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Medicinal Chemistry

Author(s): Nenad Joksimović*, Jelena Petronijević, Emilija Milović, Nenad Janković, Dejan Baskić, Suzana Popović, Danijela Todorović, Sanja Matić, Milan Vraneš and Aleksandar Tot

DOI: 10.2174/1573406417666210803094127

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Synthesis, Characterization, Antitumor Potential, BSA and DNA Binding Properties, and Molecular Docking Study of Some Novel 3-Hydroxy-3- Pyrrolin-2-Ones

Page: [337 - 352] Pages: 16

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Abstract

Background: In order to make progress in discovering the new agents for cancer treatment with improved properties and considering the fact that 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, we tested series of eleven novels 1,5-diaryl-4-(2- thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones for their antitumor potential.

Methods: All novel compounds were characterized by spectral (IR, NMR, MS) and elemental analysis. All novel 3-hydroxy-3-pyrrolin-2-ones were screened for their cytotoxic activity on two cancer cell lines, SW480 and MDA-MB 231, and non-transformed fibroblasts (MRC-5).

Results: Compounds B8, B9, and B10 showed high cytotoxicity on SW480 cells together with good selectivity towards MRC-5 cells. It is important to empathize that the degree of selectivity of B8 and B10 was high (SI = 5.54 and 12.09, respectively). Besides, we explored the mechanisms of cytotoxicity of novel derivatives, B8, B9, and B10. The assay showed that tested derivatives induce an apoptotic type of cell death in SW480 cells, with a minor percent of necrotic cells. Additionally, to better understand the suitability of the compounds for potential use as anticancer medicaments, we studied their interactions with biomacromolecules (DNA or BSA). The results indicated that the tested compounds have a great affinity to displace EB from the EB-DNA complex through intercalation. Also, DNA and BSA molecular docking study was performed to predict the binding mode and the interaction region of the compounds.

Conclusion: Achieved results indicate that our compounds have the potential to become candidates for use as medicaments.

Keywords: 3-hydroxy-3-pyrrolin-2-ones, biological evaluation, mechanisms of cytotoxic activity, DNA binding study, BSAbinding study, molecular docking study.

Graphical Abstract

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