Current topics in medicinal chemistry · 2026
Antiproliferative Activity, DNA/HSA Interactions and Human Topoisomerase Inhibition Evaluations of Indole-Thiazolidinone Derivatives: Are Two Indole Rings Better than One?
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Lima Maksuelly Libanio de, Azevedo Rafael David Souto de, Ferreira Fernanda Carvalho Manito, Alves Josival Emanuel Ferreira, Lafayette Elizabeth Almeida, Santos Jessica Celerino Dos, Sousa Gleyton Leonel Silva, Lima Maria do Carmo Alves de, Almeida Sinara Mônica Vitalino de
Аннотация
INTRODUCTION: Indole derivatives are promising candidates for anticancer drug discovery due to their occurrence in biologically active molecules and their ability to modulate cellular targets. This study aimed to evaluate the antiproliferative effects, biomolecular interactions, and topoisomerase inhibition potential of four indole-thiazolidinone derivatives.
METHODS: DNA and HSA binding were investigated by UV-Vis absorption, fluorescence spectroscopy, and molecular docking. Topoisomerase inhibition was evaluated in vitro. Antiproliferative activity and effects on cell migration were assessed in human cancer cell lines using the sulforhodamine B (SRB) and wound healing assays, respectively.
RESULTS: The bis-indole derivative (4a) showed the strongest affinity for DNA (Kb = 1.34 × 10⁶ M⁻¹) and HSA (Kb = 1.30 × 10⁶ M⁻¹), altering the IIA hydrophobic microenvironment. In vitro, 4a displayed potent antiproliferative activity against MCF-7 breast cancer cells (GI₅₀ = 4.53 μM) and inhibited cell migration by 11.65% at 1 μM. No significant inhibition of topoisomerase I and II was observed at 10 and 50 μM.
DISCUSSION: The findings suggest that the cytotoxic activity of compound 4a is more closely associated with its interaction with DNA than with topoisomerase inhibition. Spectroscopic and computational analyses indicated the occurrence of multiple binding modes with DNA and HSA, supporting its favourable interaction profile. Furthermore, the high affinity for HSA may contribute to compound transport and distribution in biological systems, while the observed reduction in cell migration indicates a potential effect on tumour progression.
CONCLUSION: Compound 4a is the most active in the series, representing a significant starting point for the development of new derivatives with potential anti-tumour activity.
METHODS: DNA and HSA binding were investigated by UV-Vis absorption, fluorescence spectroscopy, and molecular docking. Topoisomerase inhibition was evaluated in vitro. Antiproliferative activity and effects on cell migration were assessed in human cancer cell lines using the sulforhodamine B (SRB) and wound healing assays, respectively.
RESULTS: The bis-indole derivative (4a) showed the strongest affinity for DNA (Kb = 1.34 × 10⁶ M⁻¹) and HSA (Kb = 1.30 × 10⁶ M⁻¹), altering the IIA hydrophobic microenvironment. In vitro, 4a displayed potent antiproliferative activity against MCF-7 breast cancer cells (GI₅₀ = 4.53 μM) and inhibited cell migration by 11.65% at 1 μM. No significant inhibition of topoisomerase I and II was observed at 10 and 50 μM.
DISCUSSION: The findings suggest that the cytotoxic activity of compound 4a is more closely associated with its interaction with DNA than with topoisomerase inhibition. Spectroscopic and computational analyses indicated the occurrence of multiple binding modes with DNA and HSA, supporting its favourable interaction profile. Furthermore, the high affinity for HSA may contribute to compound transport and distribution in biological systems, while the observed reduction in cell migration indicates a potential effect on tumour progression.
CONCLUSION: Compound 4a is the most active in the series, representing a significant starting point for the development of new derivatives with potential anti-tumour activity.