【摘要】：腫瘤多藥耐藥(Multidrug resistance,MDR)是腫瘤化療過程中的一個(gè)巨大挑戰(zhàn)。產(chǎn)生MDR現(xiàn)象的一個(gè)主要機(jī)制是藥物外排現(xiàn)象。到目前為止,在已經(jīng)確認(rèn)的48種ABC(ATP-binding cassette)超家族外排膜蛋白中,P-糖蛋白(P-gp)、多藥耐藥相關(guān)蛋白(MRP)和乳腺癌耐藥蛋白(BCRP)是三種與MDR相關(guān)的跨膜轉(zhuǎn)運(yùn)蛋白。以P-gp為靶點(diǎn)的抑制劑已經(jīng)發(fā)展了三代,然而,只有極少數(shù)低毒、高效、特異性抑制P-gp的抗MDR逆轉(zhuǎn)劑被發(fā)現(xiàn),但卻沒有進(jìn)入臨床應(yīng)用的藥物。因此,尋找新型低毒、高效、特異性抑制P-gp的抑制劑是能否克服腫瘤多藥耐藥的關(guān)鍵。本課題組前期對(duì)表沒食子兒茶素類化合物進(jìn)行改造,首次合成和評(píng)價(jià)了一系列甲基化表沒食子兒茶素衍生物,8個(gè)苗頭化合物抑制P-gp的ECso達(dá)到140.0-280.0 nM。本課題擬對(duì)這些抑制劑進(jìn)一步優(yōu)化,以便發(fā)現(xiàn)有臨床應(yīng)用前景的對(duì)P-gp特異性抑制的抗腫瘤多藥耐藥先導(dǎo)化合物。本論文從改變B環(huán)上甲氧基數(shù)目、改變C環(huán)的C-2和C-3手性以及C環(huán)上引入含哌啶連接基團(tuán)三個(gè)方面來進(jìn)行化合物的設(shè)計(jì)合成。設(shè)計(jì)和合成了4個(gè)(2R,3R)-表兒茶素衍生物,1個(gè)(2R,3S)-表兒茶素衍生物,3個(gè)(2R,3R)-表沒食子兒茶素衍生物,以及4個(gè)(2R,3S)-表兒茶素衍生物。為提高化合物的水溶性,改善分子的脂水分配系數(shù),為此我們?cè)O(shè)計(jì)并合成了12個(gè)含哌啶連接基團(tuán)的兒茶素和表沒食子兒茶素類新化合物。所有的24個(gè)全新的化合物均經(jīng)過核磁共振氫譜和碳譜驗(yàn)證,部分已完成高分辨質(zhì)譜和旋光確認(rèn)。生物活性實(shí)驗(yàn)測(cè)試使用了乳腺癌細(xì)胞株MDA435/LCC6以及耐藥細(xì)胞株(MDA435/LCC6MDR)進(jìn)行P-gp介導(dǎo)的腫瘤MDR逆轉(zhuǎn)活性的研究。其中1.0μM濃度的化合物2、3、4、6、7、8、11能夠逆轉(zhuǎn)LCC6MDR細(xì)胞對(duì)紫杉醇的耐藥,其逆轉(zhuǎn)倍數(shù)RF值分別為10.6、12.3、10.9、62.9、26.1、47.4、12.8和32.5,遠(yuǎn)高于陽(yáng)性對(duì)照組維拉帕米(RF=3.8),對(duì)于逆轉(zhuǎn)倍數(shù)較高的4、7、11,測(cè)其EC50值分別為83.3、140、181.0 nM,這表明這些活性化合物是高效的P-gp抑制劑。
[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.
【學(xué)位授予單位】：中國(guó)海洋大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R91;R914.5

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