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  3. Design and synthesis of novel mitochondria-targeted ergosterol peroxide derivatives as potential anti-cancer agents

Design and synthesis of novel mitochondria-targeted ergosterol peroxide derivatives as potential anti-cancer agents

  • Bioorg Chem. 2024 Oct 1:153:107862. doi: 10.1016/j.bioorg.2024.107862.
Lu Wang 1,  Shuang Tian 1,  Siqi Deng 1,  Jiale Wu 2,  Haijun Wang 1,  Xiaoshan Guo 1,  Cuicui Han 1,  Wenkang Ren 1,  Yinglong Han 1,  Jianwen Zhou 3,  Yu Lin 4,  Ming Bu 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, PR China.
  • 2 College of Pharmacy, Hainan University, Haikou 570228, Hainan, PR China.
  • 3 Research Institute of Medicine & Pharmacy, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, PR China.
  • 4 College of Pharmacy, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, PR China. Electronic address: linyu7373@163.com.
  • 5 College of Pharmacy, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, PR China. Electronic address: buming@qmu.edu.cn.
PMID: 39362080 DOI: 10.1016/j.bioorg.2024.107862
Abstract

Ergosterol peroxide (EP) is a natural steroid compound that has been reported to have significant antitumor activity. However, its poor water solubility and cellular uptake mean that it has weak efficacy against tumor cells. Herein, we designed and synthesized a series of EP derivatives with mitochondrial targeting properties. Of these, compound 15a showed an IC50 value of 0.32 μM against MCF-7 cells, which was 67-fold higher than that of the parental EP (IC50 = 21.46 μM), and was better than cisplatin (IC50 = 4.23 μM), had a selectivity index of 25.28 (IC50MCF-10A/IC50MCF-7). Additionally, compound 15a promoted an increase in intracellular Reactive Oxygen Species levels and a decrease in mitochondrial membrane potential, and blocked the cell cycle in the G0/G1 phase. In a mouse model of breast Cancer, 15a showed 89.85 % tumor inhibition at a dose of 20 mg/kg, which is similar to the therapeutic effect of the cisplatin. On the basis of these results, 15a could be considered for further preclinical evaluation for Cancer therapy.

Keywords

Antitumor; Delocalized lipophilic cations; Ergosterol peroxide; Targeting mitochondria.

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