Specific Interactions of Antitumor Metallocenes with Deoxydinucleoside Monophosphates

Area of Science:

• Bioinorganic Chemistry
• Medicinal Chemistry
• Mass Spectrometry

Background:

• Bent metallocenes (Cp2MCl2, M = Ti, V, Nb, Mo) exhibit cytotoxic effects against various cancers.
• Nuclear accumulation suggests DNA as a primary target for these metallodrugs.
• Understanding the precise binding interactions is crucial for elucidating their mechanism of action.

Purpose of the Study:

• To investigate the adduct formation and binding affinities of bent metallocenes with deoxydinucleoside monophosphates.
• To compare the binding patterns of metallocenes with cisplatin using high-resolution tandem mass spectrometry.
• To elucidate the specific interaction sites (nucleobases vs. phosphate groups) based on the Hard and Soft (Lewis) Acids and Bases (HSAB) concept.

Main Methods:

• Synthesis and reaction of eight deoxydinucleoside monophosphates with metallocenes (Ti, V, Nb, Mo) and cisplatin.
• Quantification of adduct yields to determine relative binding affinities.
• High-resolution tandem mass spectrometry (MS/MS) to localize binding sites within the deoxydinucleoside monophosphates.

Main Results:

• Binding affinities followed the order: Pt > V > Ti > Mo; no adducts were observed with Nb.
• Cisplatin preferentially binds to soft nitrogen atoms in purine nucleobases.
• Metallocenes interact with both hard phosphate oxygen atoms and nucleobases, with specificities varying by metal (Ti/V favor phosphate; Mo favors nucleobases).

Conclusions:

• Metallocene binding specificity differs from cisplatin, involving interactions with both phosphate and nucleobases, consistent with HSAB principles.
• Gas-phase dissociation patterns in MS/MS reflect the intrinsic binding behavior of these metallodrugs.
• Tandem mass spectrometry is a valuable tool for understanding metallodrug-cellular target interactions relevant to cancer therapy.