Design, synthesis, biological evaluation, structure-activity relationship study, and mode of action of...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Human DNA topoisomerases (Topos) are crucial nuclear enzymes involved in DNA replication, transcription, and recombination.
• Topoisomerase levels can predict chemotherapy response, making them key targets for anticancer drugs.
• Previous research on 2,4,6-trisubstituted pyridines suggests their potential as topoisomerase-targeted anticancer agents.

Purpose of the Study:

• To design, synthesize, and evaluate novel 2-phenol-4,6-dichlorophenyl-pyridine derivatives for their topoisomerase I and IIα inhibitory and anti-proliferative activities.
• To explore the structure-activity relationships of these compounds, focusing on the role of chlorine substituents.
• To investigate the mechanism of action for potent compounds, including their interaction with DNA and effects on cell cycle progression and apoptosis.

Main Methods:

• Synthesis of twenty-seven 2-phenol-4,6-dichlorophenyl-pyridine derivatives.
• In vitro testing of synthesized compounds for topoisomerase I and IIα inhibition.
• Assessment of anti-proliferative activity against HCT-15 and T47D cancer cell lines.
• Mechanistic studies to determine the mode of action (e.g., catalytic inhibition, DNA damage, cell cycle arrest, apoptosis induction).

Main Results:

• Dichlorinated meta- and para-phenolic pyridine derivatives (compounds 1-18) demonstrated potent and selective topoisomerase IIα inhibition and significant anti-proliferative activity, outperforming etoposide in HCT-15 and T47D cells.
• Dichlorinated ortho-phenolic derivatives (compounds 19-27) showed potent dual topoisomerase inhibition but weak anti-proliferative effects.
• Structure-activity relationship analysis highlighted the importance of chlorine moieties in enhancing topoisomerase inhibitory potency.
• Compounds 2 and 12 were identified as specific, non-intercalative topoisomerase IIα catalytic inhibitors with minimal DNA damage, inducing G1 arrest and apoptosis in HCT-15 and T47D cells, respectively.

Conclusions:

• Novel 2-phenol-4,6-dichlorophenyl-pyridine derivatives are effective inhibitors of topoisomerase IIα with significant anti-cancer potential.
• The presence of chlorine substituents is critical for enhancing topoisomerase inhibitory activity.
• Compounds 2 and 12 represent promising leads for developing new anticancer therapeutics that target topoisomerase IIα through catalytic inhibition with reduced genotoxicity.