联苄类化合物的发现与逆转肿瘤多药耐药活性研究

Malignant tumour is one of the most common and frequently encounted diseases worldwide. Multidrug resistance (MDR), commonly mediated by overexpression of P-glycoprotein (P-gp), is a big obstacle of tumour chemotherapy．Many researches were carried out to elucidate the mechanisms of MDR and to find compounds which re-sensitize MDR cells to chemotherapeutic drugs．Bibenzyls were a series of phenolic natural products that are found exclusively in Liverwort and Dendrobium. Recent studies showed that these compounds exhibited distinct cytotoxicity and reversal of MDR against cancer cells．Some of them could be the prospective leading compounds for the drug discovery．In this study, the chemical constituents of bibenzyls from M.polymorpha, D. nobile and D. candidum will be achieved. We will also study MDR cancer cells screening in vivo and in vitro to find the effective components and bibenzyl compounds. The inhibition of active compounds on the expression of the mdr1 and encoding P-gp will be actualized. Those studies will broaden our understanding in MDR cancer from the cell, gene and protein levels and lead to new strategies to overcome MDR in cancer...

恶性肿瘤是当前危害人类生命和健康的严重疾病之一，肿瘤细胞过量表达P-糖蛋白(P-gp)导致多药耐药(multidrug resistance,MDR)是目前肿瘤化疗的一大障碍，研究耐药产生的相关机制、寻找有效的逆转剂一直备受关注。联苄类化合物是主要存在于苔类植物以及石斛属植物中的一种活性天然产物，近年来研究表明联苄类化合物具有良好的抗肿瘤以及逆转肿瘤多药耐药活性，可作为新药研究的先导化合物。本项目以抗MDR肿瘤活性为指导，继续对苔类植物地钱和两种石斛属植物石斛和铁皮石斛中的联苄类成分进行分离和鉴定；通过体外、体内抗MDR肿瘤活性评价，筛选出具有抗MDR肿瘤活性的有效部位或单体联苄类化合物；并针对多药耐药基因 (mdr1 )及其编码的P-gp蛋白表达和功能进行研究，从细胞、基因和蛋白三个水平揭示活性成分抗MDR肿瘤的作用机制。本课题的完成，为抗MDR药物的研发奠定基础。

多药耐药（MDR）是一种独特的广谱耐药现象，对临床治疗构成严重威胁，是导致肿瘤化疗失败的最主要原因。目前临床还未有有效的MDR逆转剂，因此筛选有效抑制的抑制剂是研究逆转MDR的主要方法之一。本课题完成了5种药用植物和一种真菌化学成分的分离、结构确证和筛选了逆转耐药活性研究。共得到化合物77个。筛选出具有逆转耐药活性的化合物3个，对活性强的化合物Gigantol进行了深入研究，确定了其逆转肿瘤细胞多药耐药性的作用机制。研究发现Gigantol对耐药细胞株K562/A02有显著的逆转耐药活性, 最大逆转倍数为7.33。在K562/A02细胞中, Gigantol明显增加阿霉素的累积, 增加了rhodaminel123（Rh123）蓄积, 同时Gigantol还在mRNA水平抑制了K562/A02细胞中P-糖蛋白的表达。本课题还进一步测试了菲类化合物对骨肉瘤细胞的细胞毒活性。本课题阐明上述药用植物的活性化学成分,扩大了活性成分的来源，也为今后新项目的开展提供了研究基础。为活性化合物联苄类和菲类提供了前期基础。