紫苏醇衍生物的设计、合成及抗癌活性研究
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摘要
紫苏醇是来源于植物的异戊二烯萜类挥发油,是为数不多的既有癌症预防又有癌症治疗作用的天然产物之一。紫苏醇具有良好的抗肿瘤作用,而且毒性小、不易产生耐药性。但紫苏醇在体内代谢迅速,口服给药生物利用度低,因而限制了其临床应用。本实验室对柠檬烯和榄香烯衍生物的研究发现,增加化合物的极性有利于抗肿瘤活性的提高。因此,本论文拟在紫苏醇结构中引入含氮基团,希望能获得抗肿瘤活性强,毒副作用小的新颖化合物。
本文以紫苏醇为先导化合物,在保持其分子骨架的前提下,以紫苏醛为起始原料,首先合成了紫苏醇、7-乙基紫苏醇、7-甲基紫苏醇和紫苏酸甲酯四个母核,再以各种取代的胺基对其进行结构修饰,共设计合成了5个系列61个化合物,包括14个紫苏醇类衍生物(Al-A14)、11个7-乙基紫苏醇类衍生物(B1-B11)、10个7-甲基紫苏醇类衍生物(C1-C10)、18个紫苏酸甲酯类衍生物(Dl-D18)和8个紫苏胺类衍生物(E1-E8),其中59个未见文献报道。所有目标化合物的结构均经MS和1H-NMR确证。
用MTT法对所合成的61个目标化合物进行了体外抗肿瘤活性筛选。以HeLa、MCF-7、HepG2、HCT116、A549、A375-S2、HT-1080、U937、HL-60和K562为测试细胞株,以5-氟尿嘧啶为阳性对照药,结果显示,所合成的大部分化合物对10种肿瘤细胞均表现出不同程度的抑制作用。说明含氮基团的引入确实有利于抗癌活性的提高,由此充分验证了本文的设计思想。
对目标化合物构效关系进行初步探讨,结果如下：在紫苏醇以及7-甲基或乙基取代的紫苏醇含氮衍生物(A,B和C系列)中,取代基为伯胺的目标化合物的抗肿瘤活性强于仲胺；在紫苏酸甲酯的含氮衍生物(D系列)中,引入的不同的含氮取代基团对化合物的抗肿瘤活性并无显著的影响；紫苏醇结构中的羟基被氨基替换的紫苏胺类衍生物(E系列)中,引入金刚烷胺基的目标化合物E5抗肿瘤活性强于其他目标化合物。
选取E5对其抗肿瘤作用机制进行了进一步研究。研究结果表明E5可以呈浓度依赖性、时间依赖性抑制A549细胞的增殖。用相差显微镜、荧光染色及流式细胞术检测表明,E5可引起A549细胞发生凋亡。免疫印迹分析结果证实了E5诱导A549细胞发生凋亡的作用,对法尼基转移酶有抑制作用,对Ras下游Raf/MEK/ERK信号通路有抑制作用。研究结果表明：E5通过抑制法尼基转移酶,从而抑制Raf/MEK/ERK信号通路而诱导细胞凋亡。
Perillyl alcohol, a plant-derived volatile oil structurally belonging to terpenes, is one of the few agents both having preventive and therapeutic effects against a variety of tumors. This agent has a good anti-tumor effect with low toxicity and little drug resistance. However, perillyl alcohol is prone to be rapidly metabolized in vivo. Combined with the low bioavailability for oral administration, its clinical application is limited. Based on the previous study about limonene analogues in our laboratory, increasing the polarity of this compound is beneficial to improve the anti-tumor activity. In this thesis, some nitrogen-containing groups would be introduced to the structure of perillyl alcohol, aiming at yielding novel agents with excellent anti-tumor activities and little side effects.
