2. Academic Validation
  3. Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells

Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells

  • J Med Chem. 2016 Sep 8;59(17):7974-90. doi: 10.1021/acs.jmedchem.6b00772.
Yi Liao 1,  Xiaojia Niu 2 3,  Bailing Chen 1,  Holly Edwards 4 5,  Liping Xu 1,  Chengzhi Xie 4 5,  Hai Lin 6,  Lisa Polin 4 5,  Jeffrey W Taub 2 5 7,  Yubin Ge 2 4 5,  Zhihui Qin 1 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan 48201, United States.
  • 2 Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
  • 3 School of Life Sciences, Jilin University , Changchun 130012, P.R. China.
  • 4 Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
  • 5 Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
  • 6 Department of Hematology and Oncology, The First Hospital of Jilin University , Changchun, P.R. China.
  • 7 Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan , Detroit, Michigan 48201, United States.
PMID: 27505848 DOI: 10.1021/acs.jmedchem.6b00772
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.

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