title: Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells.
abstract: Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1-58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1-58 yielded 3-35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7-C8 olefin of PL obtained 3-31/3-98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells. The HDACi function was crucial for modulating expression of DNA repair and apoptosis-related proteins. Collectively, PL and SAHA hybrids are potent, multifunctional anti-AML agents, acting in part, by interfering cellular GSH defense, suppressing expression of DNA repair and pro-survival proteins, and inducing expression of pro-apoptotic proteins.
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan 48201, United States.
authors: Yi
authors: Y
authors: Liao
authors: Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|School of Life Sciences, Jilin University , Changchun 130012, P.R. China.
authors: Xiaojia
authors: X
authors: Niu
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan 48201, United States.
authors: Bailing
authors: B
authors: Chen
authors: Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors: Holly
authors: H
authors: Edwards
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan 48201, United States.
authors: Liping
authors: L
authors: Xu
authors: Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors: Chengzhi
authors: C
authors: Xie
authors: Department of Hematology and Oncology, The First Hospital of Jilin University , Changchun, P.R. China.
authors: Hai
authors: H
authors: Lin
authors: Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors: Lisa
authors: L
authors: Polin
authors: Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.|Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan , Detroit, Michigan 48201, United States.
authors: Jeffrey W
authors: JW
authors: Taub
authors: Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors: Yubin
authors: Y
authors: Ge
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan 48201, United States.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors: Zhihui
authors: Z
authors: Qin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004260:DNA Repair; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute; D013329:Structure-Activity Relationship; D000077337:Vorinostat; D010881:Piperidones
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004148:Dioxolanes; D005978:Glutathione; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; C498077:piperlongumine; D010881:Piperidones