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Design, Synthesis, and Evaluation of Cytotoxic Effects of Functional Fatty Acid Derivatives as Potential
Maryam Hosseini1, Farzad Kobarfard1,2, Salimeh Amidi1
1Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Background:
Breast cancer is among the most prevalent cancers in women and is the leading cause of mortality among women worldwide. Although a definitive cure for breast cancer remains elusive, essential fatty acids offer a promising therapeutic avenue.
Objectives:
The present study aimed to synthesize 16 derivatives of docosahexaenoic acid (DHA) and linoleic acid (LA) and evaluate their anti-cancer properties in vitro.
Methods:
Fourteen derivatives of LA and DHA were synthesized using a coupling method, while two ethylenediamine derivatives were synthesized via an ester intermediate. Molecular modeling was conducted using AutoDock Vina software. The cytotoxic effects of all compounds were assessed using the MTT assay on breast adenocarcinoma (MCF-7) cells. The mechanism of cell death induction by derivatives with the most favorable EC50 values was determined through annexin V-FITC/PI flow cytometry analysis, focusing on early and late apoptosis.
Results:
Docking results revealed that these compounds effectively interact with residues in the PTPB1 active site. All synthesized DHA and LA derivatives demonstrated cytotoxic effects on the MCF-7 cell line, with no significant cytotoxicity observed in normal human dermal fibroblasts (HDFs). Compounds D3 and L3, with EC50 values of 15.96 ± 2.89 μM and 24.64 ± 1.81 μM, respectively, were identified as the most potent anti-cancer compounds among the derivatives.
Conclusions:
The findings indicate that these functional fatty acid derivatives significantly reduce cancer cell viability. In addition to necrosis, compounds L3 and D3 induced apoptosis, with apoptosis rates of 20.5% and 47.1%, respectively.
Insights
New fatty acid derivatives show potent anti-cancer activity against breast cancer cells. These docosahexaenoic acid (DHA) and linoleic acid (LA) compounds selectively kill cancer cells by inducing apoptosis, offering a promising therapeutic strategy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Breast cancer is a leading cause of cancer mortality in women globally.
- Essential fatty acids present a promising avenue for novel breast cancer therapeutics.
- Current treatments for breast cancer have limitations, necessitating the development of new agents.
Purpose of the Study:
- To synthesize novel derivatives of docosahexaenoic acid (DHA) and linoleic acid (LA).
- To evaluate the in vitro anti-cancer properties of these synthesized derivatives against breast cancer cells.
- To investigate the mechanism of action for the most potent derivatives.
Main Methods:
- Synthesis of 16 novel fatty acid derivatives (14 LA/DHA, 2 ethylenediamine).
- In vitro cytotoxicity assessment using MTT assay on MCF-7 breast cancer cells and HDFs.
- Apoptosis induction analysis via Annexin V-FITC/PI flow cytometry.
Main Results:
- All synthesized DHA and LA derivatives exhibited significant cytotoxic effects on MCF-7 cells.
- Compounds D3 and L3 demonstrated the highest potency with EC50 values of 15.96 μM and 24.64 μM, respectively.
- Selective toxicity was observed, with no significant impact on normal human dermal fibroblasts (HDFs).
Conclusions:
- Functional fatty acid derivatives effectively reduce breast cancer cell viability.
- Compounds D3 and L3 induce apoptosis in cancer cells, suggesting a targeted cell death mechanism.
- These novel derivatives represent potential lead compounds for future breast cancer therapy development.
