A New Class of Supramolecular, Mixed-Metal DNA-Binding Agents: The Interaction of Ru(II),Pt(II) and Os(II),Pt(II) Bimetallic Complexes with DNA.
A new type of mixed-metal, supramolecular complex has been designed that incorporates a platinum center to allow binding to DNA. The interaction of two such platinum heterobimetallic complexes of the general formula [(bpy)(2)M(dpb)PtCl(2)]Cl(2) (M = Ru(II), Os(II); bpy = 2,2'-bipyridine; dpb = 2,3-bis(2-pyridyl)benzoquinoxaline) with DNA is reported herein. The modular design of these systems allows for synthetic variation of individual components within this structural motif. In this case, the remote metal is varied from Ru(II) to Os(II). DNA binding was analyzed using non-denaturing agarose gel electrophoresis. The interaction of these complexes with DNA was studied relative to the known DNA cross-linkers, cis-[Pt(NH(3))Cl(2)] (cisplatin) and trans-{[PtCl(NH(3))(2)](2)(&mgr;-H(2)N(CH(2))(6)NH(2))}(2+) (1,1/t,t). Our mixed-metal Ru,Pt and Os,Pt compounds retard the migration of DNA through the gel in both a concentration- and time-dependent manner. Their effect on the migration of DNA is similar to, although much more dramatic than, that observed for either cisplatin or 1,1/t,t. Our evidence suggests a covalent binding of our mixed-metal complexes to DNA through the platinum site. The degree of retardation of DNA migration suggests a large change in DNA conformation is induced by binding of our mixed-metal complexes. This work establishes these inorganic systems as a new class of DNA-binding agents and lays the groundwork for future efforts to enhance binding in an effort to develop novel anticancer drugs through serial design and testing.
Milkevitch
Matthew
M
Departments of Biology and Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061.
Storrie
Hannah
H
Brauns
Eric
E
Brewer
Karen J.
KJ
Shirley
Brenda W.
BW