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Anti-proliferative potential of fluorinated curcumin analogues: experimental and computational analysis and review of the literature

Author(s):

Mahdi Hatamipour, Farzin Hadizadeh, Mahmoud Reza Jaafari, Zahra Khashyarmanesh, Thozhukat Sathyapalan and Amirhossein Sahebkar*  

Abstract:


Background: Curcuminoids, flavoring, and coloring agents in food have potent antioxidant, anti-tumor activity, and anti-inflammatory effects. However, they are rapidly metabolized to lesser active metabolites. Therefore, various studies have been conducted to synthesize new and stable curcumin analogues with enhanced therapeutic activity.

Methods: Fluorinated curcumin compounds (2a-2f) were synthesized by Knoevenagel condensation between fluorobenzaldehydes (1a-1f) with curcumin. Fluorinated demethoxycurcumin (3a) was synthesized by condensation between demethoxycurcumin and 3,4-difluorobenzaldehyde (1f). The structures of these compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR, 19FNMR, and mass spectroscopy. Antiproliferative activities of these synthetic compounds were evaluated against breast cancer cells (4T1), melanoma cancer cells (B16F10), and normal cell lines (NIH 3T3) using MTT assay. The interaction of curcumin, 2f and 3a with several proteins (1HCL, 2ZOQ, 3D94, 5EW3, 4WA9, 1XKK, 6CCY) was investigated. The structural preservation of the epidermal growth factor receptor (EGFR) was investigated by molecular dynamics simulation.

Results: The spectroscopic data obtained confirmed the proposed structure of fluorinated analogues. The results showed that compounds 2f and 3a inhibited cancer cells proliferation significantly more than other compounds. Compounds 2f and 3a showed the highest affinity and lowest binding energy with EGFR. The binding energies were -7.8, -10, and -9.8 kcal/mol for curcumin, 2f and 3a with EGFR, respectively. The molecular docking results demonstrated that compounds 2f and 3a were firmly bound in a complex with EGFR via the formation of a hydrogen bond.

Conclusion: In summary, we found that fluorinated demethoxycurcumin and fluorinated curcumin induces cancer cell death and binds to EGFR with high affinity.

Keywords:

Curcumin, Demethoxycurcumin, Tumor, Breast cancer

Affiliation:

Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad



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