Intercalation Ability of Novel Monofunctional Platinum Anticancer Drugs: A Key Step in Their Biological Action

Area of Science:

• Computational Chemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Phenanthriplatin (PtPPH), a platinum(II) complex, exhibits significant cytotoxicity against cancer cells.
• The precise mechanism of PtPPH's DNA interaction, specifically direct guanine binding versus an intercalated intermediate, remains debated.

Purpose of the Study:

• To elucidate the sequential mechanism of Phenanthriplatin (PtPPH) drug activation and DNA interaction.
• To systematically assess hydrolysis, intercalation, and covalent DNA damage pathways using theoretical methods.

Main Methods:

• Utilized *ab initio* quantum mechanical (QM) methods, QM/QM' schemes, and independent gradient model approaches.
• Implemented an unbiased protocol to simulate the drug-DNA interaction cascade.
• Analyzed the impact of DNA sequence and backbone on drug anchoring.

Main Results:

• Identified a three-stage reaction cascade: initial rapid intercalation, followed by hydrolysis to an aqua-activated form, and concluding with covalent binding to guanine.
• Demonstrated that DNA damage is driven by the covalent PtPPH-guanine bond, concurrent with phenanthridine intercalation.
• Provided insights into how DNA sequence and backbone influence drug binding within the double helix.

Conclusions:

• The mechanism of Phenanthriplatin (PtPPH) involves initial intercalation, subsequent hydrolysis, and final covalent binding to DNA at guanine.
• DNA damage is a combined effect of covalent bonding and π-π intercalation of the phenanthridine moiety.
• Understanding these interactions is crucial for optimizing platinum-based cancer therapeutics.