甲基化儿茶素衍生物的设计合成及抗肿瘤多药耐药活性研究
发布时间：2018-11-28 10:51
【摘要】：肿瘤多药耐药(Multidrug resistance,MDR)是肿瘤化疗过程中的一个巨大挑战。产生MDR现象的一个主要机制是药物外排现象。到目前为止,在已经确认的48种ABC(ATP-binding cassette)超家族外排膜蛋白中,P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)和乳腺癌耐药蛋白(BCRP)是三种与MDR相关的跨膜转运蛋白。以P-gp为靶点的抑制剂已经发展了三代,然而,只有极少数低毒、高效、特异性抑制P-gp的抗MDR逆转剂被发现,但却没有进入临床应用的药物。因此,寻找新型低毒、高效、特异性抑制P-gp的抑制剂是能否克服肿瘤多药耐药的关键。本课题组前期对表没食子儿茶素类化合物进行改造,首次合成和评价了一系列甲基化表没食子儿茶素衍生物,8个苗头化合物抑制P-gp的ECso达到140.0-280.0 nM。本课题拟对这些抑制剂进一步优化,以便发现有临床应用前景的对P-gp特异性抑制的抗肿瘤多药耐药先导化合物。本论文从改变B环上甲氧基数目、改变C环的C-2和C-3手性以及C环上引入含哌啶连接基团三个方面来进行化合物的设计合成。设计和合成了4个(2R,3R)-表儿茶素衍生物,1个(2R,3S)-表儿茶素衍生物,3个(2R,3R)-表没食子儿茶素衍生物,以及4个(2R,3S)-表儿茶素衍生物。为提高化合物的水溶性,改善分子的脂水分配系数,为此我们设计并合成了12个含哌啶连接基团的儿茶素和表没食子儿茶素类新化合物。所有的24个全新的化合物均经过核磁共振氢谱和碳谱验证,部分已完成高分辨质谱和旋光确认。生物活性实验测试使用了乳腺癌细胞株MDA435/LCC6以及耐药细胞株(MDA435/LCC6MDR)进行P-gp介导的肿瘤MDR逆转活性的研究。其中1.0μM浓度的化合物2、3、4、6、7、8、11能够逆转LCC6MDR细胞对紫杉醇的耐药,其逆转倍数RF值分别为10.6、12.3、10.9、62.9、26.1、47.4、12.8和32.5,远高于阳性对照组维拉帕米(RF=3.8),对于逆转倍数较高的4、7、11,测其EC50值分别为83.3、140、181.0 nM,这表明这些活性化合物是高效的P-gp抑制剂。
[Abstract]:Multidrug resistance (Multidrug resistance,MDR) is a great challenge in tumor chemotherapy. One of the main mechanisms for producing MDR is drug efflux. So far, among the 48 identified ABC (ATP-binding cassette) superfamily efflux proteins, P- glycoprotein (P-gp), Multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) are three transmembrane transporters associated with MDR. The inhibitors targeting P-gp have been developed for three generations, however, only a few low-toxicity, high-efficiency, specific anti-MDR reversal agents have been found, but have not been used in clinical use. Therefore, the key to overcome multidrug resistance is to find new inhibitors of low toxicity, high efficiency and specific inhibition of P-gp. A series of methylated epigallocatechin derivatives were synthesized and evaluated for the first time by the modification of epigallocatechin compounds in the early stage of our study. The ECso of 8 seedling compounds against P-gp reached 140.0-280.0 nM.. The aim of this study is to further optimize these inhibitors in order to find multidrug resistant lead compounds specifically inhibited by P-gp. In this paper, the design and synthesis of the compounds were carried out by changing the number of methoxy groups on B ring, changing the chirality of C ring C 2 and C 3 and introducing piperidine groups into C ring. Four (2R) -epigallocatechin derivatives, one (2RN3S) -epicatechin derivative, three (2Rn3R) -epigallocatechin derivatives and four (2RN3S) -epicatechin derivatives were designed and synthesized. In order to improve the water-solubility of the compounds and improve the lipide-water partition coefficient, we have designed and synthesized 12 new catechins and epigallocatechins containing piperidine-linked groups. All 24 new compounds were verified by NMR and C spectra, and some of them were confirmed by high resolution mass spectrometry (HRMS) and optical rotation. Breast cancer cell line MDA435/LCC6 and drug resistant cell line (MDA435/LCC6MDR) were used to study the reverse activity of MDR mediated by P-gp. The concentration of 1.0 渭 M compound 2X 3H 4N 6N 7N 7N 8N can reverse the resistance of LCC6MDR cells to paclitaxel, and its reversal multiple RF values are 10.6 渭 M 12.3% 10.9 渭 m, 26.9X 67.412.8 and 32.5, respectively, which can reverse the resistance of LCC6MDR cells to paclitaxel, and the reversion times are 10.6 渭 M, 10.9 渭 M and 10.9 渭 M, respectively. The EC50 of verapamil (RF=3.8) was 83.3140181.0 nM, which indicated that these active compounds were effective P-gp inhibitors.
【学位授予单位】：中国海洋大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R91;R914.5
本文编号：2362625
[Abstract]:Multidrug resistance (Multidrug resistance,MDR) is a great challenge in tumor chemotherapy. One of the main mechanisms for producing MDR is drug efflux. So far, among the 48 identified ABC (ATP-binding cassette) superfamily efflux proteins, P- glycoprotein (P-gp), Multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) are three transmembrane transporters associated with MDR. The inhibitors targeting P-gp have been developed for three generations, however, only a few low-toxicity, high-efficiency, specific anti-MDR reversal agents have been found, but have not been used in clinical use. Therefore, the key to overcome multidrug resistance is to find new inhibitors of low toxicity, high efficiency and specific inhibition of P-gp. A series of methylated epigallocatechin derivatives were synthesized and evaluated for the first time by the modification of epigallocatechin compounds in the early stage of our study. The ECso of 8 seedling compounds against P-gp reached 140.0-280.0 nM.. The aim of this study is to further optimize these inhibitors in order to find multidrug resistant lead compounds specifically inhibited by P-gp. In this paper, the design and synthesis of the compounds were carried out by changing the number of methoxy groups on B ring, changing the chirality of C ring C 2 and C 3 and introducing piperidine groups into C ring. Four (2R) -epigallocatechin derivatives, one (2RN3S) -epicatechin derivative, three (2Rn3R) -epigallocatechin derivatives and four (2RN3S) -epicatechin derivatives were designed and synthesized. In order to improve the water-solubility of the compounds and improve the lipide-water partition coefficient, we have designed and synthesized 12 new catechins and epigallocatechins containing piperidine-linked groups. All 24 new compounds were verified by NMR and C spectra, and some of them were confirmed by high resolution mass spectrometry (HRMS) and optical rotation. Breast cancer cell line MDA435/LCC6 and drug resistant cell line (MDA435/LCC6MDR) were used to study the reverse activity of MDR mediated by P-gp. The concentration of 1.0 渭 M compound 2X 3H 4N 6N 7N 7N 8N can reverse the resistance of LCC6MDR cells to paclitaxel, and its reversal multiple RF values are 10.6 渭 M 12.3% 10.9 渭 m, 26.9X 67.412.8 and 32.5, respectively, which can reverse the resistance of LCC6MDR cells to paclitaxel, and the reversion times are 10.6 渭 M, 10.9 渭 M and 10.9 渭 M, respectively. The EC50 of verapamil (RF=3.8) was 83.3140181.0 nM, which indicated that these active compounds were effective P-gp inhibitors.
【学位授予单位】：中国海洋大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R91;R914.5
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