title: Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer.
abstract: A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to that of single-target drugs. In this article, we describe the synthesis and evaluation of an array of dual-acting ER and histone deacetylase inhibitors. These novel hybrid compounds combine an indirect antagonism structure motif of ER (OBHS, oxabicycloheptene sulfonate) with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These OBHS-HDACi conjugates exhibited good ER binding affinity and excellent ERα antagonistic activity, and they also exhibited potent inhibitory activities against HDACs. Compared with the approved drug tamoxifen, these conjugates exhibited higher antitumor potency in ERα-positive breast cancer cells (MCF-7). Moreover, these conjugates not only showed selective anticancer activity that was more potent against MCF-7 cells than DU 145 (prostate cancer), but they had no toxicity toward normal cells.
authors.affiliation: †State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
authors.forename: Chu
authors.initials: C
authors.lastname: Tang
authors.affiliation: ‡College of Life Sciences, Wuhan University, Wuhan, 430072, China.
authors.forename: Changhao
authors.initials: C
authors.lastname: Li
authors.affiliation: †State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
authors.forename: Silong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: †State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
authors.forename: Zhiye
authors.initials: Z
authors.lastname: Hu
authors.affiliation: ‡College of Life Sciences, Wuhan University, Wuhan, 430072, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: †State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
authors.forename: Chune
authors.initials: C
authors.lastname: Dong
authors.affiliation: ‡College of Life Sciences, Wuhan University, Wuhan, 430072, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: †State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D001190:Arylsulfonates / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D001190:Arylsulfonates; D001643:Bridged Bicyclo Compounds; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D013629:Tamoxifen; D006655:Histone Deacetylases