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Identification of boholamide A analogue as a potential hypoxia-selective anti-triple-negative breast cancer agent by
Guangju Liu1, Fengyuan Zhang1, Fangzhi Han1
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China.
Abstract:
Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic forms of breast cancer, for which there are currently no satisfactory therapeutic agents. Here, we reported for the first time that boholamide A, a naturally occurring macrocyclic depsipeptide, exhibited hypoxia-selective anti-TNBC activity against in MDA-MB-231 cells. However, its structure‒activity relationships and target had not yet been elucidated. A series of boholamide A analogues were chemically synthesized and evaluated for anti-TNBC potency. The most promising compound 1j was prepared in 13 linear steps with an overall yield of 7.92%, and exhibited high potency against MDA-MB-231 cells with an IC50 value of 0.15 μmol/L under hypoxic condition. Moreover, 1j significantly inhibited proliferation and migration, and induced apoptosis in MDA-MB-231 cells. Compound 16, a prodrug of 1j, significantly inhibited the tumor volume and tumor weight in xenografts. Furthermore, we identified that 1j covalently targeted eukaryotic translation elongation factor 1alpha 1 (eEF1A1) which might underlie the anticancer activity and hypoxia selectivity of boholamide A analogues. These results suggested that boholamide A analogues represented a promising scaffold for discovering hypoxia-selective anti-TNBC agents, and compound 16 deserved further investigation as a candidate for TNBC treatment.
Insights
Boholamide A analogues show promise for treating triple-negative breast cancer (TNBC). Compound 1j targets eEF1A1, inhibiting cancer cells, while its prodrug 16 reduced tumor growth in preclinical models.
Area of Science:
- Natural Products Chemistry
- Cancer Biology
- Medicinal Chemistry
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited therapeutic options.
- Boholamide A, a natural depsipeptide, shows selective anti-TNBC activity under hypoxia.
- The mechanism of action and structure-activity relationships of boholamide A were previously unknown.
Purpose of the Study:
- To synthesize and evaluate boholamide A analogues for anti-TNBC activity.
- To identify the molecular target of boholamide A analogues.
- To explore the potential of these compounds as hypoxia-selective anti-TNBC agents.
Main Methods:
- Chemical synthesis of boholamide A analogues.
- In vitro evaluation of anti-TNBC potency and cellular effects (proliferation, migration, apoptosis).
- In vivo efficacy studies using xenograft models.
- Target identification through biochemical assays.
Main Results:
- Compound 1j demonstrated potent anti-TNBC activity (IC50 = 0.15 μmol/L) under hypoxia.
- Compound 1j inhibited proliferation, migration, and induced apoptosis in MDA-MB-231 cells.
- Prodrug 16 significantly reduced tumor volume and weight in vivo.
- Compound 1j was identified to covalently target eukaryotic translation elongation factor 1alpha 1 (eEF1A1).
Conclusions:
- Boholamide A analogues represent a promising scaffold for hypoxia-selective anti-TNBC drug discovery.
- Compound 1j's mechanism involves targeting eEF1A1, explaining its anticancer and hypoxia-selective effects.
- Compound 16 warrants further investigation as a potential TNBC therapeutic candidate.
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