抗肺癌天然产物Wentilactone A的全合成及其构效关系研究

Lung cancer is one of the leading causes of cancer-related deaths worldwide. Very recently, it was reported that Wentilactone A (WA) exerts a significantly inhibitory effect on various tumor cell lines, especially NCI-H460 and NCI-H446 cell lines. However, WA did not show markedly inhibition of HUVECs. In in vivo study, WA treatment significantly reduced lung tumor xenograft growth with little adverse toxicity compared to cisplatin. However, Wentilactone production was detected only under static cultures with very low yields, which limited further investigations. As the total synthesis of WA has not been completed yet, this project aims to accomplish the first total synthesis of WA with Deils-Alder reaction as the key step. According to these synthetic derivatives, preliminary structure-activity relationship (SAR) against lung tumor cell will be concluded via bioassay. This project may not only accomplish the first total synthesis of natural WA, obtain a new synthetic strategy for these tetranorditerpenoids, but also obtain a drug candidate targeting lung cancer cells from these synthetic derivatives.

肺癌是目前全世界最常见的致死肿瘤之一。近来，Wentilactone A (WA)被报道对肺癌细胞NCI-H460和NCI-H446有着显著的抑制作用，对正常人脐静脉内皮细胞却没有明显抑制；小鼠体内的实验结果显示，WA具有明显的肿瘤抑制活性和较低的细胞毒性。因局限于其获取途径单一、生物提取效率低等缺点，导致对其进一步的研究难以为继。WA的合成研究目前尚未见报道，本项目拟采用以Diels-Alder反应为关键步骤的全合成路线开展WA的全合成；在完成全合成工作的基础上，借助此合成路线获得多个WA衍生物，并利用化学手段对分子中的多个位点进行结构修饰，合成多个系列骨架修饰的WA类似物，完善其抗肿瘤活性的构效关系。本项目不仅有望完成WA的首次全合成，为此类四环降二萜化合物提供一种新的合成策略；并有望合成多个衍生物，以期发现活性更好的、副作用小的抗肺癌候选药物。

Wentilactone A自1980年被分离报道以来，研究者发现其对多个肿瘤细胞系都有显著的抑制作用，且表现出了较顺铂更低的细胞毒性。因受限于生物提取率较低等缺点，限制了对此降二萜类化合物的进一步研究。项目采用以Diels-Alder反应为关键步骤的合成路线，开展了该降二萜类化合物的全合成研究；在项目的实施过程中，设计、探索了两条D-A前体的合成路线，并创新性的探索了连续3步（不纯化）反应合成了关键中间体三烯结构；在获得多个D-A前体的基础上探索了双键末端官能团结构对D-A反应成环难易度的影响；研究发现，在双烯体的末端引入供电子官能团将有利于成环反应的发生。项目为该类降二萜化合物的合成提供一种可行性较高的合成策略，也为该类化合物的进一步药物化学研究奠定了基础。在本基金的资助下，一类新型查尔酮天然产物的合成及其构效关系研究也取得多项进展，项目首次合成了两个系列的羟基异戊烯基查尔酮天然产物及其衍生物，并研究探讨了其抗肿瘤和抗菌构效关系，填补了该类天然产物合成及相关构效关系研究的空白。