In this study, perilla aldehyde was chosen as the starting material and four skeletons were firstly synthesized, that is perillyl alcohol,7-methyl perillyl alcohol,7-ethyl perillyl alcohol and methyl perillate. Then, we designed five series of their analogues containing amino groups maintaining its molecular skeleton. Finally, sixty-one compounds were synthesized including59novel compounds. Among these derivatives,14compounds contain perillyl alcohol skeleton (A1-A14),11compounds containing7-ethyl perillyl alcohol skeleton (B1-B11),10compounds containing7-methyl perillyl alcohol skeleton (C1-C10) and18compounds containing methyl perillate skeleton (D1-D18). Besides these,8compounds were perillyl amine derivatives (E1-E8). The structures of all compounds were confirmed by MS and'H-NMR spectra.
To assess the anti-proliferation effect of the61target compounds, experiments with'MTT assay'were performed in HeLa, MCF-7, HepG2, HCT116, A549, A375-S2, HT-1080, U937, HL-60and K562cancer cells,5-fluorouracil as positive control drug. The results demonstrated that the ICsos (50%inhibitive concentrations) of major compounds were lower than perillyl alcohol. This result verified that introduction of amino group to the structure of perillyl alcohol is beneficial to improve the antitumor activity.
Compared with the structures and activities, preliminary structure-activity relationships (SAR) were summarized:Between perilla alcohol,7-methyl perillyl alcohol and7-ethyl perillyl alcohol derivatives (A, B, and C series), the introduction of primary amine group into the objective compound with stronger anti-tumor activity than secondary amine group; But there was no significant differences in perillic acid methyl ester derivatives (D series) with different nitrogen. Replaced Perilla alcohol structure hydroxyl group by amine (E series), the introduction of amantadine (compound E5) had stronger antitumor activity than the other compound.
Investigating the potential mechanism with compound E5, the result showed that compound E5exhibited dose-dependent and time-dependent inhibition of human lung cell A549proliferation. After Measurement with phase contrast microscope, fluorescent staining and flow cytometry, the result demonstrated that compound E5could induce apoptosis of A549cell. Western blot analysis not only verified this effect but also demonstrated E5could inhibit the Raf/MEK/ERK signaling pathway of Ras downstream. Therefore, we can conclude that E5induced apoptosis of A549cell through the inhibition of farnesyl transferase resulting the inhibition of Raf/MEK/ERK signaling pathway.
本文以紫苏醇为先导化合物,在保持其分子骨架的前提下,以紫苏醛为起始原料,首先合成了紫苏醇、7-乙基紫苏醇、7-甲基紫苏醇和紫苏酸甲酯四个母核,再以各种取代的胺基对其进行结构修饰,共设计合成了5个系列61个化合物,包括14个紫苏醇类衍生物(Al-A14)、11个7-乙基紫苏醇类衍生物(B1-B11)、10个7-甲基紫苏醇类衍生物(C1-C10)、18个紫苏酸甲酯类衍生物(Dl-D18)和8个紫苏胺类衍生物(E1-E8),其中59个未见文献报道。所有目标化合物的结构均经MS和1H-NMR确证。
用MTT法对所合成的61个目标化合物进行了体外抗肿瘤活性筛选。以HeLa、MCF-7、HepG2、HCT116、A549、A375-S2、HT-1080、U937、HL-60和K562为测试细胞株,以5-氟尿嘧啶为阳性对照药,结果显示,所合成的大部分化合物对10种肿瘤细胞均表现出不同程度的抑制作用。说明含氮基团的引入确实有利于抗癌活性的提高,由此充分验证了本文的设计思想。
对目标化合物构效关系进行初步探讨,结果如下：在紫苏醇以及7-甲基或乙基取代的紫苏醇含氮衍生物(A,B和C系列)中,取代基为伯胺的目标化合物的抗肿瘤活性强于仲胺；在紫苏酸甲酯的含氮衍生物(D系列)中,引入的不同的含氮取代基团对化合物的抗肿瘤活性并无显著的影响；紫苏醇结构中的羟基被氨基替换的紫苏胺类衍生物(E系列)中,引入金刚烷胺基的目标化合物E5抗肿瘤活性强于其他目标化合物。
选取E5对其抗肿瘤作用机制进行了进一步研究。研究结果表明E5可以呈浓度依赖性、时间依赖性抑制A549细胞的增殖。用相差显微镜、荧光染色及流式细胞术检测表明,E5可引起A549细胞发生凋亡。免疫印迹分析结果证实了E5诱导A549细胞发生凋亡的作用,对法尼基转移酶有抑制作用,对Ras下游Raf/MEK/ERK信号通路有抑制作用。研究结果表明：E5通过抑制法尼基转移酶,从而抑制Raf/MEK/ERK信号通路而诱导细胞凋亡。
