THE INTERACTION OF ELLIPTICINE DERIVATIVES WITH NUCLEIC-ACIDS STUDIEDBY OPTICAL AND H-1-NMR SPECTROSCOPY - EFFECT OF SIZE OF THE HETEROCYCLIC RING

The DNA interaction of derivatives of ellipticine with heterocyclic ri ng systems with three, four, or five rings and a dimethylaminoethyl si de chain was studied. Optical spectroscopy of drug complexes with calf thymus DNA, poly (dA-dT).(dA-dT), or poly (dG-dC).(dG-dC) showed a 10 nm bathochromic shift of the light absorption bands of the pentac yclic and tetracyclic compounds upon binding to the nucleic acids, whi ch indicates binding by intercalation. For the tricyclic compound a sm aller shift of 1-3 nm was observed upon binding to the nucleic acids. Flow linear dichroism studies show that the geometry of all complexes is consistent with intercalation of the ring system, except for the DN A and poly (dG-dC).(dG-dC) complexes of the tricyclic compound, wher e the average angle between the drug molecular plane and the DNA helix axis was found to be 65 degrees. One-dimensional H-1-nmr spectroscopy was used to study complexes between d(CGCGATCGCG)(2) and the tricycli c and pentacyclic compounds. The results on the pentacyclic compound s how nonselective broadening due to intermediate chemical exchange of m ost oligonucleotide resonances upon drug binding. The imino proton res onances are in slow chemical exchange, and new resonances with upheld shifts approaching 1 ppm appear upon drug binding, which supports inte rcalative binding of the pentacyclic compound. The results on the tric yclic compound show more rapid binding kinetics and very selective bro adening of resonances. The data suggest that the tricyclic compound is in an equilibrium between intercalation and minor groove binding, wit h a preference to bind close to the AT base pairs with the side chain residing in the minor groove. (C) 1994 John Wiley and Sons, Inc.