Multitargeted Anticancer Strategy through DNA Damage and Mitochondrial Collapse by a Ferrocene-Benzimidazolium Salt

Area of Science:

• Organometallic Chemistry
• Medicinal Chemistry
• Cancer Therapeutics

Background:

• Targeted organometallic anticancer drugs are a key research focus.
• Benzimidazolium-derived ferrocenyl compounds offer potential therapeutic avenues.

Purpose of the Study:

• Synthesize and biologically evaluate a novel benzimidazolium-derived ferrocenyl compound, FBP.
• Assess FBP's efficacy, selectivity, biocompatibility, cellular uptake, and mechanism of action against cancer cells.

Main Methods:

• Synthesis of N-ferrocenylmethyl-N'-(2-pyridylmethyl) benzimidazolium iodide (FBP).
• Cytotoxicity assays (IC50, selectivity index) against HeLa cells and fibroblasts.
• Cellular uptake studies (Hoechst, MitoTracker Green).
• Mechanistic investigations (ROS, singlet oxygen, mitochondrial membrane potential, DAPI, gamma-H2AX).
• 3D multicellular spheroid experiments.

Main Results:

• FBP demonstrated significant cytotoxicity against HeLa cells with superior selectivity compared to Doxorubicin and Ferrocene.
• No significant off-target toxicity observed in fibroblast cell lines.
• FBP was internalized by HeLa cells, localizing primarily in mitochondria.
• FBP induced oxidative stress, mitochondrial dysfunction, and apoptotic cell death, evidenced by DNA damage and nuclear fragmentation.
• FBP exhibited penetrating ability and sustained efficacy in 3D tumor spheroids.

Conclusions:

• FBP is a promising organometallic compound with potent and selective anticancer activity.
• The compound induces cancer cell death through oxidative stress and mitochondrial-mediated apoptosis.
• FBP's efficacy in 3D models suggests potential for in vivo applications in cervical cancer treatment.