Human topoisomerase inhibition and DNA/BSA binding of Ru(II)-SCAR complexes as potential anticancer candidates for...

Area of Science:

• Coordination Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Ruthenium(II) complexes are explored for their therapeutic potential.
• Understanding structure-activity relationships is crucial for drug development.
• Human topoisomerase IB (Top 1) is a validated target for anticancer drugs.

Purpose of the Study:

• To synthesize and evaluate novel ruthenium(II) phosphine/diimine/picolinate complexes for anticancer activity.
• To investigate the inhibitory effects of these complexes on human topoisomerase IB (Top 1).
• To assess the structure-lipophilicity relationship influencing membrane permeability.

Main Methods:

• Cytotoxicity assays against various cancer cell lines.
• Inhibition assays for supercoiled DNA relaxation mediated by Top 1.
• Caco-2 cell permeability studies to evaluate membrane transport.
• DNA binding studies (electrostatic and covalent).
• Bovine serum albumin (BSA) interaction studies.

Main Results:

• SCAR 5 demonstrated 45-fold greater cytotoxicity against breast cancer cells compared to cisplatin.
• SCAR 4 and 5 effectively inhibited Top 1-mediated DNA relaxation.
• SCAR 4 and 5 bind DNA electrostatically; SCAR 6 binds covalently.
• Complex permeability correlated with lipophilicity and BSA interaction.
• SCAR 4 and 5 showed high membrane permeability (Papp > 10 × 10⁻⁶ cm·s⁻¹) in the presence of BSA, suggesting passive diffusion.

Conclusions:

• Ruthenium(II) complexes exhibit significant pharmacological activity.
• Ligand combinations dictate the specific activity and properties of each complex.
• Lipophilicity and BSA interactions are key factors influencing Caco-2 cell permeability.
• These complexes represent promising candidates for anticancer drug development.