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Journal of the American Chemical Society

Mechanism and control of rare tautomer trapping at a metal-metal bond: adenine binding to dirhodium antitumor agents.


PMID 18085779

Abstract

The cause of mutations in the genome by the occurrence of nuclebases in their rare tautomeric forms was first proposed by Watson and Crick in 1953. Since this pioneering proposal, tremendous experimental and theoretical research efforts have aimed to elucidate the conditions under which nucleobase tautomerizations can occur. Previous work raised the interesting question as to whether adenine binding to the anticancer drug cisplatin can induce tautomerization of the nucleobase, but the results indicated such an event to be unlikely under physiological conditions. In this work, we have studied the reaction of three adenine (Ade) tautomers with metal-metal bonded dirhodium antitumor agents using high-level computations. The calculations reveal that the thermodynamically most stable compound in the reaction of Ade with dirhodium tetraformate in aqueous solution is a species in which a rare N6-imino tautomer spans the metal-metal bond via sites N7 and N6. However, comprehensive transition state predictions suggest that the multiple-step mechanisms leading to this bridging species are kinetically highly challenging. A number of strategies to chemically modify the metal-metal unit are considered, aiming to derive a rational plan for trapping the rare N6-imino tautomer, which is incapable of Watson-Crick pairing with canonical thymine.

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