Discovery of Novel Bromophenol Hybrids as Potential Anticancer Agents through the Ros-Mediated Apoptotic Pathway: Design, Synthesis and Biological Evaluation.

Ning Wu,Yue Zhao,Shu-Ju Guo,Hua Liu,Bo Jiang,Shuai-Yu Wang,Chuan-Long Guo,Jiao Luo,Li-Jun Wang,Da-Yong Shi,Kuo Xu,Xiang-Qian Li

doi:10.3390/md15110343

Abstract

A series of bromophenol hybrids with N-containing heterocyclic moieties were designed, and their anticancer activities against a panel of five human cancer cell lines (A549, Bel7402, HepG2, HCT116 and Caco2) using MTT assay in vitro were explored. Among them, thirteen compounds (17a, 17b, 18a, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, and 23b) exhibited significant inhibitory activity against the tested cancer cell lines. The structure-activity relationships (SARs) of bromophenol derivatives were discussed. The promising candidate compound 17a could induce cell cycle arrest at G0/G1 phase and induce apoptosis in A549 cells, as well as caused DNA fragmentations, morphological changes and ROS generation by the mechanism studies. Furthermore, compound 17a suppression of Bcl-2 levels (decrease in the expression of the anti-apoptotic proteins Bcl-2 and down-regulation in the expression levels of Bcl-2) in A549 cells were observed, along with activation caspase-3 and PARP, which indicated that compound 17a induced A549 cells apoptosis in vitro through the ROS-mediated apoptotic pathway. These results might be useful for bromophenol derivatives to be explored and developed as novel anticancer drugs.

Highlights

The development of anticancer agents is the hot topic in medicinal chemistry based on the high incidence and lethality of cancer today
The results indicated that compound 17a had a significant inhibitory effect on the colony formation of A549 cells
Western blot showed that treatment of A549 cells with compound 17a at 20 μg/mL significantly decreased the level analysis showed that treatment of A549 cells with compound 17a at 20 μg/mL significantly decreased of cyclin D1 and CDK4

Summary

Introduction

The development of anticancer agents is the hot topic in medicinal chemistry based on the high incidence and lethality of cancer today. ROS-mediated apoptotic activities against cancer cell lines anticancer and could inactivate invasion and metastasis. These pathway were reported [3,4,5]. The rings of piperidine, morpholine and piperazine were introduced into human cancer cell lines and could inactivate invasion and metastasis. (Figure 1)) and had positive effects prompted usoftodrugs further design synthesize a new of bromophenol derivativesinteractions, as potential on activities along withand several properties of class molecules, including drug-target anticancer agents.

Structures

Chemistry

N in DMF to give

Cytotoxicity

Compound

Compound 17a Inhibits Colony Formation Ability of A549 Cells

Compound 17a Causes DNA Fragmentations and Morphological

Compound 17a Triggers ROS Generation

Effect

Methods

General Procedure for the Preparation of Compounds 8–16

General Procedures for the Preparation of Compounds 17–25