Hsp90选择性抑制剂Vibsanin B的多样性导向全合成研究

The inhibition of Hsp90 chaperone function results in disruption of the multiple signaling pathways in cancer, which induces the death of cancer cells. Accordingly, Hsp90 appears to be an attractive target and about 20 chemotypes have undergone clinical trials against different types of cancers. However, most of these clinical trials have terminated perhaps due to the lack of subtype selectivity and nearly inevitable heat shock response. Our group recently found that Vibsanin B can serve as a new type of Hsp90β CTD inhibitor and confirmed the mechanism. Several lead compounds with anti-tumor activity up to 10 times that of cisplatin as positive control have obtained by structural modification. However, the structural modification of Vibsanin B is limited to a few sites, and the optimization of "drug-like properties" are far from sufficient. Diverted total synthesis strategy will address this issue through preparation of Vibsanin B compound library by the derivatization of a versatile synthetic intermediate. Breaking through the limitations of key sites of vibsanin B is difficult to modify. By means of virtual screening, luciferase refolding assay, antiproliferative activity assay, zebrafish model, the drug-like properties of Vibsanin B compounds will be optimized. The goal of this project is to find a number of Hsp90 inhibitor drug candidates with high selectivity, novel structure and improved drug-like properties. It is of great significance to achieve the huge anti-cancer potential of Hsp90 target.

抑制Hsp90的分子伴侣功能可阻断癌细胞赖以生存的多种信号传导途径从而导致癌细胞死亡，已有近20种Hsp90抑制剂进入临床实验。然而，可能由于几乎不可避免的热休克反应和缺少亚型选择性等原因导致大多数临床试验没有取得太大进展。本课题组前期首次发现Vibsanin B可作为一类全新的Hsp90βCTD选择性抑制剂并确证了其作用机制，且获得多个抗肿瘤活性最高可达阳性对照顺铂10倍的先导化合物。但前期对Vibsanin B的结构修饰局限于极少数位点，多个关键位点和骨架几乎无法进行优化。本项目拟应用多样性导向全合成策略，高效完成Vibsanin B的多样性全合成，突破天然产物关键位点难以修饰的局限。结合虚拟筛选、细胞活性、酶活性、斑马鱼模型、深入优化此类化合物的类药性质。发现多个选择性高、结构新颖、有优良类药性质的Hsp90抑制剂类型候选药物，对拓展Hsp90靶标的癌症治疗潜力具有重要意义。

选择性抑制Hsp90可阻断癌细胞赖以生存的多种信号传导途径。基于分子对接、虚拟筛选、酶水平与细胞水平实验结果，推测并验证了荚蒾二萜多个位点与Hsp90蛋白的结合起重要作用。针对上述位点，我们对荚蒾二萜进行了有针对性的改善其相互作用的结构修饰。设计并合成了60余个vibsanin类衍生物，代表性的Hsp90抑制剂化合物29和31，其IC50值分别为0.39和0.27 M。我们对所合成的衍生物的作用靶点和作用机制进行了系统研究，机理研究表明化合物29可通过线粒体介导的凋亡途径促进HL-60细胞凋亡。STD实验确认了化合物31的H-18、H-10、H-1'和H-2'与Hsp90具有强相互作用。机制研究排除了这类衍生物与Hsp90 C端的作用，其可能具有Hsp90亚型选择性。毒性试验表明，化合物29在小鼠模型中表现出低毒性(LD50> 500 mg/kg i.p.)。动物实验H22荷瘤小鼠模型证明29明显抑制肿瘤生长，显示出化合物29良好的抗肿瘤效果（实验周期内肿瘤体积减少了48.4%，肿瘤重量显著减少了约42.4%）。在vibsanin类二萜的合成研究中我们发展了一类铜催化酮与氨基吡唑的环化反应。在本项目的资助下，在European Journal of Medicinal Chemistry, Journal of Organic Chemistry, Chemistry Biodiversity等SCI期刊共发表论文3篇，其中1篇为领域内Top级期刊，申请发明专利1项。