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题名: 嘧啶酮类膦酸二酯酶抑制剂的设计、合成及生物活性评价和2-脱氧-2-氟-2-碳-甲基-D-核糖-γ-内酯类衍生物的合成研究
作者: 公绪栋
答辩日期: 2013-05-28
导师: 阿吉艾克拜尔·艾萨、沈敬山
专业: 有机化学
授予单位: 中国科学院大学
授予地点: 北京
学位: 硕士
关键词: PDE5抑制剂 ; 嘧啶酮类衍生物 ; ED ; HCV ; (2R)-3,5-二-O-苯甲酰-2-脱氧-2-氟-2-碳-甲基-D-核糖-γ-内酯 ; (2R)-3,5-二-O-苄基-2-脱氧-2-氟-2-碳-甲基-D-核糖-γ-内酯
摘要:

本论文的研究工作由两个部分组成:

第一部分:嘧啶酮类5型膦酸二酯酶抑制剂的设计、合成及生物评价

5型膦酸二酯酶(PDE5)抑制剂通过抑制PDE5酶的活性,调控体内cGMP水平,进而介导或调节一系列的相关的生物功能或药理作用。1998年西地那非的上市,将PDE5抑制剂的研究推入热潮。PDE5抑制剂不仅是ED治疗的一线药物,其用于肺动脉高压(PAH)和下尿路症状(BPH/LUTS)的治疗也被FDA批准,且对于其他疾病的治疗也有良好的前景。目前上市的PDE5抑制剂虽然治疗效果显著,但是因选择性不理想或者其他原因会产生副作用,且目前上市药物均为外国公司产品,价格昂贵,因此寻找具有自主知识产权,高活性和安全性的PDE5抑制剂是本课题研究的主要目的。

本文在已报道的构效关系研究基础上,以嘧啶酮类PDE5抑制剂为模板,结合PDE5抑制剂与PDE5酶的三维晶体结构,设计并合成出结构新颖的嘧啶酮类化合物14个,并都进行了PDE5活性测试。其中化合物52b52d52e52j的体外抑制活性都强于上市药物西地那非,尤其化合物52dIC50=0.12 nM),其抑制活性为西地那非的32.5倍。本文还通过对47cb47lbPDE5A酶共晶解析,解释了该类化合物与PDE5A酶的结合方式及其作用力,为进一步的结构优化提供了理论依据。

第二部分:2-脱氧-2--2--甲基-D-核糖-γ-内酯类衍生物的合成研究

本文在已有合成路线的基础之上,对(2R)-3,5--O-苯甲酰-2-脱氧-2--2--甲基-D-核糖-γ-内酯(72)的合成路线及其工艺进行了优化,最终成功地构建了三个连续手性中心,并以32.8%的总摩尔收率,98.0%的液相纯度,完成了实验室的中试。接着以72为原料设计了(2R)-3,5--O-苄基-2-脱氧-2--2--甲基-D-核糖-γ-内酯(73)的合成路线,成功地以6步反应,总收率45.7%,液相纯度99%,完成了73的制备,并对其合成方法进行实验室的工艺优化

英文摘要:
This dissertation contains two parts: Part 1. Design, Synthesis and Bioactivity Evaluation of novel Pyrimidinone Derivatives as Phosphodiestrase 5 inhibitors Phosphodiestrase 5 (PDE5) inhibitors are able to increase the intracellular cGMP levels by inhibition of the activity of Phosphodiestrase 5 which is the only enzyme that specifically catalyzes the hydrolysis of cGMP, and as a result initiate a cascade of cGMP-driven reactions. Since sildenafil was launched in 1998, PDE5 inhibitors have been not only widely used as first-line therapy for erectile dysfunction (ED), but also approved for the treatment of pulmonary arterial hypertension (PAH) and lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) by FDA. They also have a golden prospect in treating other various illnesses related to PDE5, resulting in great interest in discovering novel PDE5 inhibitors. Despite of their effectiveness, PDE5 inhibitors show significant adverse effects in clinic due to their low selectivity towards other PDE isoforms. Moreover, all the approved drugs are foreign products which are expensive for patients. So our study is aimed at developing a novel drugable PDE5 inhibitors with higher activity, selectivity and safety. Based on the existing knowledge of structure-activity relationship (SAR) on pyrimidinone derivatives and crystal structure of pyrimidinone derivatives and PDE5, we designed and synthesized 14 novel compounds which were all evaluated for their PDE5 inhibitory activity, with the goal of seeking the key SAR clues on pyrimidinone derivatives as PDE5 inhibitors. Compounds with higher PDE5 inhibitory activity and selectivity than that of sildenafil in vitro were obtained such as compound 52b,52d,52e and 52j. Especially compound 52d (IC50=0.12 nM) exhibited excellent PDE5 inhibitory activity by 32.5-fold compared to that of sildenafil. The binding mode and interaction between the pyrimidinone derivatives and PDE5 active site was also well explained in this paper by the eutectic crystallization of 47cb and 47lb with PDE5, providing theoretical basis for further optimization. Part 2. Study on the synthesis of derivatives of 2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone Based on the existing synthetic routes of (2R)-3,5-di-O-benzoyl-2-deoxy-2- fluoro-2-C-methyl-D-ribono-γ-lactone (72), we optimized the synthetic route and process in which three continuous chiral centers were constructed and completed pilot production of 72 with the total yield of 32.8% and the purity of 98% in the lab. Starting with the compound 72, we designed and synthesized (2R)-3,5-di-O-benzyl-2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone (73)(45.7%, 99%) in six steps, and subsequently optimized its laboratory process.
内容类型: 学位论文
URI标识: http://ir.xjipc.cas.cn/handle/365002/2499
Appears in Collections:资源化学研究室_学位论文

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作者单位: 中国科学院新疆理化技术研究所

Recommended Citation:
公绪栋. 嘧啶酮类膦酸二酯酶抑制剂的设计、合成及生物活性评价和2-脱氧-2-氟-2-碳-甲基-D-核糖-γ-内酯类衍生物的合成研究[D]. 北京. 中国科学院大学. 2013.
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