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
  • 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.