卷柏属瑶药中新型PDE4 / MMPs双靶点抑制剂的协同抗肿瘤耐药机制

Multidrug resistance (MDR) is the main cause of chemotherapy failure and the great challenge that cancer therapy is facing, continuous development of novel drug resistance target inhibitors and design of ligands to polypharmacological profiles may beneficial to overcoming MDR. Selaginella species as traditional YAO ethnic medicine have been found to have anti-tumor and anti-drug resistant activities and contains a large number of anti-cancer active polyphenols. However, its anti-tumor drug resistant mechanism is unclear. In the previous study of our group, novel structured alkyne phenols and biflavonoids were found to have highly inhibitory activities against phosphodiesterase (PDE4)/ microtubule-associated proteins (MAPs) and matrix metalloproteinases (MMPs), and also have effect of anti-tumor drug resistant. During this project, we will develop novel structured and highly effective dual target inhibitors against PDE4/MAPs or MMPs from five Guangxi YAO ethnic medicine of Selaginella species and further confirmation by the Drug Affinity Responsive Target Stability (DARTS) tests, to study their P-gp-mediated and NO/cGMP/PKG/ERK signaling pathway involved mechanism of their sensitizing effect on the drug resistant strains and synergistic anti-tumor mechanism, establishing a reliable QSAR models from Large Sample Size Trial. Then the drug-like property optimization of the hits will be carried out by structure modification. Furthermore, the correlation between “Surflex Docking” of biflavonoid rotamers with their targeted protein will be studied from a dynamic stereochemistry perspective. The fingerprint characteristics of different Selaginella species will be compared based on their components. The results obtained from this study would be helpful to elucidate the anti- drug resistant mechanism of the above-mentioned YAO ethnic medicine, and to provide the most direct basis for establishing the quality control method based on the active components.

多药耐药性(MDR)是化疗失败的主因和肿瘤医学面临的巨大挑战，而不断发现新的耐药靶点抑制剂或开发多药多靶复合制剂有利于克服MDR。传统瑶药卷柏具有抗肿瘤和抗耐药作用，富含抗癌活性多酚，但其抗耐药机制不清。本课题组已从该属植物中发现新结构的炔酚类和双黄酮类，能高效抑制磷酸二酯酶PDE/微管聚集蛋白MAP和基质金属蛋白酶MMP等，并可敏化耐药细胞株。本项目拟从五种卷柏属瑶药中筛选PDE4/ MMPs双靶点新抑制剂，经药物亲和力反应靶稳定性(DARTS)确认，研究其对P-糖蛋白介导NO/cGMP/PKG通路下抗耐药新机制，以及结构类群间协同抗肿瘤机制，并以大样本量分析阐明其定量构效关系；进而优化苗头化合物结构及成药性；研究双黄酮旋转异构体结构与靶蛋白柔性识别效应的相关性；明确不同种卷柏成分的指纹图谱特征。为阐明上述瑶药的抗耐药机理、建立质量标准提供最直接的研究基础。

从还魂草，石上柏，翠云草，江南卷柏等瑶药中分离得到炔酚、复杂多酚、木脂素、取代菲和双黄酮等类型化合物85种，其中19种新结构。建立了取代菲和双黄酮指纹图谱和bacording特征码分析方法。发现其中四类成分靶向PDE4D2、MMP-9和微管蛋白聚合等抗肿瘤耐药机制。开展了瑶药灵香草、活血丹、两面针、羊开口等抗肿瘤和微环境相关的抗炎活性等研究，共分离得到182个化合物，其中新化合物51个，发现针对NF-κB、NLRP3/caspase1、YAP及VEGF等靶点影响肿瘤微环境克服耐药的机制。拓展了活性衍生物合成及抗肿瘤耐药研究，发现双靶向IDO1和STAT3的1,4-萘醌芳胺肟衍生物，在黑色素瘤和HepG2荷瘤鼠模型中表现出免疫治疗和化学治疗的双重作用。本项目共发表SCI论文24篇，申请国家发明专利6件，获专利授权3件。培养博士4名、硕士11名。培养广西特聘专家团队1支；成功举办2届国际漓江药学论坛，在国际会议作邀请报告4次；举办国内会议两次，应邀作学术报告3次。获2021年广西自治区教学成果一等奖。