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Cationic lipid-conjugated bis-arylidene oxindole derivatives as broad-spectrum breast cancer-selective therapeutics
Md Yousuf1, Kathyayani Sridharan2, Tanushree Mishra3
1Department of Chemistry, University of Calcutta, Kolkata 700073, India; Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Chemistry, Ramnagar College, Purba Medinipur, West Bengal 721453, India.
Abstract:
Breast cancer is a heterogeneous malignancy with wide-ranging variations in therapeutic responses, overall survival etc. Major challenges for available chemotherapeutic agents in achieving clinical success are in maintaining systemic bio-distribution and avoiding non-specific adverse effects. Bis-arylidene oxindoles are estrogen receptor (ER)-selective bioactive molecules with moderate potency. In here, we have designed, synthesized and evaluated a series of twin aliphatic chain cationic lipid-conjugated bis-arylidene oxindole molecules with variations in nature of linker, lengths of carbon spacer and hydrophobic twin chains. We observed that among the various structural analogues, C8 twin-chain containing molecules, PGC8, S2C8 and S3C8 showed effective cancer cell-selective cytotoxicity in different cancer cell lines with an IC50 ranging from 4 to 7 µM. These molecules selectively induced apoptosis, ROS production and cell cycle inhibition at G1/S phase in ER + breast cancer cells but not in non-cancer cells. Additionally, these molecules formed homogenous self-assemblies exhibiting effective hydrodynamic diameter with positive surface charge. The self-assemblies also showed prominent cancer cell-selective uptake and DNA-binding abilities. Hence, we have shown successful incorporation of dexamethasone to the self-assemblies, and its enhanced cytotoxicity even in ER-negative breast cancer cells. All these results indicate that PGC8, S2C8 and S3C8 molecules, albeit their potent and selective ER-positive anti-breast cancer activity, can be repurposed as targeted delivery systems and hold promise as unique, broader spectrum breast cancer cell-selective therapeutic payloads.
Insights
New bis-arylidene oxindole derivatives show potent, selective cytotoxicity against breast cancer cells. These novel compounds can be repurposed as targeted delivery systems for broader therapeutic applications.
Area of Science:
- Medicinal Chemistry
- Oncology
- Nanotechnology
Background:
- Breast cancer heterogeneity leads to varied therapeutic responses.
- Current chemotherapeutics face challenges in systemic distribution and off-target effects.
- Bis-arylidene oxindoles are ER-selective agents with moderate potency.
Purpose of the Study:
- To design, synthesize, and evaluate novel twin aliphatic chain cationic lipid-conjugated bis-arylidene oxindole molecules.
- To assess their cancer cell-selective cytotoxicity and mechanism of action.
- To explore their potential as targeted delivery systems.
Main Methods:
- Synthesis of a series of bis-arylidene oxindole derivatives with varying linkers, spacers, and hydrophobic chains.
- In vitro evaluation of cytotoxicity (IC50), apoptosis induction, ROS production, and cell cycle analysis in ER-positive and non-cancer cells.
- Characterization of self-assembly properties (hydrodynamic diameter, surface charge) and cellular uptake.
- Assessment of DNA-binding abilities and incorporation of dexamethasone for enhanced cytotoxicity.
Main Results:
- C8 twin-chain molecules (PGC8, S2C8, S3C8) demonstrated potent cancer cell-selective cytotoxicity (IC50: 4-7 µM).
- These compounds selectively induced apoptosis, ROS production, and G1/S phase cell cycle arrest in ER-positive breast cancer cells.
- Self-assemblies exhibited favorable hydrodynamic diameters, positive surface charges, selective uptake, and DNA-binding capabilities.
- Dexamethasone incorporation enhanced cytotoxicity, even in ER-negative breast cancer cells.
Conclusions:
- PGC8, S2C8, and S3C8 possess potent and selective ER-positive anti-breast cancer activity.
- These molecules can be repurposed as targeted delivery systems.
- They hold promise as broader spectrum, breast cancer cell-selective therapeutic payloads.
