要本论文主要围绕以天然产物新肉球菌素(Neoengleromycin)为模板,合成了其类似物并进行了体外抗肿瘤活性的筛选工作。设计并合成了光学纯手性叔醇分子,运用量子力学和自创矩阵模型的方法进行了旋光计算,参考该分子的实验值对计算方法进行了评价。 第一部分、主要综述了异羟肟酸的物理及化学性质,天然异羟肟酸的主要来源,综述了异羟肟酸类化合物的主要合成方法,异羟肟酸的生物活性和其作为氧化催化剂、金属离子的高效萃取剂的应用。 第二部分、以L-天冬氨酸为基本骨架,通过对末端羧基,α-氨基和N-OR酰胺基进行结构修饰,设计合成了178个新肉球菌素类似物异羟肟酸类化合物,其中116个苄基酯类异羟肟酸化合物,62个异羟肟酸类化合物。部分化合物经过了体外抗肿瘤活性筛选,结果表明:化合物213aj有很强的抗人早幼粒细胞白血病细胞株(HL60)的活性(<10 ng/mL, DDP IC50=50 ng/mL),此外,化合物216ac和化合物216ai有和DDP在同一个数量级的抗人淋巴瘤细胞株(Raji)的活性。发现了一种在温和条件下将酰胺官能团转化到氰基官能团的方法,在CDMT/NMM存在下,可以将L-天冬酰胺末端酰胺转化成氰基。第三部分、介绍了导师自创矩阵模型的假设、推导和讨论。通过量子力学和导师自创矩阵模型的方法,完成了对4个手性叔醇的旋光计算工作,并完成了其中2个化合物的绝对构型的测定工作。运用Gaussian 03计算软件,在多个计算层次计算了手性叔醇的旋光值。合成了(S)-3-苯基3-己醇,通过X-Ray研究证实了(S)-3-苯基3-己醇的绝对构型。同时完成了(R)-3-(2-甲基-苯基)3-己醇的旋光计算、合成和拆分工作,通过了X-Ray研究证实了该化合物的绝对构型。部分完成了其它2个化合物的合成和手性拆分的尝试工作。
其他摘要Neoengleromycin analogues were synthesized as well as its anti-tumor bioactivities were studied. Optically Pure tert-alcohol were design and synthesized, experimental results confirmed the computational specific rotation predictions by QM model and Matrix model. Chapter 1, An review of hydroxamic acids has been summarized. The chemical & physical characters, advances in synthetic-method, application in metalloenzyme inhibitors and transition metal ion extractor were reviewed respectively. Chapter 2, A library of 178 Neoengleromycin analogues, including 62 hydroxamic acid and 116 hydroxamic acids ester derivatives, was designed and synthesized based on L - aspartic acid skeleton by modification of terminal carboxyl moiety, α-amino moiety and N-OR moiety. Then the bioassay of anti-tumor in vitro were studied, the results indicated that 213aj showed excellent inhibitory activity toward HL-60 tumor cell than DDP, with IC50 in nanomolar range (<10 ng/mL, DDP IC50=50 ng/mL). Both 216ac and 216ai showed potent inhibitory activity against Raji tumor cell in the same range of DDP, too. A facial method of conversion amides to nitriles in mild conditions using CDMT and NMM was disclosed. Chapter 3, Matrix model was introduced to analysis the relationship between chiral molecules and its specific optical rotation, which was constructed by director prof. Zhu in 2007. (S)-3-phenylhexan-3-ol and (R)-3-o-tolylhexan-3-ol were synthesized, and the absolute configurations were identified by X-ray study. The enantiomer separation conditions were investigated. The experimental results of the optical rotation were identical with both of the computational result by QM model and matrix model. The computational and experimental attempts of other 2 tertiary alcohols analogues, which were not completed yet, were also detailed.
页数187
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/302
专题昆明植物所硕博研究生毕业学位论文
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廖头根. 新肉球菌素类似物的合成及手性叔醇的旋光研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所,2008.
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