title: Design, synthesis, and antitumor evaluation of novel histone deacetylase inhibitors equipped with a phenylsulfonylfuroxan module as a nitric oxide donor.
abstract: On the basis of the strategy of creating multifunctional drugs, a novel series of phenylsulfonylfuroxan-based hydroxamates with histone deacetylase (HDAC) inhibitory and nitric oxide (NO) donating activities were designed, synthesized, and evaluated. The most potent NO donor-HDAC inhibitor (HDACI) hybrid, 5c, exhibited a much greater in vitro antiproliferative activity against the human erythroleukemia (HEL) cell line than that of the approved drug SAHA (Vorinostat), and its antiproliferative activity was diminished by the NO scavenger hemoglobin in a dose-dependent manner. Further mechanism studies revealed that 5c strongly induced cellular apoptosis and G1 phase arrest in HEL cells. Animal experiment identified 5c as an orally active agent with potent antitumor activity in a HEL cell xenograft model. Interestingly, although compound 5c was remarkably HDAC6-selective at the molecular level, it exhibited pan-HDAC inhibition in a western blot assay, which is likely due to class I HDACs inhibition caused by NO release at the cellular level.
authors.affiliation: †Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Duan
authors.affiliation: †Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: ‡Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Inks
authors.affiliation: ‡Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
authors.affiliation: §Shandong Academy of Pharmaceutical Sciences, Ji'nan, Shandong 250101, People's Republic of China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Jia
authors.affiliation: ∥Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong 261061, People's Republic of China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Chu
authors.affiliation: †Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Li
authors.affiliation: †Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
authors.affiliation: †Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D020030:Nitric Oxide Donors