基于三尖杉生物碱构效规律的新颖抗肿瘤酯碱的挖掘与构建

The rapid development of targeted tyrosine kinase inhibitors had once made people believe that cytotoxic drugs were no longer useful. However, tumors in about one third of patients became resistant to these targeted drugs. Nevertheless, the cytotoxic compound homoharringtonine (HHT) was still effective, which made HHT a valued renewal. As a result, FDA rapidly approved HHT in 2012. The industrialization of HHT still relied on the extraction of Cephalotaxus sp. The low content of HHT, scarcity of plant resources, and slow growth restricted its industrialization. Studies on the structure-activity relation of Cephalotaxus alkaloids had shown that the ester-based side chain was the key pharmacophore of HHT and its analogues. Previous studies on the synthesis of side chains and analogues had been conducted but none of them had broken through or replaced of natural HHT. In our previous study, a serie of Cephalotaxus alkaloids with new ester chains showed significant antitumor activity, indicating that the natural ester alkaloids were waiting for excavated. In addition, three ester alkaloids were constructed based on erythrina, the homologous cephalotaxine. The introduction of simplified side chain made the inactive erythrina alkaloids better anti-tumor potential. This project would continue the discovery esterification cephalotaxines by guided LC-MS and systematically constructed esterifiable erythrina and homoerythrina, aming to the new antitumor lead compounds.

新兴靶向药物酪氨酸激酶抑制剂的快速发展一度让人们认为细胞毒类药物再无用武之地；但在临床上，这些靶向药物在约三分之一的病人中短期内产生耐药性，而细胞毒类成分高三尖杉酯碱（HHT）对此依然有效，使得HHT重新引起人们的重视，以至于美国FDA在2012年迅速批准了此药。HHT产业化依靠三尖杉属植物提取，但成分含量低、植物资源稀缺且生长缓慢，制约了其临床应用。抗肿瘤构效研究表明酯基侧链是三尖杉酯碱类成分关键药效团，前人开展了侧链及类似物的合成研究，但是均没突破或替代天然HHT。研究组前期研究发现系列新侧链的三尖杉酯碱成分及其显著的抗肿瘤活性，提示天然的酯碱成分有待深入挖掘；其次以三尖杉碱同源的刺桐碱为基本骨架构建了简化侧链的刺桐酯碱，使得无活性的刺桐碱显示较好的抗肿瘤活性。本项目继续以LC-MS导向寻找三尖杉新酯碱成分、系统构建刺桐酯碱及其同源的高绿刺桐酯碱，探讨新的抗肿瘤先导分子。

高三尖杉酯碱是我国原创的抗肿瘤药物，2012年美国FDA也批准其作为非淋巴细胞白血病的药物。其药源主要源于植物提取和半合成，而其在植物中含量很低，寻找高含量资源、及高效价比分子是值得研究的课题。通过研究完成了海南粗榧、高山三尖杉和贡山三尖杉枝叶、三尖杉茎、高山/篦子三尖杉种子中生物碱的挖掘，从中获得33个酯碱，其中新成分13个，体外抗非实体瘤活性评价发现3个酯碱活性优于高山三尖杉酯碱; 发现高含量的高山三尖杉酯碱植物资源，为开发利用奠定了基础；还发现12个骨架新颖的四氢异喹啉生物碱，可能是该属植物中三尖杉碱、高绿刺桐碱的生源平行结构类型，直接支持的三个生源假说完整体系，拓展对三尖杉碱的结构多样性、生源途径的新认识。从刺桐中发现三尖杉生物碱同源的新的二聚刺桐碱28个，这些成分是含有超共轭系统的新颖骨架，但是均没有抗肿瘤活性，但有显著的听力保护的活性，具有潜在科学价值和应用潜力。基于刺桐碱、三尖杉碱的C-3/11位构建四个系统的41个酯碱，活性筛选表明但是这类成分没有抗肿瘤活性，但对三尖杉酯碱构效规律有更深入地认识。已发表论文8篇，其中SCI论文6篇，培养硕士/博士研究生、博士后6人。