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Rhodanine-Piperazine Hybrids as Potential VEGFR, EGFR, and HER2 Targeting Anti-Breast Cancer Agents
Jacek Szczepański1, Dmytro Khylyuk1, Agnieszka Korga-Plewko2
1Chair and Department of Organic Chemistry, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland.
Abstract:
Breast cancer is one of the most common malignancies affecting women worldwide, with a significant need for novel therapeutic agents to target specific molecular pathways involved in tumor progression. In this study, a series of rhodanine-piperazine hybrids were designed, synthesized, and evaluated for their anticancer activity, targeting key tyrosine kinases such as VEGFR, EGFR, and HER2. Biological screening against breast cancer cell lines (MCF-7, MDA-MB-231, T47D, and MDA-MB-468) revealed 3 of the 13 tested compounds as the most potent, with 5-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}methylidene)-2-thioxo-1,3-thiazolidin-4-one (12) showing the strongest activity, particularly against the MCF-7 and MDA-MB-468 cell lines. Molecular docking studies indicated favorable binding interactions of compound 12 and its 3-phenyl-2-thioxo-1,3-thiazolidin-4-one analogue (15) with HER2, VEGFR, and EGFR, and molecular dynamics simulations further confirmed their stable binding to HER2. These findings highlight the potential of rhodanine-piperazine hybrids as promising leads for developing new anticancer agents targeting breast cancer, particularly HER2-positive subtypes. Further structural optimization could enhance their efficacy and therapeutic profile.
Insights
Researchers developed novel rhodanine-piperazine hybrids as potential breast cancer treatments. Compound 12 demonstrated significant anticancer activity, particularly against HER2-positive breast cancer cell lines.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Breast cancer remains a leading global malignancy in women, necessitating innovative therapies targeting tumor-specific molecular pathways.
- Existing treatments face challenges, driving the search for novel anticancer agents with improved efficacy and targeted action.
Purpose of the Study:
- To design, synthesize, and evaluate novel rhodanine-piperazine hybrids for anticancer activity.
- To identify potent compounds targeting key tyrosine kinases (VEGFR, EGFR, HER2) implicated in breast cancer progression.
Main Methods:
- Synthesis of a series of rhodanine-piperazine hybrids.
- In vitro anticancer screening against four human breast cancer cell lines (MCF-7, MDA-MB-231, T47D, MDA-MB-468).
- Molecular docking and dynamics simulations to assess binding interactions with target kinases.
Main Results:
- Thirteen compounds were synthesized and screened; three exhibited significant potency.
- Compound 12 (5-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}methylidene)-2-thioxo-1,3-thiazolidin-4-one) showed the strongest activity, especially against MCF-7 and MDA-MB-468 cell lines.
- Docking and dynamics studies confirmed favorable and stable binding of compounds 12 and 15 to HER2, VEGFR, and EGFR kinases.
Conclusions:
- Rhodanine-piperazine hybrids show promise as novel therapeutic leads for breast cancer.
- Compound 12 is a particularly strong candidate for further development, especially for HER2-positive breast cancer subtypes.
- Structural optimization of these hybrids may enhance their anticancer efficacy and therapeutic potential.
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