College of Chemistry, and Green Catalysis Center, Zhengzhou University, Zhengzhou, 450001, China.
School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, Zhengzhou, 450001, China.
Eur J Med Chem. 2021 Nov 15;224:113708. doi: 10.1016/j.ejmech.2021.113708. Epub 2021 Jul 22.
We report the structural optimization of tanshinone IIA, a natural product which possesses anti-tumor properties but low water-solubility, weak antiproliferative activity and poor PK properties. A new series of ring A/C/D modified tanshinone analogues were synthesized and studied for their antiproliferative capacities against six human cancer cell lines. SAR study revealed that ring A cleavage of tanshinone IIA led to improved anti-cancer activity. Introduction of a methoxy group to the phenyl ring could enhance the anti-cancer activity even further. Compound 2f with methoxy group at C-8 position was selected as an early lead with IC values of 0.28-3.16 μM against six tested cell lines. 2f could bind to tubulin colchicine site, inhibit tubulin assembly and disrupt the normal formation of microtubule networks. Cellular mechanistic studies revealed that 2f induced apoptotic cell death of A549 cells in a dose-dependent manner. In vitro investigations showed that 2f impeded the tubule-formation of HUVECs and potently inhibited the proliferation, migration and invasion of A549 cells as well as HUVECs. Furthermore, the in vivo anti-angiogenic effect of 2f was confirmed via a zebrafish model test. The satisfactory physicochemical property and metabolic stability of 2f, as well as improved water-solubility, further suggested that 2f could serve as a promising tubulin inhibitor and anti-angiogenic agent.
我们报告了丹参酮 IIA 的结构优化，这是一种具有抗肿瘤特性但水溶性低、增殖抑制活性弱和药代动力学性质差的天然产物。合成了一系列 A/C/D 环修饰的丹参酮类似物，并研究了它们对六种人癌细胞系的增殖抑制能力。SAR 研究表明，丹参酮 IIA 的 A 环裂解导致抗癌活性提高。在苯环上引入甲氧基可以进一步增强抗癌活性。具有 C-8 位甲氧基的化合物 2f 被选为具有 0.28-3.16μM 的 IC 值的早期先导化合物，对六种测试的细胞系具有活性。2f 可以与微管蛋白结合秋水仙碱结合位点，抑制微管蛋白组装并破坏微管网络的正常形成。细胞机制研究表明，2f 以剂量依赖的方式诱导 A549 细胞的凋亡性细胞死亡。体外研究表明，2f 抑制 HUVECs 的管形成，并有效抑制 A549 细胞和 HUVECs 的增殖、迁移和侵袭。此外，通过斑马鱼模型试验证实了 2f 的体内抗血管生成作用。2f 令人满意的物理化学性质和代谢稳定性，以及改善的水溶性，进一步表明 2f 可以作为一种有前途的微管蛋白抑制剂和抗血管生成剂。
