title: A novel quinazoline-based analog induces G2/M cell cycle arrest and apoptosis in human A549 lung cancer cells via a ROS-dependent mechanism.
abstract: 6-amino-4-(4-phenoxyphenylethylamino)quinazoline (QNZ) is an excellent quinazoline-containing NF-κB inhibitor also acting as a novel anticancer agent. Considering both the medicinal significance of quinazoline scaffold and the tunable functionality of Michael acceptor-centric pharmacophores in the electrophilicity-based prooxidant strategy, we designed a novel QNZ-inspired electrophilic molecule QNZ-A by introducing a Michael acceptor unit at position-6 of quinazoline ring in QNZ. Our results identified QNZ-A as a promising selective cytotoxic agent against A549 cells. QNZ-A, by virtue of its Michael acceptor unit, induced reactive oxygen species (ROS) accumulation associated with collapse of the redox buffering system in A549 cells. This caused up-regulation of p53-inducible p21 and down-regulation of redox sensitive Cdc25C along with Cyclin B1/Cdk1, leading to a G2/M cell cycle arrest and final cell apoptosis. By contrast, QNZ-B, a reduction product of QNZ-A lacking the Michael acceptor unit failed to induce ROS generation and all these cell cycle-related events. In conclusion, this work provided a successful example of designing QNZ-directed anticancer agent by a ROS-promoting strategy and identified QNZ-A as a selective anticancer agent against A549 cells through G2/M cell cycle arrest and apoptosis via a ROS-dependent mechanism.
authors.affiliation: Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang Province 312000, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang Province 312000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang Province 312000, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Ren
authors.affiliation: Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang Province 312000, China.
authors.forename: Yaohong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang Province 312000, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang Province 312000, China. Electronic address: qichenze@usx.edu.cn.
authors.forename: Chenze
authors.initials: C
authors.lastname: Qi
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D016203:CDC2 Protein Kinase; D056744:Cyclin B1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D010084:Oxidation-Reduction; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000737:chemistry; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011799:Quinazolines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases
keywords: Cell cycle; G2/M arrest; Michael acceptor; Quinazoline; Reactive oxygen species