Discovery of a novel piperlongumine analogue as a microtubule polymerization inhibitor with potent anti-angiogenic and anti-metastatic efficacy
- Eur J Med Chem. 2022 Dec 5:243:114738. doi: 10.1016/j.ejmech.2022.114738.
- 1. School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
- 2. Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China.
- 3. School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
- 4. School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
- 5. School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
In an effort to discover Anticancer agents with simultaneous effects on tubulin and angiogenesis, we designed and synthesized two series of piperlongumie (PL) derivatives by replacing of phenyl group with a variety of benzoheterocycle (series II) or cyclizing the C7-C8 olefin into an aromatic heterocycle (series I). Most of the new compounds showed better antiproliferative activities against six Cancer cell lines than the parent drug PL. Compound II-14b had the best cytotoxic profile of these two series in Cancer cells, whilst being relatively low cytotoxicity against normal human cells and high potency against drug-resistant cells. It disrupted cellular microtubule networks and inhibited tubulin assembly with an IC50 value of 5.8 μM. Further studies elucidated that II-14b showed antitumor activities through multiple mechanisms, including the pruduction of abundant ROS, the dissipation of mitochondrial membrane potential, the accumulation of DNA double-strand breaks, and the induction of cell cycle in G2/M phase. More importantly, we have observed that it possesses potential anti-angiogenesis capabilities, including suppression of HUVECs cell migration, invasion, and endothelial tube formation in vitro and in vivo. In vivo assessment indicated that II-14b inhibits the growth and metastasis of MGC-803 xenograft tumour in zebrafish. These findings show that II-14b is a high-efficacy and non-toxic antitumor agent.