【作者】 黄睿；

【导师】 熊远珍；

【作者基本信息】 南昌大学 ， 药物化学， 2013， 硕士

【摘要】 慢性髓性白血病（CML）是首个被发现有固定细胞遗传学异常的恶性肿瘤，目前的研究一致认为，Bcr-Abl蛋白异常增高的酪氨酸激酶活性是导致CML发生的主要原因。酪氨酸激酶抑制剂（TPKI）应用于CML治疗的研究日益加深。目前有关多靶点受体酪氨酸激酶抑制剂的研究非常活跃,出现了一些新药,有的已取得了重大突破性进展,为肿瘤治疗开启了希望之门,如，Bcr-Abl激酶的小分子抑制剂伊马替尼。本文对达沙替尼等已上市的小分子蛋白酪氨酸激酶抑制剂结构进行分析，提出以芳基氨基作为药效基团，连接羟脯氨酸作为载体基团，设计并合成了一系列新化合物，表征了结构，并测定了它们的抗k562细胞的活性，发现了三个具有一定活性的先导物，为进一步的研究奠定了基础。本文主要包括以下方面的研究内容：1、磷酸二异丙酯取代的L-羟脯氨酸的合成：用次氯酸钠与磷酸二异丙酯反应，氯取代磷酸酯上的氢，增加磷原子的正电性再与L-羟脯氨酸发生亲核取代反应，用氢氧化钠调PH值，本文采用的是一锅法合成，产率在54%左右。2、杂环类化合物噻唑的合成：用NBS与乙酰乙酸乙酯反应生成溴代乙酰乙酸乙酯，再与硫脲反应生成噻唑。3、酰胺键的合成：将磷酸二异丙酯取代的L-羟脯氨酸与一些用氨基芳环、氨基芳杂环通过酰胺键连起来，用DCC做脱水剂，常温下反应即得终产物。4、通过MTT法对合成的十个目标新化合物进行活性研究，活性研究测定了十个目标化合物在10^-5mol/L、（1/2）×10^-5mol/L、（1/2）²×10^-5mol/L、（1/2）³×10^-5mol/L浓度下对体外K562细胞的杀伤作用。合成了九个新化合物，初步发现了几个具有活性的新化合物，进一步的活性研究正在进行中。更多还原

【Abstract】 Chronic myeloid leukemia （CML） was the first malignant tumors to have fixedcytogenetic abnormalities, the current study agreed that the abnormally high levels ofthe activity of Bcr-Abl protein tyrosine is the main reason leading to CML. Tyrosinekinase inhibitors （TPKI） applied CML therapy research deepened. Currently researchabout multi-target receptor tyrosine kinase inhibitors is very active, there are somenew drugs, and some have made significant breakthrough, opens the door of hope forcancer treatment, such as, Bcr-Abl kinase small molecule inhibitors imatinib. In thispaper, I have been analysised the structure of small molecule protein tyrosine kinaseinhibitor such as dasatinib, in order to put forword arylamino group as apharmacophore, connectioning hydroxyproline as a carrier group, designed andsynthesized a series of new compounds, analysis structural characterization andevaluate their anti-k562cell activity and found three leading compounds with certainactivity for further research foundation. This paper mainly includes the followingaspects of the research:1. The synthesis of phosphoric acid two isopropyl ester substituted L-hydroxyproline: with sodium hypochlorite and phosphoric acid two isopropyl esterreaction, chlorine substitut on hydrogen phosphate, increased electropositivephosphorus atoms and react nucleophilic reactions with L-hydroxyproline, adjustingpH value with sodium hydroxide, this paper adopts the one-pot synthesis, the yield ofaround54%.2. The synthesis of heterocyclic thiazole: the reaction of NBS with ethylacetoacetate into bromo ethyl acetoacetate, and then reacts with thiourea to producethiazole.3. The synthesis of amide bond: phosphoric acid two isopropyl ester substitutedL-hydroxyproline and some amino aromatic, heteroaromatic bond together throughamino amide, with DCC as dehydrating agent, reacting to obtain the final product atnormal atmospheric temperature. 4. We evaluate ten new synthetic compounds activation through the MTTmethod, active research evaluate ten compounds’ killing effect on K562cells in the10^-5mol/L、（1/2）×10^-5mol/L、（1/2）²×10^-5mol/L、（1/2）³×10^-5mol/L vitroconcentration.Nine new compounds were synthesized. Several new compounds was foundwith activity in preliminary research. Further research activities are underway.更多还原