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<p>The anticancer effects of six <i>tert</i>-butyl peresters derivatives were investigated against MDA‑MB‑231 (triple‑negative) and MCF‑7 (hormone receptor‑positive) breast cancer cells. Specifically, only the nitro‑substituted derivatives, including <i>tert</i>-butyl-4-nitroperbenzoate (1SS) and <i>tert</i>-butyl-3,5-dinitroperbenzoate (6SS), showed significant cytotoxicity against the cancer cells while displaying lower cytotoxicity against the non-cancerous L929 cell line. The triple‑negative cell line was consistently more sensitive. Compound 6SS was the more potent agent, with IC₅₀ values reaching 0.35&#xa0;µg/mL in MDA‑MB‑231 monolayer cultures after 72&#xa0;h (compared to 3.18&#xa0;µg/mL for 1SS). Both compounds were cytotoxic in three‑dimensional (3D) spheroid models, although higher IC₅₀ values indicated greater resistance in the 3D environment. Caspase‑3/7 activity increased by 3.0‑fold (6SS) and 2.0‑fold (1SS) in MDA‑MB‑231 cells, and by 4.4‑fold (6SS) and 2.8‑fold (1SS) in MCF‑7 cells, suggesting that apoptosis is the primary cell death pathway. Neither compound inhibited the enzymatic activity of MMP‑9 or MMP‑2. Notably, while MMP‑9 appeared as a hub protein in the 1SS network, no direct enzymatic inhibition was detected, suggesting a non‑enzymatic or indirect regulatory mechanism. In silico predictions showed favorable drug‑likeness, high gastrointestinal absorption, absence of P‑glycoprotein substrate activity, and lower predicted acute toxicity (LD₅₀ of 914–1200&#xa0;mg/kg) compared to doxorubicin (205&#xa0;mg/kg), all of which await experimental confirmation. Network pharmacology predicted distinct target profiles: 1SS hubs include PTGS2, MMP9 and RELA (inflammation and tumor microenvironment), whereas 6SS targets EGFR, ERBB2, CASP3, PTGS2 and HSP90AA1 (proliferation, apoptosis and protein stability). Taken together, the dinitro derivative 6SS exhibits potent, multi‑targeted anti‑breast cancer activity through a proposed caspase‑dependent apoptotic mechanism, with a safety profile that supports further development.</p>

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Nitro-substituted tert-butyl peresters induce apoptosis and exhibit multi-targeted anticancer activity in breast cancer cells

  • 期刊论文

  • 发表日期：

    2026年5月28日

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  • Hedyeh Zafari,
  • Raheleh Shakeri,
  • Khadijeh Pouraghajan,
  • Saadi Samadi,
  • Zakaria Vahabzadeh

摘要

The anticancer effects of six tert-butyl peresters derivatives were investigated against MDA‑MB‑231 (triple‑negative) and MCF‑7 (hormone receptor‑positive) breast cancer cells. Specifically, only the nitro‑substituted derivatives, including tert-butyl-4-nitroperbenzoate (1SS) and tert-butyl-3,5-dinitroperbenzoate (6SS), showed significant cytotoxicity against the cancer cells while displaying lower cytotoxicity against the non-cancerous L929 cell line. The triple‑negative cell line was consistently more sensitive. Compound 6SS was the more potent agent, with IC₅₀ values reaching 0.35 µg/mL in MDA‑MB‑231 monolayer cultures after 72 h (compared to 3.18 µg/mL for 1SS). Both compounds were cytotoxic in three‑dimensional (3D) spheroid models, although higher IC₅₀ values indicated greater resistance in the 3D environment. Caspase‑3/7 activity increased by 3.0‑fold (6SS) and 2.0‑fold (1SS) in MDA‑MB‑231 cells, and by 4.4‑fold (6SS) and 2.8‑fold (1SS) in MCF‑7 cells, suggesting that apoptosis is the primary cell death pathway. Neither compound inhibited the enzymatic activity of MMP‑9 or MMP‑2. Notably, while MMP‑9 appeared as a hub protein in the 1SS network, no direct enzymatic inhibition was detected, suggesting a non‑enzymatic or indirect regulatory mechanism. In silico predictions showed favorable drug‑likeness, high gastrointestinal absorption, absence of P‑glycoprotein substrate activity, and lower predicted acute toxicity (LD₅₀ of 914–1200 mg/kg) compared to doxorubicin (205 mg/kg), all of which await experimental confirmation. Network pharmacology predicted distinct target profiles: 1SS hubs include PTGS2, MMP9 and RELA (inflammation and tumor microenvironment), whereas 6SS targets EGFR, ERBB2, CASP3, PTGS2 and HSP90AA1 (proliferation, apoptosis and protein stability). Taken together, the dinitro derivative 6SS exhibits potent, multi‑targeted anti‑breast cancer activity through a proposed caspase‑dependent apoptotic mechanism, with a safety profile that supports further development.