Discovery of Novel Quinoline-Chalcone Derivatives as Potent Antitumor Agents with Microtubule Polymerization Inhibitory Activity.

Wenlong Li,Hequan Yao,Honghao Sun,Zheying Zhu,Wen Shuai,Cong Ma,Jinyi Xu,Dong-Hua Yang,Shengtao Xu,Feijie Xu,Zhe-Sheng Chen,Hong Yao

doi:10.1021/acs.jmedchem.8b01755

Abstract

A series of novel quinoline-chalcone derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Among them, compound 24d exhibited the most potent activity with IC50 values ranging from 0.009 to 0.016 μM in a panel of cancer cell lines. Compound 24d also displayed a good safety profile with an LD50 value of 665.62 mg/kg by intravenous injection, and its hydrochloride salt 24d-HCl significantly inhibited tumor growth in H22 xenograft models without observable toxic effects, which was more potent than that of CA-4. Mechanism studies demonstrated that 24d bound to the colchicine site of tubulin, arrested the cell cycle at the G2/M phase, induced apoptosis, depolarized mitochondria, and induced reactive oxidative stress generation in K562 cells. Moreover, 24d has potent in vitro antimetastasis and in vitro and in vivo antivascular activities. Collectively, our findings suggest that 24d deserves to be further investigated as a potent and safe antitumor agent for cancer therapy.

Highlights

Microtubules provides a dynamic scaffold for maintenance of cell structure, protein trafficking, chromosomal segregation, and mitosis.[1]
They are long, hollow structures that are mainly composed of α- and β-tubulin dimers. 2-4 Microtubule-targeting agents (MTAs) including microtubule stabilizers or destabilizers can interfere with microtubule dynamics, leading to mitotic blockade and cell apoptosis.[5]
The synthetic route of key intermediates acetylquinoline 16 and propionylquinoline 21 was outlined in Scheme 1. 2-Methylquinoline-4-carboxylic acid (14) was prepared by refluxing the commercially available material isatin (13) with acetone under basic conditions, which was further converted into Weinreb amide 15, and reacted with methylmagnesium bromide (CH3MgBr) to obtain acetylquinoline in high yields