1. Academic Validation
  2. Discovery and synthesis of sulfur-containing 6-substituted 5,8-dimethoxy-1,4-naphthoquinone oxime derivatives as new and potential anti-MDR cancer agents

Discovery and synthesis of sulfur-containing 6-substituted 5,8-dimethoxy-1,4-naphthoquinone oxime derivatives as new and potential anti-MDR cancer agents

  • Eur J Med Chem. 2019 Mar 1:165:160-171. doi: 10.1016/j.ejmech.2019.01.005.
Guang Huang 1 Jin-Yun Dong 1 Qi-Jing Zhang 1 Qing-Qing Meng 2 Hui-Ran Zhao 3 Bao-Quan Zhu 4 Shao-Shun Li 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 2 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: qqmeng@sjtu.edu.cn.
  • 3 School of Pharmaceutical Sciences and Chemistry, Dali University, Dali, 671000, China.
  • 4 Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, PR China.
  • 5 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: ssli@sjtu.edu.cn.
Abstract

Multi-drug resistance (MDR) to Anticancer drugs is the primary impediment to successful treatment of Cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer Cancer Drug Resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant Cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) > 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 ± 0.01 to 1.33 ± 0.05 μM toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell Apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents.

Keywords

1,4-Naphthoquinone oxime; Anti-MDR activity; Apoptosis induction; Drug resistance; Selective cytotoxicity.

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