Synthesis, characterization, and in vitro–in ovo toxicological screening of silibinin fatty acids conjugates as prodrugs with potential biomedical applications

Authors

  • Cristina Dehelean Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania; Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
  • Ersilia Alexa Faculty of Food Engineering, University of Life Sciences "King Michael I" from Timisoara, Timisoara, Romania
  • Iasmina Marcovici Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania; Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
  • Andrada Iftode Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania; Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
  • Geza Lazar “Ioan Ursu” Institute of the Faculty of Physics, Babes-Bolyai University, Cluj-Napoca, Romania; RDI Institute of Applied Natural Sciences, Babeș-Bolyai University, Cluj-Napoca, Romania
  • Andrea Simion “Ioan Ursu” Institute of the Faculty of Physics, Babes-Bolyai University, Cluj-Napoca, Romania; National Institute of Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca, Romania
  • Vasile Chis “Ioan Ursu” Institute of the Faculty of Physics, Babes-Bolyai University, Cluj-Napoca, Romania
  • Adrian Pirnau National Institute of Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca, Romania
  • Simona Cinta Pinzaru “Ioan Ursu” Institute of the Faculty of Physics, Babes-Bolyai University, Cluj-Napoca, Romania; RDI Institute of Applied Natural Sciences, Babeș-Bolyai University, Cluj-Napoca, Romania
  • Estera Boeriu Faculty of Medicine, Department of Pediatrics, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania; Department of Oncology and Hematology, “Louis Turcanu” Emergency Clinical Hospital for Children, Timisoara, Romania

DOI:

https://doi.org/10.17305/bb.2024.10600

Keywords:

Silibinin (SIL), oleic acid (OA), linoleic acid (LA), derivatization, physicochemical characterization, cytotoxicity, cell migration, irritant effect

Abstract

Silibinin (SIL), the most active phytocompound from Silybum marianum (L.), exerts many biological effects but has low stability and bioavailability. To overcome these drawbacks, the current research proposed the synthesis of silibilin oleate (SIL-O) and silibilin linoleate (SIL-L) derivatives as prodrugs with potentially optimized properties for biomedical applications, and the establishment of their in vitro–in ovo safety profiles. The physicochemical characterization of the obtained compounds using density functional theory (DFT) calculations, and Raman and 1H liquid-state nuclear magnetic resonance (NMR) spectroscopy confirmed the formation of SIL-O and SIL-L complexes. Computational predictions revealed that these lipophilic derivatives present a lower drug-likeness score (−29.96 for SIL-O and−23.55 for SIL-L) compared to SIL, but an overall positive drug score (0.07) and no risk for severe adverse effects. SIL-O and SIL-L showed no cytotoxicity or impairment in cell migration at low concentrations, but at the highest concentration (100 μM), they displayed distinct toxicological profiles. SIL-L was more cytotoxic (on cardiomyoblasts – H9c2(2-1), hepatocytes – HepaRG, and keratinocytes – HaCaT) than SIL-O or SIL, significantly inhibiting cell viability (<60%), altering cellular morphology, reducing cell confluence (<70%), and inducing prominent apoptotic-like nuclear features. At the concentration of 100 μM, SIL-O presented an irritation score (IS) of 0.61, indicating a lack of irritant effect on the chorioallantoic membrane (CAM), while SIL-L was classified as a slight irritant with an IS of 1.99. These findings outline a more favorable in vitro and in ovo biocompatibility for SIL-O compared to SIL L, whose applications are dosage limited due to potential toxicity.

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Synthesis, characterization, and in vitro-in ovo toxicological screening of silibinin fatty acids conjugates as prodrugs with potential biomedical applications

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Published

17-10-2024

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Research article

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How to Cite

1.
Synthesis, characterization, and in vitro–in ovo toxicological screening of silibinin fatty acids conjugates as prodrugs with potential biomedical applications. Biomol Biomed [Internet]. 2024 Oct. 17 [cited 2024 Dec. 11];24(6):1735–1750. Available from: https://bjbms.org/ojs/index.php/bjbms/article/view/10600