Antitumor activity of bent metallocenes: electronic structure analysis using DFT computations

The antitumor activities of bent metallocenes [Cp–M–Cp]²⁺ (M = Ti, V, Nb, Mo) and complexes of them with guanine, adenine, thymine and cytosine nucleotides have been probed using electronic structure calculations. DFT/BP86 calculations have revealed that the bent metallocene–nucleotide interaction strongly depends on the stability of the hydrolyzed form of the bent metallocene dichloride [Cp₂M]²⁺ species, and in turn the stability of the [Cp₂M]²⁺ species strongly depends on the electronic structure of [Cp₂M]²⁺. Detailed electronic structure and Walsh energy analyses have been carried out for the hydrolyzed forms of four [Cp–M–Cp]²⁺ (M = Ti, V, Nb, Mo) species to find out why the bent structure is unusually stable. Energy changes that occur during the bending process in frontier molecular orbitals as well as the p(π)–d(π) overlap have been invoked to account for the anticipated antitumor activities of these species. The bonding situation and the interactions in bent metallocene–nucleotide adducts were elucidated by fragment analysis. Of the four nucleotides complexed with the four bent metallocenes, adenine and guanine show better binding abilities than the other two nucleotides. Metallocenes of second-row transition metals exhibit better binding with pyrimidine-base nucleotides. In particular, the Lewis acidic bent metallocenes interact strongly with nucleotides. The antitumor activity is directly related to the binding strength of the bent metallocene with nucleotide adducts, and the computed interaction energy values correlate very well with the experimentally observed antitumor activities.