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Thesis Advisor阿吉艾克拜尔·艾萨、沈敬山
Degree Grantor中国科学院大学
Place of Conferral北京
Degree Discipline有机化学
KeywordPde5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
Other Abstract




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。



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.
Document Type学位论文
Recommended Citation
GB/T 7714
公绪栋. 嘧啶酮类5型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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