title: Novel cinnamohydroxamic acid derivatives as HDAC inhibitors with anticancer activity in vitro and in vivo.
abstract: A novel series of cinnamohydroxamic acid derivatives were synthesized and their biological activities against HDAC were assessed. Our results showed that the compound with more strong inhibitory activity to HDAC would exhibited more significant anti-proliferative effect on tumor cells. Among these compounds, 7e displayed clearly inhibitory effects on HDAC and tumor cell growth. Furthermore, HDAC isoforms enzyme data indicated that, compared to HDAC pan-inhibitor SAHA, 7e owned an enhanced inhibitory effect on HDAC1, 3 and 6 isoforms. Meanwhile, it also significantly suppressed cell growth of lung cancer cells compared to SAHA, but with lower toxicity in normal cells. Mechanistically, 7e prompted acetylation of histone3 and histone4, led to up-regulation of p21, and then mediated cell cycle arrest and pro-apoptosis. Moreover, the in vivo study indicated that compound 7e could retard tumor growth of A549 xenograft models. These findings support the further investigation on the anti-tumor potential of this class of compounds as HDAC inhibitor.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Bao
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Huahuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Qifan
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Xiangzhong
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Junli
authors.initials: J
authors.lastname: Chen
authors.affiliation: Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: guoliang222@gmail.com.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: wucf@syphu.edu.cn.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms
keywords: Apoptosis; Cancer; Cell cycle; Histone deacetylase inhibitor