Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells
| Autor: | Chengzhi Xie, Jeffrey W. Taub, Yubin Ge, Liping Xu, Bailing Chen, Holly Edwards, Yi Liao, Lisa Polin, Hai Lin, Zhihui Qin, Xiaojia Niu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DNA Repair DNA repair DNA damage Antineoplastic Agents Hydroxamic Acids Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Cell Line Tumor Drug Discovery medicine Humans Cytotoxicity Vorinostat Piperlongumine Myeloid leukemia Dioxolanes Glutathione Histone Deacetylase Inhibitors Leukemia Myeloid Acute 030104 developmental biology Biochemistry chemistry Cell culture Apoptosis 030220 oncology & carcinogenesis Cancer research Molecular Medicine Drug Screening Assays Antitumor Apoptosis Regulatory Proteins medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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