Perillyl alcohol, a plant-derived volatile oil structurally belonging to terpenes, is one of the few agents both having preventive and therapeutic effects against a variety of tumors. This agent has a good anti-tumor effect with low toxicity and little drug resistance. However, perillyl alcohol is prone to be rapidly metabolized in vivo. Combined with the low bioavailability for oral administration, its clinical application is limited. Based on the previous study about limonene analogues in our laboratory, increasing the polarity of this compound is beneficial to improve the anti-tumor activity. In this thesis, some nitrogen-containing groups would be introduced to the structure of perillyl alcohol, aiming at yielding novel agents with excellent anti-tumor activities and little side effects.
In this study, perilla aldehyde was chosen as the starting material and four skeletons were firstly synthesized, that is perillyl alcohol,7-methyl perillyl alcohol,7-ethyl perillyl alcohol and methyl perillate. Then, we designed five series of their analogues containing amino groups maintaining its molecular skeleton. Finally, sixty-one compounds were synthesized including59novel compounds. Among these derivatives,14compounds contain perillyl alcohol skeleton (A1-A14),11compounds containing7-ethyl perillyl alcohol skeleton (B1-B11),10compounds containing7-methyl perillyl alcohol skeleton (C1-C10) and18compounds containing methyl perillate skeleton (D1-D18). Besides these,8compounds were perillyl amine derivatives (E1-E8). The structures of all compounds were confirmed by MS and'H-NMR spectra.
To assess the anti-proliferation effect of the61target compounds, experiments with'MTT assay'were performed in HeLa, MCF-7, HepG2, HCT116, A549, A375-S2, HT-1080, U937, HL-60and K562cancer cells,5-fluorouracil as positive control drug. The results demonstrated that the ICsos (50%inhibitive concentrations) of major compounds were lower than perillyl alcohol. This result verified that introduction of amino group to the structure of perillyl alcohol is beneficial to improve the antitumor activity.
Compared with the structures and activities, preliminary structure-activity relationships (SAR) were summarized:Between perilla alcohol,7-methyl perillyl alcohol and7-ethyl perillyl alcohol derivatives (A, B, and C series), the introduction of primary amine group into the objective compound with stronger anti-tumor activity than secondary amine group; But there was no significant differences in perillic acid methyl ester derivatives (D series) with different nitrogen. Replaced Perilla alcohol structure hydroxyl group by amine (E series), the introduction of amantadine (compound E5) had stronger antitumor activity than the other compound.
Investigating the potential mechanism with compound E5, the result showed that compound E5exhibited dose-dependent and time-dependent inhibition of human lung cell A549proliferation. After Measurement with phase contrast microscope, fluorescent staining and flow cytometry, the result demonstrated that compound E5could induce apoptosis of A549cell. Western blot analysis not only verified this effect but also demonstrated E5could inhibit the Raf/MEK/ERK signaling pathway of Ras downstream. Therefore, we can conclude that E5induced apoptosis of A549cell through the inhibition of farnesyl transferase resulting the inhibition of Raf/MEK/ERK signaling pathway.
引文
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