本文選題：嘌呤 + 嘌呤-8-酮��； 參考：《山東大學(xué)》2017年碩士論文

【摘要】：嘌呤環(huán)是自然界中最普遍存在的含氮雜環(huán),不僅在各種海洋生物和植物中發(fā)現(xiàn)了大量嘌呤衍生物,而且它也是核酸(RNA和DNA)中腺嘌呤和鳥嘌呤的核心結(jié)構(gòu)。由于其廣譜的生物活性,嘌呤及其衍生物在醫(yī)藥行業(yè)被廣泛應(yīng)用于各種疾病的治療。如,抗哮喘藥、心血管藥物、中樞神經(jīng)系統(tǒng)(CNS)興奮劑、免疫增強(qiáng)劑、抗病毒、抗真菌和抗菌、抗腫瘤等等方面均有著廣泛的應(yīng)用。而本文重點(diǎn)是研究嘌呤衍生物在抗腫瘤方面的作用。在抗腫瘤方面,嘌呤類化合物的研究很早,比如6-巰基嘌呤和6-巰基鳥嘌呤等很早就用于白血病的治療。以及奈拉濱、克羅拉濱、Idelalisib和R-roscovitine等均具有很好的抗腫癌活性。本文首先針對(duì)嘌呤類化合物在抗腫瘤方面的應(yīng)用進(jìn)行分類介紹。然后在本課題組前期對(duì)嘌呤類化合物研究工作的基礎(chǔ)上,通過構(gòu)效關(guān)系研究,設(shè)計(jì)合成了一系列嘌呤-8-酮類化合物,并應(yīng)用MTT法對(duì)所合成的化合物進(jìn)行了體外抗增殖活性研究。本課題共合成30個(gè)結(jié)構(gòu)全新的目標(biāo)化合物,所有目標(biāo)化合物均經(jīng)過1W-NMR、13C-NMR和HRMS結(jié)構(gòu)確證。以2,4-二氯-5-硝基嘧啶為起始原料,與不同取代伯胺發(fā)生芳香親核取代反應(yīng)后制得硝基嘧啶胺類中間體。該中間體經(jīng)氯化亞錫還原后,再與氯甲酸苯酯發(fā)生縮合和環(huán)合反應(yīng)后生成嘌呤中間體。隨后與不同取代苯胺反應(yīng)即可制得目標(biāo)化合物5a～5j。所得5a～5j與鹵代物反應(yīng)后制得目標(biāo)化合物6a～6r,目標(biāo)化合物7a和7b的制備是以5j和6r為原料.在酸性條件下脫除Boc保護(hù)基后得到。在體外抗增殖活性實(shí)驗(yàn)中發(fā)現(xiàn),多個(gè)化合物在50 μmol·L-1濃度下對(duì)Hela細(xì)胞株有明顯抑制作用。通過構(gòu)效關(guān)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較差,而引入丙基、烯丙基、炔丙基及芐基的活性明顯提高;當(dāng)嘌呤-8-酮的N9位為環(huán)已基或苯基取代時(shí),化合物的活性較好;而苯環(huán)上引入羥基、哌嗪基或Boc-哌嗪基時(shí),化合物的抗增殖活性也明顯提高。其中化合物5h、6h、6i和6j的活性優(yōu)為突出,對(duì)Hela、MOLT-4和K562腫瘤細(xì)胞株的抑制活性相當(dāng)或優(yōu)于陽性對(duì)照藥R-roscovitine,可作為先導(dǎo)化合物,進(jìn)一步進(jìn)行結(jié)構(gòu)優(yōu)化和修飾以期得到活性更好的抗腫瘤化合物。
[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.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914;R96

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