新型嘌呤-8-酮衍生物的设计、合成与抗肿瘤活性研究

发布时间：2018-04-28 10:07

本文选题：嘌呤 + 嘌呤-8-酮　；参考：《山东大学》2017年硕士论文

【摘要】：嘌呤环是自然界中最普遍存在的含氮杂环,不仅在各种海洋生物和植物中发现了大量嘌呤衍生物,而且它也是核酸(RNA和DNA)中腺嘌呤和鸟嘌呤的核心结构。由于其广谱的生物活性,嘌呤及其衍生物在医药行业被广泛应用于各种疾病的治疗。如,抗哮喘药、心血管药物、中枢神经系统(CNS)兴奋剂、免疫增强剂、抗病毒、抗真菌和抗菌、抗肿瘤等等方面均有着广泛的应用。而本文重点是研究嘌呤衍生物在抗肿瘤方面的作用。在抗肿瘤方面,嘌呤类化合物的研究很早,比如6-巯基嘌呤和6-巯基鸟嘌呤等很早就用于白血病的治疗。以及奈拉滨、克罗拉滨、Idelalisib和R-roscovitine等均具有很好的抗肿癌活性。本文首先针对嘌呤类化合物在抗肿瘤方面的应用进行分类介绍。然后在本课题组前期对嘌呤类化合物研究工作的基础上,通过构效关系研究,设计合成了一系列嘌呤-8-酮类化合物,并应用MTT法对所合成的化合物进行了体外抗增殖活性研究。本课题共合成30个结构全新的目标化合物,所有目标化合物均经过1W-NMR、13C-NMR和HRMS结构确证。以2,4-二氯-5-硝基嘧啶为起始原料,与不同取代伯胺发生芳香亲核取代反应后制得硝基嘧啶胺类中间体。该中间体经氯化亚锡还原后,再与氯甲酸苯酯发生缩合和环合反应后生成嘌呤中间体。随后与不同取代苯胺反应即可制得目标化合物5a～5j。所得5a～5j与卤代物反应后制得目标化合物6a～6r,目标化合物7a和7b的制备是以5j和6r为原料.在酸性条件下脱除Boc保护基后得到。在体外抗增殖活性实验中发现,多个化合物在50 μmol·L-1浓度下对Hela细胞株有明显抑制作用。通过构效关系分析可知,在嘌呤-8-酮的N7位引入乙酸乙酯片段、丙酮片段及乙酸片段的活性较差,而引入丙基、烯丙基、炔丙基及苄基的活性明显提高;当嘌呤-8-酮的N9位为环已基或苯基取代时,化合物的活性较好;而苯环上引入羟基、哌嗪基或Boc-哌嗪基时,化合物的抗增殖活性也明显提高。其中化合物5h、6h、6i和6j的活性优为突出,对Hela、MOLT-4和K562肿瘤细胞株的抑制活性相当或优于阳性对照药R-roscovitine,可作为先导化合物,进一步进行结构优化和修饰以期得到活性更好的抗肿瘤化合物。
[Abstract]:Purine ring is the most common nitrogen heterocyclic in nature. It is not only found in various marine organisms and plants, but also the core structure of adenine and guanine in nucleic acid (RNA and DNA). Because of its broad spectrum biological activity, purine and its derivatives are widely used in various diseases in the pharmaceutical industry. Treatment. Such as antiasthmatic drugs, cardiovascular drugs, central nervous system (CNS) stimulants, immune enhancers, antiviral, antifungal and antitumor, antitumor, and so on. This article focuses on the study of the role of purine derivatives in anti-tumor. In anti-tumor, the study of purine compounds is very early, such as the 6- sulfhydryl group. Purine and 6- mercapto guanine are used early for the treatment of leukemia. And the anti tumor activity of the purine, clrobin, Idelalisib and R-roscovitine all have good antitumor activity. On the basis of the study of structure-activity relationship, a series of purine -8- ketones were designed and synthesized, and the antiproliferative activity in vitro was studied by MTT method. 30 new target compounds were synthesized in this subject. All target compounds were confirmed by 1W-NMR, 13C-NMR and HRMS structure. 2,4- two chlorine -5- Nitropyrimidine was used as the starting material to produce nitropyrimidine intermediates after the aromatic nucleophilic substitution reaction of different substituent primary amines. After reduction of tin chloride, the intermediate was reacted with benzoate chloroformate and then formed a purine intermediate. Then the target compound 5A to 5J. could be prepared with different substitutions of benzamine. The target compounds 6A ~ 6R were obtained after the reaction of 5A ~ 5J with halogen. The preparation of target compounds, 7a and 7b, was prepared with 5J and 6R as raw materials. The Boc protection group was removed under acid conditions. In the experiment of anti proliferation in vitro, it was found that multiple compounds inhibited the Hela fine cell under 50 micron mol. L-1 concentration. It is known that the activity of acetone fragment and acetic acid fragment is poor at the N7 site of purine -8- ketone, and the activity of propyl, allyl, propargyl and benzyl is obviously improved. When the N9 position of purine -8- ketone is cyclohexyl or phenyl substituent, the activity of the compounds is better, while hydroxyl, piperazine or piperazine are introduced into the benzene ring. The antiproliferative activity of the compounds is also obviously improved. The compounds 5h, 6h, 6I and 6J are protruding, and the inhibitory activity to the Hela, MOLT-4 and K562 tumor cell lines is equivalent or superior to the positive control drug R-roscovitine, which can be used as a precursor compound and further structural optimization and modification to obtain better active antitumor compounds.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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